A PROCESS FOR PREPARATION OF HALQUINOL PRODUCT
FIELD OF THE INVENTION
Present invention relates to process for the preparation of Halquinol comprising reacting glycerin, 2-amino-4, 6-dichlorophenol and sulfuric acid with 2-nitro-4-chlorophenol and acetic acid.
BACKGROUND OF THE INVENTION
Halquinol is a mixture of chlorinated derivative of 8-hydroxy quinoline compound of structural formula I,

Formula I
and is added to animal feeds for prevention of e-coli, salmonella infection and intestinal infection. Halquinol chemically designated as mixture of 5,7-dichloro-8-quinolinol and 5-chloro-8-quinolinol. The major component of this mixture is dichloro derivative 5,7-dichloro-8-quinolinol which is within the percentage range of 57.0% to 74.0% (both inclusive), another component 5-chloro-8-quinolinol is within the percentage range of 23.0% to 40.0% (both inclusive). The third component 7-chloro-8-quinolinol may present in the mixture up to 4.0%. Due to antifungal or anti protozoal properties, it is basically used as a veterinary feed additive and supplement. The antimicrobial effect of Halquinol derives from its ability to chelate metal ions, particularly iron, copper and zinc. In bacteria, fungi and protozoa, essential trace elements are thus removed, and enzyme functioning ceases. Additionally, Halquinol acts directly on gastrointestinal smooth muscle to slow down peristaltic activity. Thus absorption of nutrients, particularly in animals suffering from diarrhea, is enhanced, and performance criteria are improved markedly.

Since very little Halquinol is absorbed, residues are not a concern and no withholding period is
needed, even for laying birds. Halquinol acts entirely in the gut and systemic activity is not
necessary.
French Patent No. 1, 372, 414 disclosed process for preparing Halquinol comprising reacting
compound of structural formula I, with sulfuryl chloride in glacial acetic acid at 50°C for 1.5
hours, as shown in below reaction scheme I.




OH
OH
Fourmua I

S02C12
Glacial acetic acid 50°C1.5hrs


CI Fourmua III 23 - 40%

Fourmua IV less than 3%

Sulfuryl chloride tends to decompose to sulfur dioxide and chlorine and has to be consumed
freshly. It has to be used very carefully due to its toxic and corrosive nature, and tear gas action.
It can form fuming mixtures with water. Lots of precautions are necessary during its commercial
scale use to avoid hazards and damages.
There are references in prior art about preparing Formula I compound i.e. 8-hydroxyquinoline by
Skraup's reaction. In US4044011 Jean-Marie Cognion reported improvements in Skraup's
reaction.
However, all efforts in past were regarding improving the quality and yield of 8-
hydroxyquinoline which then chlorinated to give Halquinol using chlorination techniques
including the one mentioned above.
Pelayo Camps Garcia et. al. in their book Fundamentos de sintesis de farmacos (2005 edition)
described synthesis of clioquinol on pages 236-237, in which 8-hydroxy quinoline is prepared
by Skraup's method and then it is chlorinated and iodinated to obtain clioquinol.
In fact, there was no simple, safe and economic process for preparing Halquinol.

SUMMARY OF THE INVENTION:
Present invention provides a process for preparing halquinol comprising reacting glycerin, 2-amino-4, 6-dichlorophenol and sulfuric acid with 2-nitro-4-chlorophenol and acetic acid wherein 2-nitr.o-4-chlorophenol is taken within the range of 0.7 time to equal weight quantity of 2-amino-4,6-dichlorophenol. The obtained halquinol product contain from 57.0% to 74.0% of 5, 7-dichloro-8-quinolinol and from 23.0% to 40.0% 5-chloro-8-quinolinol. The process is simple, safe, cost effective, does not use any hazardous chemical and yield desired components in desired percentages.
BRIEF DESCRIPTION OF THE DRAWINGS:
For more complete understanding of the features and advantages of the present invention,
reference is now made to the detailed description of the invention along with the accompanying
figure and in which:
Figure I depicts IR of Halquinol
Figure II depicts GC Chromatogram of Halquinol obtained by the following example 1
Figure III depicts GC Chromatogram of Halquinol obtained by the following example 2
Figure IV depicts GC Chromatogram of Halquinol obtained by the following example 3
DETAIL DESCRIPTION OF INVENTION:
Present invention provides a process for preparing halquinol comprising reacting 2-amino-4,6-dichlorophenol with glycerin, sulfuric acid, 2-nitro-4-chlorophenol and acetic acid wherein 2-nitro-4-chlorophenol is taken within the range of 0.7 time to equal weight quantity of 2-amino-4,6-dichlorophenol. The obtained halquinol product contain from 57.0% to 74.0% of 5, 7-dichloro-8-quinolinol and from 23.0% to 40.0% 5-chloro-8-quinolinol.
The quantities of raw materials can be varied depending upon the available reactor size. The reactants can be added in reactor in any sequence. In one embodiment glycerin and 2-amino-4,6-dichlorophenol are added in reactor followed by addition of sulfuric acid slowly under cooling

and then adding 2-nitro-4-chlorophenol and acetic acid. Alternatively, in another embodiment glycerin, 2-amino-4,6-dichlorophenol, 2-nitro-4-chlorophenol are added in reactor followed by addition of acetic acid and then adding sulfuric acid to it. 2-nitro-4-chlorophenol is added 0.7 time to equal weight quantity of 2-amino-4,6-dichlorophenol. After the addition is complete the reaction mixture can then be heated for a sufficient time to complete the reaction, the time being a period of about thirty minutes to two and half hours. Heating at a temperature of about 130° to 150°C is preferable. The time and temperature will vary depending upon the quantities of reactants employed. In case exotherm is observed then heating be interrupted in between and then again continued. The un-reacted 2-nitro-4-chlorophenol may be removed by distillation.
Finally the temperature is lower down and the reaction mass quenched in water, given charcoal treatment and filtered. Halquinol product is isolated at acidic pH range, preferably within pH range of 1.5 to 4 till the maximum precipitation takes place. This precipitate can be further washed with hot water and dried.
The process directly gives the halquinol product and is very simple. No hazardous waste products are produced in this process and the distilled nitrophenol can be collected and reused in the next cycle of reaction. Further economic significance of the process of current invention is it is not necessary to prepare and isolate 8-hydroxyquinoline and then chlorinate it to give Halquinol, thus saving many lengthy steps and chemicals, making the process lucrative. Also, it eliminates the use of sulfuryl chloride making the process safe.
Example 1:
In clean and dry container with short neck distillation setup, charged glycerine (197.5 gm) and 2-amino-4,6-dichlorophenol (100 gm) stirred well at ambient temperature, slowly added sulphuric acid (246.5 gm) at below 70°C and stirred well, further added 2-nitro-4-chlorophenoI (70 gm) at 60°C to 70°C, followed by addition of acetic acid (21.25 gm), reaction mixture was slowly heated at 130°C to 140°C for 2 to 3 hours till the TLC confirmed, cooled to 90°C and quenched in (3.00 liters) of water below 30°C, added sulphuric acid (50gm) stirred for 30 minutes at 25°C to 30°C, further treated with charcoal (5 gm) stirred well and filtered, collected filtrate's pH was

adjusted at 3.7 using 50% caustic lye, washed with plenty of water, filtered and dried to get
Halquinol product.
Yield: 164 gm
Product contains:
5, 7-dichloro-8-quinolinol: 68.06%
5-chloro-8-quinolinol: 31.16%)
Example 2:
In clean and dry container with short neck distillation setup, charged glycerine (197.5 gm), 2-amino-4,6-dichlorophenol (100 gm) and 2-nitro-4-chlorophenol (100 gm) at 30°C, followed by addition of acetic acid (15 gm). Stirred well and heated up to 70°C, slowly added sulphuric acid (246 gm) at 70°C in 1 to 2 hours, after addition reaction mixture was slowly heated at 130°C to 140°C 3 to 4 hours till the TLC confirmed, cooled to 90°C and quenched in (6.00 liters) of water, filtered insoluble, further treated with charcoal (5 gm) stirred well and filtered, collected filtrate pH was adjusted at 1.6 using 50% caustic lye at room temperature filtered and wash with plenty of water filtered and dried to get product. Yield: 168 gm Product contains:
5, 7-dichloro-8-quinolinol: 62.44% 5-chloro-8-quinolinol: 35.86%
Example 3:
In clean and dry container with short neck distillation setup, charged glycerine (274 gm) and 2-amino-4,6-dichlorophenol (139 gm) stirred for 15 minutes, slowly added sulphuric acid (342 gm) in 45 to 60 minutes at temperature below 55°C, stirred for 15 minutes, further added 2-nitro-4-chlorophenol (139 gm) at 40°C to 45°C, followed by addition of acetic acid (24.3 gm) at 40°C to 45°C, reaction mixture was slowly heated at 140°C up to 2 hours till the TLC confirmed, cooled to 80°C and quenched in water (4.5 liters), further treated with charcoal (5 gm) stirred well and filtered, collected filtrate's pH was adjusted at 3.5 using 30% caustic lye at room temperature.

i
After stirring for 30 minutes and ensuring pH 3.5 it was filtered and wash with plenty of water filtered and dried to get product. Yield: 184 gm
Product contains:
5, 7-dichlor'o-8-quinolinol: 65.67 %
5-chloro-8-quinolinol: 33.20%

I CLAIM:
1. A process for preparing halquinol comprising reacting 2-amino-4,6-dichlorophenol with glycerin, sulfuric acid, 2-nitro-4-chlorophenol and acetic acid wherein 2-nitro-4-chlorophenol is taken within the range of 0.7 time to equal weight quantity of 2-amino-4,6-dichlorophenol.
2. The process of claim 1, wherein obtained halquinol contain from 57.0% to 74.0% of 5, 7-dichloro-8-quinolinol and from 23.0% to 40.0% 5-chloro-8-quinolinol.
3. The process of claim 1, wherein glycerin, 2-amino-4,6-dichlorophenol, sulfuric acid, 2-nitro-4-chlorophenol and acetic acid are heated in a reactor at a temperature of about 130° to 150°C.
4. The process of claim 3, wherein heating is at 140°C.
5. A process for preparing halquinol comprising reacting 100 gm 2-amino-4,6-dichlorophenol with 197.5 gm glycerin, 246.5 gm sulfuric acid, 70 gm 2-nitro-4-chlorophenol and 21.25 gm acetic acid within the temperature range of 130° to 140°C.
6. A process for preparing halquinol comprising reacting 100 gm 2-amino-4,6-dichlorophenol with 197.5 gm glycerin, 246 gm sulfuric acid, 100 gm 2-nitro-4-chlorophenol and 15 gm acetic acid within the temperature range of 130° to 140°C.
7. A process for preparing halquinol comprising reacting 139 gm 2-amino-4,6-dichlorophenol with 274 gm glycerin, 342 gm sulfuric acid, 139 gm 2-nitro-4-chlorophenol and 24.3 gm acetic acid at temperature 140°C for two hours.
8. The process of claim 1, 5, 6 and 7, further comprising quenching reaction mass in water, giving charcoal treatment, filtering and then precipitating Halquinol at acidic pH range, preferably within pH range of 1.5 to 4.