The present invention relates to a process for the preparation of 2-butyl-4-chloro-5-formyl imidazole. More particularly, the present invention relates to a simple, economical, industrially efficient and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I.
l~
\ H
—\ N
Formula I
BACKGROUND OF THE INVENTION
Formyl-imidazoles are important intermediates for pharmaceutical active ingredients of diuretics and antihypertensive agents. 2-butyl-4-chloro-5-formyl imidazole is key starting material for Losartan. The CAS registry number of 2-butyl-4-chloro-5-formyl imidazole is [83857-96-9].
The chemical name for Losartan is (2-butyl-4-chloro-l-{[2'-(2H-tetrazol-5-yl)biphenyl -4-yl]methyl}-lH-imidazol-5-yl)methanol. The CAS Registry Number of Losartan is [114798-26-4] which has the following structure.

Losartan and its potassium salt are angiotensin-II receptor (Type ATI) antagonists. In adults Losartan is currently indicated for the treatment of hypertension. The incidence

of hypertension is very high with every third person in the world is suffering from this condition. This provides a huge market potential for antihypertensive drugs. Due to its high market value over the world, cost effective synthesis of Losartan is highly desirable. A most common and practical synthesis of Losartan in commercial scale is coupling of 4-bromomethyl-2-cyanobiphenyl (Br-OTBN) and 2-butyl-4-chloro-5-formyl imidazole (BCFI) followed by reduction of aldehyde group and finally conversion of cyano group to the tetrazole moiety. BCFI is one of the key starting material for the synthesis of widely used antihypertensive drug Losartan, hence a commercially viable and cost effective process with reduced effluent for the synthesis of BCFI is desired.
Various methods for the preparation of 2-butyl-4-chloro-5-formyl imidazole are known in prior art. Watson et al. in Synthetic Communications, Volume: 22, Issue: 20, Pages: 2971-7, 1992 uses butylimidazole as starting material, which on treatment with bromine in presence of chloroform gives dibromide intermediate. This dibromo intermediate upon reduction with sodium sulfite gives mono bromo imidazole, which undergoes hydroxymethylation followed by oxidation gives bromo aldehyde intermediate that on prolonged heating in cone. HC1 resulted in 2-butyl-4-chloro-5-formyl imidazole.


^ Br2/CHCI3
Na2S03 H20 EtoH reflux, 18 h

HCI Reflux
CHO
Mn02 DCM/ Dioxane (1:1)

HCHO Aq. NaOH EtOH/Water Br

Process of Watson et al., have certain drawbacks such as use of expensive raw material (butyl imidazole), chlorinated and carcinogenic Class-II solvent i.e. chloroform and use of Mn02 which is difficult to handle/filter in commercial scale.

Further, high temperature and longer time is required for halo-exchange and incomplete halo-exchange Br to CI.
Dawood et al uses valeraldehyde and dihydroxy acetone in concentrated ammonia in the presence of copper acetate (II) monohydrate as catalyst, which upon chlorination with N-chlorosuccinamide (NCS) and followed by oxidation with manganese dioxide resulted in 2-butyl-4-chloro-5-formyl imidazole.

M + HO-/^Y^C,H o

Cu(OAc)2 Conc.NH

NCS, 2-ME: 1,4-Dioxane dark, RT, 24 h

CHO
Mn02 DCM/ Dioxane (1:1)

Process of Dawood et al, have certain drawbacks such as use of high temperature and pressure and also the formation of dichloroimidazole as by-product.
The alternate process described by Griffith et al. in Journal of Organic Chemistry, Volume: 64, Issue: 22, Pages: 8084-8089, 1999. This process involves the preparation of ethyl pentanimidate, its condensation with glycine and then cyclization-chlorination-formylation using Vilsmeier reagent. In this process, preparation of ethyl pentanimidate in dibutyl ether itself takes six days for completion of the reaction, followed by work up procedures at several stages to isolate and purify the intermediates. Generation / procurement / storage of HCl gas is very expensive and difficult to handle on commercial scale.


The known processes suffer from problems, such as long reaction time, procurement and maintenance of dry HC1 gas, generation of huge volumes of effluent, use of costly reagents on industrial scale. In view of the preparation methods available for 2-butyl-4-chloro-5-formyl imidazole, there is a need for simple, industrially scalable, cost effective, environmentally-friendly and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole that is free from above mentioned drawbacks.
Despite the progress in the manufacturing operations for Active Pharmaceutical Ingredients various controls applied to make the drugs acceptable for human consumption. In the past, several drug companies voluntarily recalled their drugs after finding trace amount of unexpected impurities i.e. nitrosamine, thus in light of probable contamination of nitrosamine impurities particularly N-nitrosodimethylamine (NMDA/NDMA) of and N-nitrosodiethylamine (NEDA/NDEA) of, particularly when the manufacturing process lead to the formation of a nitrosamine or when recycled raw materials / solvents can create unacceptable contamination or due to probable saturation of nitrosamine in environment, it becomes inevitable to identify potential cross contamination risks for drugs manufactured, to include enhanced evaluation of impurity controls and to demonstrate a capability of predicting, controlling, and preventing impurities in the drug substance and subsequently in the drug product.
Nitrosamines (N-Nitrosodipropylamine, N-Nitrosodiisopropylamine, N-Nitrosoethyl-isoproplymiane, N-Nitrosodimethylamine, N-Nitrosodiethylamine) which are highly carcinogenic and are point of concern as per ICH M7. The processes disclosed in the prior art fail to provide the control of impurities/genotoxic nitrosamine impurities.

Consequently, there is a need for an improved process for the preparation of 2-butyl-4-chloro-5-formyl imidazole, which not only overcomes the problems in the prior art processes as mentioned above, but also is simple, economically viable, industrially feasible and environment friendly for the preparation of 2-butyl-4-chloro-5-formyl imidazole having a good control over impurities/genotoxic nitrosamine impurities and effluent generation.
In view of the same, there is a need for simple, industrially feasible, cost effective and environmentally-friendly and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole that is free from above mentioned drawbacks.
The problem has been solved by providing an improved process, wherein by-product (HC1 gas) of last step is reused in first step of the process.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations of the prior arts by providing an efficient process for the preparation of 2-butyl-4-chloro-5-formyl imidazole.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing 2-butyl-4-chloro-5-formyl imidazole.
It is still another object of the present invention to provide an improved and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole, wherein by¬product of last step is reused in first step of the process.
It is still another object of the present invention to provide an improved and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole, wherein by¬product (HC1 gas) of last step is reused in first step of the process.

It is still another object of the present invention to provide an improved and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole, wherein HC1 gas is reused in same process.
It is still another object of the present invention to provide 2-butyl-4-chloro-5-formyl imidazole substantially free from nitrosamine impurities.
It is still another object of the present invention to provide 2-butyl-4-chloro-5-formyl imidazole substantially free of nitrosamines, wherein nitrosamine is selected from the group comprising of N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitrosodiisopropylamine (NDIPA), N-Nitrosoethylisopropylamine (NEIPA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NDPA), N-Nitrosodibutylamine (NDBA), N-Nitrosomethyldodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, N-nitroso-N-methyl-4-aminobutyric acid (NMBA).
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided an efficient, cost effective and green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I, as shown in scheme 1.

Scheme 1


CN Valeronitrile Formula II

MeOH
HCl(g)

NH Glycine (Formula IV) -0"
MeOH
Formula III

Formula V

POCI3, DMF

HCl(g)
Formula I
It has been found that 2-butyl-4-chloro-5-formyl imidazole is efficiently prepared from environment friendly process, wherein HCl gas is reused in the same process.
2-butyl-4-chloro-5-formyl imidazole is efficiently prepared from valeronitrile, wherein HCl gas formed as by-product in last step of process is reused in first step of same process.
Reusing HCl gas helps in achieving goal of developing green process for the preparation of 2-butyl-4-chloro-5-formyl imidazole, wherein no effluent is generated.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic representation of process of 2-butyl-4-chloro-5-formyl imidazole showing reusing of HCl gas.
DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I

Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with methanol in presence of dry HC1 gas
followed by basification to obtain compound of Formula III;

Valeronitrile O
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV to obtain compound of Formula V; and



Formula IV

(iii) reacting compound of Formula V with phosphoryl chloride followed by addition of dimethylformamide to obtain 2-butyl-4-chloro-5-formyl imidazole and HC1 gas; wherein HC1 gas of step (iii) is reused in step (i).
In step (i), reaction of HC1 gas with valeronitrile is carried out at temperature of -10°C to 5°C and preferably at -10°C to 0°C.
In step (i), basification of reaction mixture is carried out with base selected from the group comprising of sodium hydroxide and potassium hydroxide. Basification in step (i) is carried out preferably with sodium hydroxide.

In step (ii), reaction is carried out in methanol.
In step (ii), reaction with Glycine is carried out at temperature of 0°C to 10°C and preferably at 0°C to 5°C.
In step (iii), reaction is carried out in toluene.
In step (iii), addition of Phosphoryl chloride is carried out at temperature of -5°C to 0°C; addition of dimethylformamide is carried out at 70°C to 95°C and reaction is further stirred at 100°C to 105°C.
In step (iii), HCl gas is formed as by-product, which is further reused in step (i) of the process.
In an embodiment, the present invention relates to a process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I
O
\\{ Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with methanol in presence of dry HCl gas
followed by basification to obtain compound of Formula III;
/\ /\ NH
"-"^-^CN II
Valeronitrile u
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV in methanol to obtain compound of Formula V; and



Formula IV

(iii) reacting compound of Formula V with phosphoryl chloride in toluene followed by addition of dimethylformamide to obtain 2-butyl-4-chloro-5-formyl imidazole and HCl gas; wherein HCl gas of step (iii) is reused in step (i).
In an another embodiment, the present invention relates to a process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I

CI Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with methanol in presence of dry HCl gas at
temperature of -10°C to 5°C, followed by basification to obtain compound of Formula
III;
NH
TN II
Valeronitrile u
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV in methanol at temperature of 0°C to 5°C to obtain compound of Formula V; and



Formula IV

(iii) reacting compound of Formula V with phosphoryl chloride in toluene followed by addition of dimethylformamide to obtain 2-butyl-4-chloro-5-formyl imidazole and HCl gas; wherein HCl gas of step (iii) is reused in step (i).
In an another embodiment, the present invention relates to a process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I

CI Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with methanol in presence of dry HCl gas at temperature from -10°C to 5°C, followed by addition of aqueous sodium hydroxide to obtain compound of Formula III;
NH
TN II
Valeronitrile u
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV in methanol at temperature of 0°C to 5°C to obtain compound of Formula V; and



Formula IV

(iii) reacting compound of Formula V with phosphoryl chloride in toluene at temperature of -5°C to 0°C followed by addition of dimethylformamide at temperature of 70°C to 95°C to obtain 2-butyl-4-chloro-5-formyl imidazole and HC1 gas; wherein HC1 gas of step (iii) is reused in step (i).
Nitrosamines are potent carcinogens in animals and probable carcinogens in humans. The probable reason of formation of nitrosamine as impurities is that they can form when certain reaction conditions are met such as use of organic amines during the reaction. Nitrosamines are highly carcinogenic and are cohort of concern as per ICH M7. ICH M7 recommends that these mutagenic carcinogens be controlled at or below the acceptable cancer risk level. Due to their known potent carcinogenic effects, and because it is feasible to limit these impurities by taking reasonable steps to control or eliminate their presence, the goal is to have no quantifiable nitrosamine impurities or well within the declared limits which is safe for human consumption.
FDA has identified nitrosamine impurities that could be present in drug products such as nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA). Some of these impurities have actually been detected in drug substances or drug products.
The guidance outlines several possible root causes for the formation of nitrosamines in drug products, including: (1) chemicals introduced during the manufacturing process; (2) contamination during production or transport of raw materials; (3) reuse of solvents, catalysts, and reagents; (4) addition of nitrous acid; (5) lack of process

optimization and control; and (6) possible degradation of the products. FDA recommends that manufacturers consider these potential causes of nitrosamine formation and evaluate the risk for nitrosamine contamination in their APIs and drug products. Starting material also should be free from impurities like organic or inorganic impurities.
Use of recycled solvents, catalysts and reagents in drug products is one of probable cause of nitrosamine impurity formation. Recycled raw materials or reused solvents are at a higher risk of harboring impurities. Furthermore, the recycling of materials and solvents is often outsourced to third parties who may not implement adequate controls in view of the content of the materials they are processing. Materials and solvents can become cross-contaminated with nitrosamines or with impurities that could react downstream to form nitrosamines, if equipment is not adequately cleaned. Despite of this, the present invention devised the conditions of reusing HC1 gas in process for preparing 2-butyl-4-chloro-5-formyl imidazole, which is substantially free of nitrosamine impurities such as N-nitrosodimethylamine (NDMA) and N-nitroso diethylamine (NDEA).
2-butyl-4-chloro-5-formyl imidazole, which obtained by process of the present invention being substantially free of nitrosamines, wherein nitrosamine is selected from the group comprising of N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitrosodiisopropylamine (NDIPA), N-Nitrosoethylisopropylamine (NEIPA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NDPA), N-Nitrosodibutylamine (NDBA), N-Nitrosomethyl dodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, N-nitroso-N-methyl-4-aminobutyric acid (NMBA). Nitrosamine impurity is preferably less than 0.01 ppm in 2-butyl-4-chloro-5-formyl imidazole. Nitrosamine impurities are well within the specifications prescribed safe for human consumption, preferably nitrosamine impurity is less than 0.01 ppm, wherein the limit of detection is 0.01 ppm.

2-Butyl-4-chloro-5-formyl imidazole obtained by process of the present invention is substantially free from Pentanimidoyal aminoacetic acid (PAAA), 2-Butyl-4-chloro-5-[hydromethyl]-lH-imidazole (BCHI), N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA), wherein each impurity is less than 0.01 ppm.
HCl is a colourless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapour. This gas is hazardous and when released into the atmosphere undergo wet and dry deposition, and then readily incorporated into cloud, rain and fog water. It thus forms a component of acid rain. It also contributes to the process that cause photochemical smog. To neutralize this, it requires huge amount of alkali. Hence, recycling of this HCl is required for health and environment safety.
Manufacturing of 2-butyl-4-chloro-5-formyl imidazole involves purging of dry HCl gas which needs to be procured commercially or a setup of HCl gas generation system is needed at the site of manufacturing. HCl gas is manufactured commercially by either from ammonium chloride/Sulfuric acid or Sodium chloride/Sulfuric acid or 35% aqueous HCl/Sulfuric acid or Calcium chloride/Sulfuric acid methods. All of these methods generate tons of effluent which needs to be treated before its disposal and also involve significant capital/investment for setup and maintenance. Dry HCl gas is expensive and contributes significantly to the cost in addition to its procurement and maintenance. For production of one ton of 2-butyl-4-chloro-5-formyl imidazole, more than about 10000 L of effluent gets generated when HCl gas cylinders are used and more than about 15000 L of effluent gets generated when HCl generator system is used. This effluent, which gets generated during synthesis of 2-butyl-4-chloro-5-formyl imidazole needs to be disposed after neutralization which incurs significant cost and possess safety risk. For about 2000 Kg of HCl gas, approximately 2400 Kg of NaOH is required for scrubbing.
The problem has been solved by providing an improved process in which HCl gas formed as by-product in last step is again reused in first step of the process. By reusing HCl gas various objectives are achieved such as effluent generation is eliminated, no

waste generation and no need of NaOH scrubbing, less operational step and reducing time cycle of the instant process. This green process of 2-butyl-4-chloro-5-formyl imidazole not only helps in reducing cost but also protect our environment by generating no waste.
The process for the preparation of 2-butyl-4-chloro-5-formyl imidazole as described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example 1: Preparation of 2-butyl-4-chloro-5-formyl imidazole
HC1 gas (32 g) was passed through a solution of valeronitrile (50 g) and methanol (25 g) at -10°C to 5°C and then the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with toluene (250 mL), cooled to -10°C and neutralized with 40% aqueous NaOH solution to pH 9 to 9.5 at below 5°C. Organic layer was separated and the aqueous layer was extracted with toluene (100 mL). The combined toluene layer was directly added to the glycine (45.15 g) in methanol (137 mL) at below 5°C and added water (23 mL). After stirring the reaction mixture for 16 h at ambient temperature, the water and methanol was removed azeotropically. The slurry was cooled to -5°C to 0°C, phosphoryl chloride (258.22 g) was added dropwise and stirred for 1 hr. Then the reaction mixture was heated to 70°C. Then dimethylformamide (131.78 g) was added at 70°C to 95°C and stirred at 100°C to 105°C for further 3 hr. The reaction mixture was cooled to 50°C and the hot reaction mixture was poured into ice cold water (500 mL) below 30°C, after adjusting pH 2.0 to 2.5 with 30% aqueous NaOH solution. Organic layer was separated and the aqueous layer was extracted with toluene. Combined toluene layer was charcolized at 50°C to 55°C and evaporated up to 150 mL under vacuum, then cooled to 0°C to 5°C, stirred for 4 h, filtered the precipitated solid and washed with chilled toluene at 0°C to 5°C.

The wet solid was dried under vacuum at 55°C to 60°C to obtain 2-butyl-4-chloro-5-formyl imidazole as yellow solid. Yield - 60 g; HPLC purity - 99.7%; Impurities:
1) Pentanimidoyal aminoacetic acid (PAAA): Not detected
2) 2-Butyl-4-chloro-5-[hydromethyl]-lH-imidazole (BCHI): Not detected
3) Nitrosoamines:
N-nitrosodimethylamine (NDMA): Not detected (Limit NMT 0.01 ppm) N-nitrosodiethylamine (NDEA): Not detected (Limit NMT 0.01 ppm)
Example 2: Preparation of 2-butyl-4-chloro-5-formyl imidazole reusing HC1 gas
HC1 gas (32 g) was passed through a solution of valeronitrile (50 g) and methanol (25 g) at -10°C to 5°C and then the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with toluene (250 mL), cooled to -10°C and neutralized with 40% aqueous NaOH solution to pH 9 to 9.5 at below 5°C. Organic layer was separated and the aqueous layer was extracted with toluene (100 mL). The combined toluene layer was directly added to the glycine (45.15 g) in methanol (137 mL) at below 5°C and added water (23 mL). After stirring the reaction mixture for 16 h at ambient temperature, the water and methanol was removed azeotropically. Then toluene (500 mL) was added to the residue and the solvents was removed under vacuum below 50°C to obtain (pentanimidoyalamino)acetic acid, which was taken in a 4-necked round bottom flask attached with a mechanical stirrer, a nitrogen inlet, a condenser above which a gas outlet. Toluene (250 mL) was added and stirred for 45 min at 20-25C. The reaction mixture was cooled to -5°C to 0°C, phosphoryl chloride (258.22 g) was added dropwise and stirred for 1 hr. Then the reaction mixture was heated to 70°C. Then dimethylformamide (131.78 g) was added at 70°C to 95°C and stirred at 100°C to 105°C for further 3 hr. HC1 gas is obtained as by-product in this reaction was passed through an another reactor containing a solution of Valeronitrile and methanol as depicted in the drawing and 2-butyl-4-chloro-5-formyl imidazole was prepared as per Example 1. The reaction mixture was cooled to 50°C and the hot reaction mixture was poured into ice cold water (500 mL) below 30°C, after adjusting

pH 2.0 to 2.5 with 30% aqueous NaOH solution. Organic layer was separated and the aqueous layer was extracted with toluene. Combined toluene layer was charcolized at 50°C to 55°C and evaporated up to 150 mL under vacuum, then cooled to 0°C to 5°C, stirred for 4 h, filtered the precipitated solid and washed with chilled toluene at 0°C to 5°C. The wet solid was dried under vacuum at 55°C to 60°C to obtain 2-butyl-4-chloro-5-formyl imidazole as yellow solid. Yield - 60 g; HPLC purity - 99.7%; Impurities:
1) Pentanimidoyal aminoacetic acid (PAAA): Not detected
2) 2-Butyl-4-chloro-5-[hydromethyl]-lH-imidazole (BCHI): Not detected
3) Nitrosoamines:
N-nitrosodimethylamine (NDMA): Not detected (Limit NMT 0.01 ppm) N-nitrosodiethylamine (NDEA): Not detected (Limit NMT 0.01 ppm)

WE CLAIM:

1. A process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I

O
H 11
\ N" r H
—v 1
N^ kci
Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with methanol in presence of dry HC1 gas
followed by basification to obtain compound of Formula III;

CN
Valeronitrile O
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV to obtain compound of Formula V: and

H2N
° H °
OH NH
Formula IV Formula V

(iii) reacting compound of Formula V with Phosphoryl chloride followed by addition of dimethylformamide to obtain 2-butyl-4-chloro-5-formyl imidazole and HC1 gas; wherein HC1 gas of step (iii) is reused in step (i).
2. The process as claimed in claim 1, wherein step (i) is carried out at temperature from-10°Cto5°C.

3. The process as claimed in claim 1, wherein basification in step (i) is carried out with base selected from the group comprising of sodium hydroxide and potassium hydroxide.
4. The process as claimed in claim 1, wherein basification in step (i) is carried out with sodium hydroxide.
5. The process as claimed in claim 1, wherein step (ii) is carried out in methanol.
6. The process as claimed in claim 1, wherein step (iii) is carried out in toluene.
7. The process as claimed in claim 1, wherein 2-butyl-4-chloro-5-formyl imidazole of Formula I is further converted to Losartan.
8. The process as claimed in claim 1, wherein process for the preparation of 2-butyl-4-chloro-5-formyl imidazole of Formula I
O
Ny^H \\{ Formula I
comprising the steps of:
(i) reacting valeronitrile of Formula II with dry HC1 gas in methanol followed by
basification to obtain compound of Formula III;
/\ /\ NH
Valeronitrile u
Formula II Formula III
(ii) reacting compound of Formula III with glycine of Formula IV in methanol to obtain compound of Formula V; and

OH

H2N
OH
Formula IV

NH Formula V

(iii) reacting compound of Formula V with Phosphoryl chloride in toluene followed by addition of dimethylformamide to obtain 2-butyl-4-chloro-5-formyl imidazole and HC1 gas; wherein HC1 gas of step (iii) is reused in step (i).
9. The process as claimed in claim 1, wherein 2-butyl-4-chloro-5-formyl imidazole is
substantially free of nitrosamines which is selected from the group comprising of N-
Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-
Nitrosodiisopropylamine (NDIPA), N-Nitrosoethylisopropylamine (NEIPA), N-
Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NDPA), N-
Nitrosodibutylamine (NDBA), N-Nitrosomethyl dodecylamine, N-Nitroso-N-methyl-
N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-
phenyl) ethylamine, N-nitroso-N-methyl-4-aminobutyric acid (NMBA).
10. The process as claimed in claim 1, wherein 2-butyl-4-chloro-5-formyl imidazole is
free from Pentanimidoyal aminoacetic acid (PAAA), 2-butyl-4-chloro-5-
[hydromethyl]-lH-imidazole (BCHI), N-Nitrosodi- methylamine (NDMA) and N-
Nitrosodiethylamine (NDEA), wherein each impurity is less than 0.01 ppm.