FORM - 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (SECTION 10, RULE 13)
"PROCESS FOR THE PREPARATION OF 2-BUTYL-4-CHLORO-5-FORMYLIMIDAZOLE"
DISHMAN PHARMACEUTICALS AND CHEMICALS LIMITED A Company Incorporated Under The Indian Companies Act,
Bhadr-Raj Chambers, C.G. Road,
Navrangpura, Ahmedabad-380 009,
Gujarat State, India
The following specification particularly describes the nature of this invention and manner in which it is to be performed: -
1150/MUM/2004

Field of Invention
This invention relates to a process for the preparation of 2-Butyl-4-Chloro-5-Formylimidazole which is used as an intermediate for an Antihypertensive drug.
Prior Art
US patent 5696272 for the process of 2-Butyl-4-Chloro-5-Formylimidazole carried out with the following steps.
1). 37.91 gm of Glycine, 9. g of water and 160 ml of methanol was cooled to 0° C and pH was adjusted by addition of 30 % NaOH up to 9.5 and thereafter methyl pentanimidate in toluene having strength of 41% was added with the stirring and stirring is made continuous for 20 hours at room temperature.
2). After completion of stirring the pH of suspension of step (1) is maintained upto 10.13 to 7 by addition of sulphuric acid.
3). After adjustment of the pH, 500 ml toluene was added to the suspension of the step (2) and thereafter water and methanol distilled out by vacuum below 50 ° C and thereafter toluene was added to the remaining mixture which is cooled to 0° C.
4).On completion of addition of toluene, Phosphorous oxychloride with dimethylfomamide was added to the suspension of the step (3) wherein mixture was heated for 2hrs.at 100°C.
5). Mixture of step (4) was admixed with ethyl acetate and celite and pH was adjusted by the addition of sodium hydroxide. Thereafter celite was filtered off and phases were separated from which organic layer was washed with water twice and concentrated to dryness to get the 2-Butyl-4-Chloro-5-Formylimidazole with 85 % of purity measured by HPLC.

Disadvantages of Process.
1).ln the known process during the step (1) addition of methanol and step (3) toluene lead to the contamination of the final product with the less purity and less yield
2). During the step (1) use of water lead to contamination of the final product with the less purity.
3). During the process in step (2) first the suspension is treated with the addition of sulphuric acid to maintain pH 9 to 13 and thereafter in step (4) suspension is made alkaline by addition of sodium hydroxide such kind of addition consume more time and which increases the cost of the product and process.
4). Use of solvents methanol, ethyl acetate and toluene leads to contamination of the final product and reduces the quantum of the product.
Objects of the Invention
The main object of the invention is the use of single solvent toluene to prevent the contamination of the final product and thereby to increase the good quality of the product.
The another object of the invention is to get the product with the more purity.
The another object of the invention is that pH of the solution is not maintained and process is carried out in the basic medium to get the product with high purity which would be very precious in the of quality assurance environment.
The another object of the invention is to provide more economically with simple process, a better quality product having good quality.

Detailed Description Of The Process
This invention relates to a process for the preparation of 2-Butyl-4-Chloro-5-Formylimidazole of the formula:

In one pot process (continuous process without solid isolation of any intermediate) for the preparation of 2-Butyl-4-Chloro-5- Formylimidazole, Glycine is added to the freshly prepared Methanolic Sodium hydroxide solution at 30-35°C and it is stirred for 15 min. Then Methylpentanimidate is added to the above suspension at 30-35°C in 10-15 min and it is stirred for 5-6 hrs. Methanol is distilled out by using U/Vaccum method at around 45 to 50°C. Residue remains after distillation, which is treated with Toluene. Addition of Phosphorous oxychloride in the above suspension is started from 30 till 80°C within time span of 60 min. Further, N, N- dimethyl formamide is added slowly within time span of 1-2 hrs. This mixture is heated up to 100°C and which is further stirred for 2-3 hrs and is further cooled to 30°C. This mixture is quenched in cold water below 25°C. In this quench mixture Hi-flow (Hyflow super-cel) is added and pH is adjusted to 1.2 - 1.3 by adding 30 % aqueous sodium hydroxide solution in to it. Hi-flow sludge is obtained out of the filtration. This hi-flow sludge is washed with Toluene that generates two layers; one layer is aqueous while the other layer is toluene layer. During separation of the layers, aqueous layer is discarded and the toluene layer is washed twice with water. After every wash, two layers are formed and each time after the separation, water layer is discarded. After
completion of last separation, carbon is added to the Toluene layer within time span of 30 min at 30-35°C with continuous stirring. The mixture is filtered and washed with

Toluene. The filtrate, which consists of the Toluene, is collected and concentrated up to 50 % volume by U/Vacuum method at around 50 to 55°C. The concentrated Toluene solution is cooled up to 0-5°C and it is stirred for 2-3 hrs. This solution is filtered and residue obtained after filtration is washed with chilled Toluene. Residue is further dried at 50-55°C to get crystalline 2-BUTYL-4-CHLORO-5-FORMYLIMIDAZOLE with purity of 99.5% measured by HPLC. The Entire process is given below




Glycine

NaOH
NH Methyl pentanimidate

2-Butyl-4-Chloro-5-Formyl Imidazole
Conclusion : The process with the single solvent toluene results into the final product with the high purity of 99.5 %

Advantages of the present invention
The main advantage of the invention is the use of single solvent toluene to prevent the contamination of the final product and thereby to increase the quality of the product.
Process is to be used to get the product with the more purity of 99.5%
The another object of the invention is that pH of the solution is not required to be maintained by addition of acid and thereby process is carried out in the basic medium to get the product with high purity which would be very precious in the of quality assurance environment
Preparatory Examples
Example 1
Preparation of 2-Butyl-4-Chloro-5-Formyl Imidazole (lab scale)
Add 50 gm (0.666 mol) of Glycine to the freshly prepared Methanolic Sodium hydroxide solution (Sodium hydroxide 26.64 gm (0.666 mol) in 250 ml Methanol) at 30-35°C and stir for 15 min. Add 80 gm Methylpentanimidate to the above suspension at 30-35°C in 10-15 min and stir for 5-6 hrs. Distill the solvent UA/acuum below 50°C (weight of the residue: 158 gm). Add 500 ml Toluene to the above residue followed by 320 gm (2.05 mol) Phosphorous oxychloride at 30-80°C in 60 min. Add 150 gm (2.05 mol) N, N-dimethyl formamide slowly in 1-2 hrs. Heat the reaction mixture to 100°C and stir for 2-3 hrs. Cool to 30°C and quench the reaction mass in 260 ml cold Water below 25°C. Add 30 gm hi-flow and adjust the pH to 1.2 -1.3 with 440 ml of 30 % aqueous sodium hydroxide solution. Filter and wash with 100 ml Toluene then separate the layers (discard the aqueous layer). To the Toluene layer give water wash twice with 400 ml each, discard the aqueous wash. Add 8 gm carbon to the Toluene and stir for 30 min at 30-35°C followed by filtration and wash with 100 ml Toluene. Collect all Toluene and concentrate up to 50 %

volume UA/acuum below 55°C. Cool the concentrated Toluene solution to 0-5°C and stir for 2-3 hrs followed by solid filtration wash with 25 ml chilled Toluene gave the wet material, which is dried at 50-55°C up to constant weight, gave 55 gm crystalline material. The analysis of this product by HPLC gave 99.8 %purity, confirmed by IR.
Example 2
Preparation of 2-Butyl-4-Chloro-5-Formyl Imidazole (Pilot Scale)
Add 25 Kg of Glycine to the freshly prepared Methanolic Sodium hydroxide solution (Sodium hydroxide 13.32 Kg in 125 L Methanol) at 30-35°C and stir for 15 min. Add 40 Kg Methylpentanimidate to the above suspension at 30-35°C in 10-15 min and stir for 5-6 hrs. Distill the solvent UA/acuum below 50°C. Add 250 L Toluene to the above residue followed by 160 Kg Phosphorous oxychloride at 30-80°C in 60 min. Add 75 Kg N, N-dimethyl formamide slowly in 2-3 hrs. Heat the reaction mixture to 100°C and stir for 2-3 hrs. Followed by cooling to 30°C and quench the reaction mass in 130 L cold Water below 25°C. Add 15 Kg hi-flow and adjust the pH to 1.2 -1.3 with 30 % aqueous sodium hydroxide solution. Filter and wash with 50 L Toluene then separate the layers (discard the aqueous layer). To the Toluene layer give water wash twice with 200 L each, discard the aqueous wash. Add 4 Kg carbons to the Toluene and stir for 30 min at 30-35°C followed by Sparkler filtration and wash with 50 L Toluene. Collect all Toluene and concentrate up to 50 % volume using Vacuum below 60°C. Cool the concentrated Toluene solution to 0-5°C and stir for 2-3 hours followed by Centrifuge, spin for 15 min wash with 15 L chilled Toluene gave the wet material, which is dried at 50-55°C in Rotary Vacuum Drier until to get below 0.5 % LOD. Cool to 30°C and unload in to double polyethylene bags. Weight of the product is 28 Kg, light yellow crystalline powder. The analysis of this product by HPLC gave 99.5 % purity.

We Claim,
1. Process for the preparation of 2-BUTYL-4-CHLORO-5-FORMYLIMIDAZOLE comprises of following sequential steps;
i). Adding Glycine to Methanolic Sodium hydroxide solution at 30-35°C with stirring
ii) Adding Methylpentanimidate to the mixture of step (i) with constant stirring, distilling out Methanol and treating the residue with Toluene, Phosphorous oxychloride and N, N- dimethyl formamide
iii) Heating the mixture of step (ii), stirring and cooling and then quenching in cold water wherein Hi-flow (Hiflow super-eel) is added;
iv) Adjusting the pH to 1.2 - 1.3 by adding 30 % aqueous sodium hydroxide solution then by filtering and washing the filtrate with Toluene wherein the toluene layer is washed twice with water
v) Adding carbon to the toluene layer within time span of 30 min at 30-35°C with continuous stirring;
vi) Filtering the mixture, washing filtrate with Toluene which is further concentrated up to 50 % volume by UA/acuum method at around 50 to 55°C
vii) Cooling the concentrated filtrate of step (vi) up to 0-5°C, stirring to get crystalline 2-BUTYL-5-CHLORO-4-FORMYL IMIDAZOLE.

2. Process for the preparation of 2-BUTYL-4-CHLORO-5-FORMYLIMIDAZOLE as per claims in claim 1, use of single solvent toluene to reduce contamination of mixture and thereby provide high yield with high purity.

Dated this 25tn day of October 2004.


To,
The Controller of Patents,
Patent Office.
Mumbai.

JATIN Y. TRIVEDI (Authorized Agent of the Applicant)