DESC:Field of the Invention
The present invention provides synthetic process for preparing substituted biphenyl tetrazole derivatives.

Background of the Invention
Substituted biphenyl tetrazole derivatives are useful as Angiotensin-II receptor antagonist that selectively inhibits the binding of Angiotensin-II to Angiotensin-I thus effectively inhibiting the Angiotensin-I mediated vasoconstrictive and aldosterone-secreting effects of Angiotensin-II resulting in a decrease in vascular resistance and blood pressure. Substituted biphenyl tetrazole derivatives are therefore used in regulating high blood pressure, cardiac insufficiency, diabetes related hypertension, heart attack, post myocardial infarction and lung cancer.
There are certain processes available for the synthesis of substituted biphenyl tetrazole derivatives, however, the processes and the starting material are very costly or final product is of very low yield, leading to a very costly final product. Therefore there remains a need for efficient synthetic processes for the large scale preparation of substituted biphenyl tetrazole derivatives from commercially available sources.
A common method for the preparation of a tetrazole moiety is the transformation of a cyano group. Suzuki-Miyaura reaction describe a chemical process in which 2-bromobenzonitrile is used as an electrophile for the making of 2-cyanobiphenyl in Hird, M., J.C.S. Perkin. Trans. I. 1998, 20, 3479 and Norman H. M., J. Med. Chem. 1995, 38, However, 2-cyanophenylboronic acid under goes exothermic decomposition at temperatures above 900 oC disclosed by Ura et al. J. Organomel. Chem. 2002, 653, 269.
PCT/IB2011/001483, claims the preparation of tetrazole intermediate with more than 99 % purity but yield hasn’t been disclosed as the material was not isolated. In this process tributyltin was reacted with NaN3 in the presence of 2, 6-lutidine in 50 hours.
US 2013/0144067 used toluene as solvent but reaction requires more than 50 hrs for completion wherein also yield were not given.
According to US 5,399,578, the process for making of Valsartasn tetrazole intermediate with tributyl tin azide followed by flash chromatography which usually not feasible in commercial scale preparations. Moreover, the yields are not consistent as the intermediate was not isolated.
Although, US 5,260,325, EP 1714963A, WO 2005/049587 describes the preparation of tetrazole intermediates but all of the said process involve either high temperatures or longer reaction hours. Moreover, the intermediates have not been isolated and characterized and result in improve final product with unknown impurities.
WO/2010/091169 is drawn to a process which discloses tetrazole compounds. WO ‘169 discloses the tetrazole formation is good at 25 hrs and 145oC in o-xylene as a solvent. Though, the reaction time is lower, the reaction temperatures are high and need to be maintained at this temperature for longer periods. These conditions are not advantageous when synthesized in industrial scale.
The general preparation of tetrazole intermediate has been mentioned with ZnCl2/NaN3/Butanol in the presence of isoleucine in Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385-387 (2001).
However, this scheme has been demonstrated only at a small scale and poses several problems in isolation of isoleucine and other intermediates.
Various other processes for the preparation of tetrazole intermediate are known in the art which involves the use of hazardous organotin compounds for the formation of tetrazole ring, unavoidable use of toxic azides, use of pyridine as a solvent, oily nature of the intermediates, repeated crystallization, non-reproducibility of the results, low purity, long reaction time, poor yield and industrially non-viable processes are also disclosed.
Therefore there is a significant need to develop a simple, less time consuming, economical and industrially applicable process for the preparation of intermediates for the preparation of substituted biphenyl tetrazole derivatives like valasratan, candesartan and losartan in high purity and high yield.
Object of the Invention
An object of the present invention is to provide a process for synthesis of substituted biphenyl tetrazole derivatives in good yield with high chemical purity.
Summary of the Invention
A process for the preparation of substituted biphenyl tetrazole derivatives of formula (I)

Formula (I)
or a salt thereof, wherein A is selected from the group comprising

R1 is independently selected from the group comprising C1-C8 straight or branched chain alkyl, -OR2, -COR2, -COOR2, OCOR2, CH2OH, CH2OR2, -CONHR2,
wherein R2 is selected from C1-C8 straight or branched chain alkyl group comprising the steps of:
i) conversion of hydrochloride salt of A to its base,
ii) reacting base of A with 2-cyano 4-substituted biphenyl compound of formula (II)

Formula (II)
wherein, X is halide, acetate, trifluoro acetate, sulfonate to obtain the compound of formula (III),

Formula (III)
(iii) preparation of zinc complex of formula(IV),

Formula (IV)
(iv) reacting the compound of formula (III) and formula (IV) to form crude substituted biphenyl tetrazole derivatives of Formula (I)

Formula (I)
wherein A is defined as above,
(v) optionally, purification of crude substituted biphenyl tetrazole derivatives of Formula (I) to get pure substituted biphenyl tetrazole derivatives of Formula (I).
Description of the Invention
The present invention relates to a novel synthetic process for preparing substituted biphenyl tetrazole derivatives of Formula (I) and their pharmaceutically acceptable salts.

Formula (I)

Wherein, A is selected from the group comprising

R1 is independently selected from the group comprising C1-C8 straight or branched chain alkyl, -OR2, -COR2, -COOR2, OCOR2, CH2OH, CH2OR2, -CONHR2,
wherein R2 is selected from C1-C8 straight or branched chain alkyl group comprising the steps of:
iii) conversion of hydrochloride salt of A to its base;
iv) reacting base of A with 2-cyano 4-substituted biphenyl compound of formula (II)

Formula (II)
wherein, X is halide, acetate, trifluoro acetate, sulfonate to obtain the compound of formula (III);

Formula (III)
(iii) preparation of zinc complex of formula(IV);

Formula (IV)
(iv) reacting the compound of formula (III) and formula (IV) to form crude substituted biphenyl tetrazole derivatives of formula (I) ;
(v) purification of crude substituted biphenyl tetrazole derivatives of formula (I) to get pure substituted biphenyl tetrazole derivatives of formula (I).
The conversion of hydrochloride salt of A to its base as disclosed in present invention may be achieved by following steps:
i) dissolving salt of A in solvent;
ii) treating the product of step (i) with liquid ammonia and separation in an organic solvent;
The hydrochloride salt of the present invention may be converted to its base by dissolving in solvent treating the product of step (i) with liquid ammonia and separation in an organic solvent, wherein the solvent may preferably be selected from the group comprising demineralised water, methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, and the like more or combination of above solvents and demineralised water. More preferably the dissolution solvent is demineralised water.
The solution after treatment with base (liquor ammonia) may further be separated in an organic solvent which may be present as a single solvent or a mixture. The organic solvent may be preferably selected from the group comprising chloroform, ethyl acetate, dioxane, diethyl ether, dimethyl formaamide, dichloro methane, butyl alcohol derivatives, toluene, chloro benzene, dichloro benzene and their mixture, most preferably the organic solvent is chloroform.
Reacting base of A with 2-cyano 4-substituted biphenyl compound of formula (II)
The reaction of base of A with 2-cyano 4-substituted biphenyl compound of formula (II) may be carried out as set in the specification

Formula (II)
wherein, X is halide, acetate, trifluoro acetate, sulfonate to obtain the compound of formula (III);

Formula (III)
The reaction may be preferably carried out in presence of a base. The said base may be preferably selected from the group comprising N,N’-diisopropylethylamine, triethylamine, piperidine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, alkali and alkaline earth metal, C1-C6 alkoxide and the like. More preferably the base is N, N’-diisopropyl ethylamine.
The reaction may be maintained at ambient temperature to reflux temperature for a time period of 1 to 8 hours. More preferably, the reaction may be maintained reflux temperature for 4 to5 hours.

Preparation of zinc complex of formula (IV)

Formula (IV)
The reaction may be carried out by adding zinc chloride to a solvent or mixture of solvents.
The said solvent may be selected from the group comprising N, N -dimethyl formamide dimethyl sulfoxide, dimethylacetamide, 1,4-dioxane and the like, more preferably the solvent is N, N -dimethyl formamide.
The reaction may be preferably carried out at a temperature range between 5°C to 40°C for 10 to 60 minutes, more preferably at 15°C to 30°C for 20 to 50 minutes and most preferably at temperature range between 25°C to 30°C for 30 to 40 minutes.
The zinc complex may preferably be zinc chloride bis (dimethyl formamide) complex.
Reacting the compound of formula (III) and formula (IV) to form crude substituted biphenyl tetrazole derivatives of Formula (I)
The compound of formula (I) may be arrived by a process as set out herein. The compound of formula (III) and formula (IV) may be reacted to obtain the compounds of formula (I).

Formula (I)

Formula (III) Formula (IV)

Wherein A is defined as above
The reaction may be preferably carried out in presence of an organic solvent. The said organic solvent may preferably be selected from the group comprising N, N-dimethyl formamide, toluene, monochlorobenzene, dichlorobenzene, dimethyl sulfoxide, dimethyl acetamide, 1,4-dioxane and the like, more preferably the solvent is N, N-dimethyl formamide.
The reaction is further carried out by adding azide donor at an appropriate temperature. The azide donor may be preferably selected from the group comprising trimethylsilyl azide, sodium azide, alkyl azide, alkenyl azide, aryl azide, vinyl azide and the like, more preferably the azide is sodium azide.
Addition of said azide donor may preferably be carried out at temperature range between 5°C to 40°C, more preferably at 15°C to 30°C and most preferably at temperature range between 25°C to 30°C.
The reaction may preferably be maintained at temperature range between 50°C to 150°C for 10 to 50 hours, more preferably at 70°C to 125°C for 25 to 40 hours and most preferably at temperature range between 95°C to 105°C for 35 to 40 hours.
The reaction mixture may further optionally be separated in an organic solvent followed by base catalysed hydrolysis. The said organic solvent may individually or in combination, selected from the group comprising chloroform, demineralized water, N, N-dimethyl formamide, toluene, monochlorobenzene, dichlorobenzene, ethyl acetate and the like, more preferably the solvent is chloroform and demineralized water. Most preferably the solvent is used in combination.
The said base may be preferably selected from the group comprising sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate sodium hydroxide potassium hydroxide, lithium hydroxide, barium hydroxide, alkali and alkaline earth metals, C1-C6 alkoxide and the like, more preferably the base is sodium hydroxide.
The reaction may be maintained at temperature range between 5°C to 40°C for 10 to 35 hours, more preferably at 20°C to 30°C for 15 to 30 hours and most preferably at temperature range between 25°C to 30°C for 10 to 15 hours.
Purification of crude substituted biphenyl tetrazole derivatives of Formula (I) to get pure substituted biphenyl tetrazole derivatives of Formula (I).
The reaction mixture again may optionally be further separated to obtain organic layer which may further be subjected to charcoalization.
The compound of formula (I) may be further purified in a solvent or mixture of solvents followed by charcoalization.
The said organic solvent of formula (I) may be used individually or in combination and may be preferably selected from the group comprising ethyl acetate and n-hexane ,ethyl acetate and ethers (diethyl ether, diisopropyl ether) and only ethyl acetate and the like, more preferably solvent is ethyl acetate. Most preferably the solvent ethyl acetate is used in combination with n-hexane.
The charcoalization may preferably be carried out at temperature range between 40°C to 75°C, more preferably at 50°C to 65°C and most preferably at temperature range 60°C to 65°C.
The reaction mixture may further optionally be cooled at temperature range between 0°C to 25°C, more preferably at 0°C to 15°C and most preferably at temperature range 0°C to 5°C.
The invention is described in detail herein below with respect to the following examples, which are provided merely for illustration and are not intended to restrict scope of invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of present invention.

Example-1: Preparation of N1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro [4.4]non-2-en-4-one
2-butyl-1,3-diazaspiro[4.4]non-2-en-4-one hydrochloride (104.19 gm, 0.453 moles) was dissolved in water (76 g) followed with chloroform (590 ml) with stirring while slowly adding liquid ammonia (56.88 g, 3.345 moles). Separated aqueous layer was extracted one more time with chloroform (210 g). Then the combined organic layers were collected and dried with anhydrous sodium sulfate. To the organic layer, a 100gm (0.367 mol) of 4-bromomethyl-2'-cyanobiphenyl was added, followed by slow addition of N,N’-diisopropyl ethylamine (60 g, 0.465 moles) at 60° to 65°C and maintained for 2 to 3 hours at ambient temperature. Reaction monitored by TLC (Ethyl Acetate: Hexane, 2:8). After completion of the reaction cooled the mass to 0 to 50C and the mass was washed with 10% sodium bicarbonate solution, followed by DM water. Separated organic layer dried over anhydrous sodium sulfate followed by distilling the same completely give 91.9 g (Yield 65%) of crude 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-2-en-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile was obtained.
Preparation of Zinc chloride bis (dimethyl formamide) complex
Zinc chloride (108.1 g 0.79 mol) was added to N,N-dimethyl formamide (121.9 g , 1.67 moles) at 25 to 30°C under nitrogen over 30 to 40 min. The reaction observed to be highly exothermic, but controllable on its own.
Added 150 ml of N,N-dimethylformamide and 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-2-en-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile to zinc complex. Added sodium azide (74.4g, 1.14 mol) at 25 to 30°C. Temperature was raised to gradually to 1050C and maintained for 35 to 40 hours. Reaction monitored by TLC and Starting material was found to be = 1.0 %. Reaction mass cooled to room temperature and diluted with water (100 ml). The reaction mass quenched into chloroform and water mixture (500 ml, 1:1). Separated organic layer washed simultaneously with 20 ml of HCl and NaNO2 (20 g) to neutralize generated hydrozoic acid during the reaction. The resultant organic layer was washed with saturated sodium bicarbonate solution followed by charcoalization. Organic layer was subjected to vacuum distillation at 40 to 450C, to yield about 125 g (yield 83%) of crude N1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro [4.4]non-2-en-4-one which up on recrystalized from ethyl acetate and hexane mixture to give a half white solid.
Example-2: Preparation of 2-ethoxy-1-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl} methyl)-1H-1,3-benzodiazole-7-carboxylic acid
2-ethoxy-1H-benzo[d]imidazole-4-carboxylic acid (93.31 gm, 0.453 moles) was dissolved in Chloroform (590 ml) and stirred for 30 minutes. To the organic layer, a 100gm (0.367 mol) of 4-bromomethyl-2'-cyanobiphenyl was added, followed by slow addition of N,N’-diisopropyl ethylamine (60 g, 0.465 moles) at 60° to 65°C and maintained for 2 to 3 hours at ambient temperature. Reaction monitored by TLC (Ethyl Acetate: Hexane, 2:8). After completion of the reaction cooled the mass to 0 to 50C and the mass was washed with 10% sodium bicarbonate solution, followed by DM water. Separated organic layer dried over anhydrous sodium sulfate followed by distilling the same completely give 73.22 g (Yield 38%) of crude methyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-4-carboxylate was obtained.
Preparation of Zinc chloride bis (dimethyl formamide) complex
Zinc chloride (83.5 g 0.61 mol) was added to N,N-Dimethyl formamide (94.2 g , 1.29 mol) at 25 to 30°C under nitrogen over 30 to 40 min. The reaction observed to be highly exothermic, but controllable on its own.
Added 150 ml of N,N-dimethylformamide and methyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-4-carboxylate to zinc complex. Added sodium azide (57.53g, 0.88mol) at 25 to 30°C. Temperature was raised to gradually to 1050C and maintained for 35 to 40 hours. Reaction monitored by TLC and Starting material was found to be = 1.0 %. Reaction mass cooled to room temperature and diluted with water (100 ml). The reaction mass quenched into chloroform and water mixture (500 ml, 1:1). Separated organic layer washed simultaneously with 20 ml of HCl and NaNO2 (20 g) to neutralize generated hydrozoic acid during the reaction. The resultant organic layer was washed with saturated sodium bicarbonate solution followed by charcoalization. Organic layer was subjected to vacuum distillation at 40 to 450C, to yield 28.40 g (yield 35%) of crude 2-ethoxy-1-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid which recrystalized from ethyl acetate and hexane mixture to give a white solid.
Example-3: Preparation of (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-4,5-dihydro-1H-imidazol-5-yl)methanol
(2-butyl-4-chloro-4,5-dihydro-1H-imidazol-5-yl)methanol (70.2 gm, 0453 mol) was dissolved in chloroform (300 ml) stirred for 30 minutes. To the organic layer, a 100gm (0.367 mol) of 4-bromomethyl-2'-cyanobiphenyl was added, followed by slow addition of N,N’-diisopropyl ethylamine (60 g, 0.465 moles) at 60° to 65°C and maintained for 2 to 3 hours at ambient temperature. Reaction monitored by TLC (Ethyl Acetate: Hexane, 2:8). After completion of the reaction cooled the mass to 0 to 50C and the mass was washed with 10% sodium bicarbonate solution, followed by DM water. Separated organic layer dried over anhydrous sodium sulfate followed by distilling the same completely give 51.89 g (Yield 37%) of crude 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-4,5-dihydro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl] -2-carbonitrile.
Preparation of Zinc chloride bis (dimethyl formamide) complex
Zinc chloride (61.5 g, 0.45 mol) is added to N’N-dimethyl formamide (69.4 g, 0.59 mol) at 25 to 30°C under nitrogen condition for 30 to 40 min.
Added N’N-dimethyl formamide (150 ml) and 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-4,5-dihydro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile to zinc complex. Add sodium azide (42.4g, 0.65 mol) at 25 to 30°C. Temperature is raised to 1050C and maintained for 35 to 40 hours. Reaction mass cooled to room temperature and diluted with water (100 ml). The reaction mass quenched into chloroform and water mixture (500 ml, 1:1). Separated organic layer washed simultaneously with 20 ml of HCl and NaNO2 (20 g) to neutralize generated hydrozoic acid during the reaction. The resultant organic layer was washed with saturated sodium bicarbonate solution followed by charcoalization. Organic layer was subjected to vacuum distillation at 40 to 450C to yield about 20.16 g (yield 35%) of crude (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-4,5-dihydro-1H-imidazol-5-yl)methanol which recrystalized from ethyl acetate and hexane mixture to give a white solid.
Example-4: Preparation of N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl] methyl}-L-valine
L-Valine methyl ester hydrochloride (76 g, 0.453 moles) is dissolved in demineralized water (76 g) and stirred to get clear solution at an ambient temperature. Add chloroform (400 g). Slowly add liquid ammonia (56.88 g, 3.345 moles). Stir, settle & separate the layers. Aqueous layer is extracted one more time with chloroform (210 g). Then the combined organic layer is dried with anhydrous sodium sulfate. To the organic layer, 4-bromomethyl-2'-cyanobiphenyl (100 g, 0.367 moles) is added, followed by slow addition of N,N’-diisopropyl ethylamine (60 g, 0.465 moles) at reflux temperature and maintained for 2 to 3 hours. The in-process check of reaction is monitored by TLC (or) HPLC. Cool the mass to 0 to 50C. Valeroyl chloride (62.4 g, 0.517 moles) is added at 0 to 50C, followed by slow addition of N,N’-diisopropyl ethylamine (65.6 g 0.508 moles) at 0 to 50C. Stir for 10 to 15 minutes at 0 to 50C. The in-process check of reaction is monitored by TLC (or) HPLC. Then, the reaction mass is washed with 10% sodium bicarbonate solution, followed by DM water. Take organic layer and dry over anhydrous sodium sulfate followed by distilling the solvent completely. About 140 g (Yield 93%) of crude N-[(2'-cyanobiphenyl-4-yl) methyl]-N-valeroyl-(L)-Valine methyl ester is obtained. HPLC Chromatographic purity: - 99.10 %
Preparation of Zinc chloride bis (dimethyl formamide) complex
Zinc chloride (156.8 g 1.18 mol) is added to dimethyl formamide (179.2 g 2.357 moles) at 25 to 30°C under nitrogen condition for 30 to 40 min the reaction is highly exothermic, but controllable on its own.
Add N, N’-dimethyl formamide (150 ml) and N-[(2'-cyanobiphenyl-4-yl) methyl]-N-valeroyl-(L)-Valine methyl ester crude to zinc complex. Add sodium azide (107.5g, 1.65 moles) at 25 to 30°C. Temperature is raised to 1040C and maintained for 35 to 40 hours. The in-process check of reaction is monitored by TLC (or) HPLC. Starting material is found to be = 1.0 %. Cooled to room temperature and add DM water (120 g). Quench the mass into chloroform & DM water mixture. Stirred, settle & separate the layers. Take organic layer & treated with HCl & NaNO2 (20 g) to neutralize generated hydrozoic acid during the reaction at control pH 1.50 to 2.00. Stirred, settled & separated the layers. Organic layer is washed with 6% sodium bicarbonate solution
Take organic layer in RBF, add 48% caustic soda lye (140 g) and maintained the mass for 20 to 24 hours at 25 to 300C. The in-process check of reaction was monitored by TLC and HPLC. Starting material is found to be = 1.0 %. Separate the organic layer and aqueous layer. To the aqueous layer add ethyl acetate and adjusted pH to 1.5 to 2.0 with HCl at 0 to 50C. Stirred, settled & separated the layers. Aqueous layer is extracted with additional quantity of ethyl acetate. Organic layer is washed with 20% sodium chloride solution followed by charcoalization. Organic layer is subjected to vacuum distillation at 40 to 450C, to yield about 125 g (yield 83%) of crude N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl}-L-valine. HPLC Chromatographic purity: - 96.95 %
Add ethyl acetate (4 times) and n-hexane (2.0 times) to the crude N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl] methyl}-L-valine, followed by charcoalization at 60 to 650C. Gradually cool the mass to 25 to 300C followed by final cooling to 0 to 50C. Filter & wash the cake with ethyl acetate & n-hexane mixture. The wet material is further subjected to three crystallizations to get 65 to 70 gm of desired quality of pure N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl}-L-valine. HPLC Chromatographic purity: - 99.86 % ,CLAIMS:1. A process for the preparation of substituted biphenyl tetrazole derivatives of formula (I)

Formula (I)
or a salt thereof, wherein A is selected from the group comprising

R1 is independently selected from the group comprising C1-C8 straight or branched chain alkyl, -OR2, -COR2, -COOR2, OCOR2, CH2OH, CH2OR2, -CONHR2,
wherein R2 is selected from C1-C8 straight or branched chain alkyl group comprising the steps of:
v) conversion of hydrochloride salt of A to its base,
vi) reacting base of A with 2-cyano 4-substituted biphenyl compound of formula (II)

Formula (II)
wherein, X is halide, acetate, trifluoro acetate, sulfonate to obtain the compound of formula (III),

Formula (III)
(iii) preparation of zinc complex of formula(IV),

Formula (IV)
(iv) reacting the compound of formula (III) and formula (IV) to form crude substituted biphenyl tetrazole derivatives of Formula (I)

Formula (I)
wherein A is defined as above,
(v) optionally, purification of crude substituted biphenyl tetrazole derivatives of Formula (I) to get pure substituted biphenyl tetrazole derivatives of Formula (I).
2. The process as claimed in step (i) of claim 1 , where conversion of hydrochloride salt of A to its base comprises :
i) dissolving salt of A in solvent selected from group comprising demineralised water, methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, and their combination with demineralised water, preferably demineralised water.
ii) treating the product of step (i) with liquid ammonia and separation in an organic solvent selected from the group comprising chloroform, ethyl acetate, dioxane, diethyl ether, dimethyl formaamide, dichloro methane, butyl alcohol derivatives, toluene, chloro benzene, dichloro benzene and their mixture, preferably chloroform.
3. The process as claimed in step (ii) of claim 1, wherein reaction is carried out in presence of base; selected from the group comprising of N,N’-diisopropylethylamine, triethylamine, piperidine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, alkali and alkaline earth metal, C1-C6 alkoxide, preferably N, N’-diisopropyl ethylamine; at a temperature ranging from ambient to reflux temperature conditions for a time period of 1 to 8 hours.
4. The process as claimed in step (iii) of claim 1, where in zinc complex is prepared by reacting zinc chloride with a solvent, selected from group comprising N, N-dimethyl formamide, dimethyl sulfoxide, dimethylacetamide, 1,4-dioxane and their mixture, preferably N, N-dimethyl formamide.
5. The process as claimed in claim 4, wherein zinc complex intermediate is prepared by reacting zinc chloride with dimethyl formamide; at a temperature range between 5°C to 40°C for 10 to 60 minutes, preferably at 15°C to 30°C for 20 to 50 minutes and more preferably at temperature between 25°C to 30°C for 30 to 40 minutes.
6. The process as claimed in claim 4, wherein the zinc complex intermediate is zinc chloride bis-(dimethyl formamide) complex.
7. The process as claimed in step (iv) of claim 1, wherein crude substituted biphenyl tetrazole derivatives of Formula (I) is prepared by reacting 2-cyano 4-substituted biphenyl compound and zinc chloride bis-(dimethyl formamide) complex comprising:
i) dissolving 2-cyano 4-substituted biphenyl compound of formula (II) in a solvent;
ii) adding a azide donor at appropriate temperature range to the solution of step (i);
iii) separation of intermediate of step (ii) by use of an organic solvent;
iv) hydrolysis of intermediate of step (iii) in presence of base ;
v) charcolization to obtain crude substituted biphenyl tetrazole derivatives of formula (I).
8. The process as claimed in step (i) of claim 7, wherein the solvent is selected from group comprising N, N-dimethyl formamide, toluene, monochlorobenzene, dichlorobenzene, dimethyl sulfoxide, dimethyl acetamide, preferably N, N-dimethyl formamide.
9. The process as claimed in step (ii) of claim 7, wherein azide donor is selected from the group comprising trimethylsilyl azide, sodium azide, alkyl azide, alkenyl azide, aryl azide, vinyl azide, preferably sodium azide, and reaction is carried out at appropriate temperature range between 5°C to 40°C, preferably 15°C to 30°C, and reaction is maintained at temperature range between 50°C to 150°C for 10 to 50 hours, preferably 70°C to 125°C for 25 to 40 hours.
10. The process as claimed in step (iii) of claim 7, where in organic solvent is selected from the group comprising chloroform, demineralized water, N, N-dimethyl formamide, toluene, monochlorobenzene, dichlorobenzene, ethyl acetate and their mixtures, preferably mixture of chloroform and demineralized water.
11. The process as claimed in step (iv) of claim 7, wherein base used for hydrolysis is selected from the group comprising sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate sodium hydroxide potassium hydroxide, lithium hydroxide barium hydroxide alkali and alkaline earth metals, C1-C6 alkoxide, preferably sodium hydroxide and reaction is maintained at temperature range between 5°C to 40°C for 10 to 35 hours, preferably between 20°C to 30°C for 15 to 30 hours and more preferably between 25°C to 30°C for 10 to 15 hours.
12. The process as claimed in step (v) of claim 7, wherein charcoalization is carried out at temperature range between 40°C to 75°C, preferably between 50°C to 65°C and more preferably between 60°C to 65°C.
13. The process as claimed in step (v) of claim 1, wherein optionally purification of compound of formula (I) is carried out by:
i) separating the crude substituted biphenyl tetrazole derivatives of formula (I) of step (iv) in organic solvent;
ii) charcoalization of crude substituted biphenyl tetrazole derivatives of formula (I) of step (i) to obtain pure substituted biphenyl tetrazole derivatives of formula (I).
14. The process as claimed in step (i) of claim 13, wherein organic solvent is selected from the group comprising ethyl acetate, n-hexane, ethers (diethyl ether, diisopropyl ether) and their mixtures, preferably mixture of ethyl acetate and n-hexane.
15. The process as claimed in step (ii) of claim 13, wherein the charcoalization is carried out at temperature range between 40°C to 75°C, preferably between 50°C to 65°C.
16. A process for the preparation of N-substituted biphenyl tetrazole derivatives of formula (I) or a salt thereof as claimed in claim1,

Formula (I)
where A is

R1 is independently selected from the group comprising C1-C8 straight or branched chain alkyl, -OR2, -COR2, -COOR2, OCOR2, CH2OH, CH2OR2, -CONHR2,
wherein R2 is selected from C1-C8 straight or branched chain alkyl group.
17. The compounds as claimed in Claim 1, selected from the group comprises:
i) [2-butyl-5-chloro-3-[[4-[2-(1H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
ii) 2-ethoxy-1-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
iii) (N1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro [4.4]non-2-en-4-one.
iv) N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl] methyl}-L-valine
v) 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(1H-tetrazol-5-yl)phenyl]phenyl]methyl] imidazole-4-carboxylic acid.
vi) 2-[2-butyl-4-methyl-6-oxo-1-[[4-[2-(1H-tetrazol-5-yl)phenyl]phenyl]methyl]pyrimidin-5-yl]-N,N-dimethylethanethioamide.