Description:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Olaquindox of Formula (I)

Formula (I)

BACKGROUND OF THE INVENTION

Olaquindox belongs to a group of quindoxin derived compounds. Olaquindox finds extensive application in cattle breeding, pig husbandry and poultry farming, as a feed additive with antimicrobial and growth-promoting effects. Olaquindox is an important antimalarial drug used to treat malaria. It is said to have significant benefits for promoting growth and is commonly used in the farming industry.

The process for preparation of Olaquindox is disclosed in CN1687038A, CN103242250A and PL127905

The common disadvantages of the above known procedures are that the process can be carried out at an uneconomical and dangerous industrial procedure and require extra equipment and were carried out at an extreme reaction condition as described above.

However, the above methods involve expensive raw materials and lengthy and time taking procedures. In addition, the conventional arts do not focus on increasing yields.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of Olaquindox compound of Formula (I), by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a cost effective process for the preparation of Olaquindox of Formula (I).

Formula (I)

SUMMARY OF THE INVENTION

In one aspect, the present invention is to provide a cost effective, novel and an efficient process for the preparation of Olaquindox of Formula (I);

Formula (I)
In another aspect, the present invention provides a process for the preparation of Olaquindox of Formula (I)

Formula (I)
Wherein the process comprising the steps of:
a)oxidation of compound of Formula IV

Formula (IV)
in presence of sodium hypochlorite and sodium hydroxide to obtain compound of Formula III;

Formula (III)

b)reaction of compound of Formula III with ethyl-3-oxobutanoate in presence of isopropanol and calcium oxide to obtain compound of Formula II;

Formula (II)
c)Amination of compound of Formula II with Calcium oxide and Mono-ethanolamine in methanol to obtain compound of Formula I.

In another aspect, present invention is to provide a process for the preparation of 2-Ethoxycarbonyl-3-methylquinoxaline 1,4-Dioxide compound of Formula II

Formula II
a)oxidation of compound of Formula IV

Formula IV

in presence of sodium hypochlorite and sodium hydroxide to obtain compound of Formula III;

Formula III

b)reaction of compound of Formula III with ethyl-3-oxobutanoate in presence of isopropanol and calcium oxide to obtain compound of Formula II;

DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is advantageous from environmental point of view, economical from time duration point of view, safe from the avoiding the hazardous chemical point of view and advancement in view of good yield
Accordingly, the present invention provides a process for the preparation of Olaquindox of Formula (I).

Formula (I)
The main embodiment of the present invention provides process for the preparation of 2 - [N - (2 -Hydroxy ethyl) carbamoyl]-3-methyl quinoxaline 1,4-Dioxide compound of Formula (I) which is outlined in below mentioned scheme:

In steps a), oxidation of compound of Formula IV in presence of sodium hypochlorite and sodium hydroxide to obtain compound of Formula III;

The reaction is carried out at a temperature range of 10-60 °C for the duration of 19-30 hours. Preferably at a temperature in the range from 15-55 oC for the duration of 22-26 hours.
In step b), reaction of compound of Formula III with ethyl-3-oxobutanoate in presence of isopropanol and calcium oxide to obtain compound of Formula II;

The reaction is carried out at a temperature range of -20-45 °C for the duration of 8-16 hours. Preferably at a temperature in the range from 0-35 oC for the duration of 10-14 hours.
In step c), amination of compound of Formula II with Calcium oxide and Mono-ethanolamine ethanol amine in presence of suitable catalyst in methanol and a solvent to obtain compound of Formula - I.

The reaction is carried out at a temperature range of 25-90 °C for the duration of 1-8 hours. Preferably at a temperature in the range from 40-70 oC for the duration of 3-5 hours.

In another embodiment, the present invention provides process for the preparation of 2-Ethoxycarbonyl-3-methylquinoxaline 1,4-Dioxide compound of Formula (II) which is outlined in below scheme:

In step a), oxidation of compound of Formula IV in presence in presence of sodium hypochlorite and sodium hydroxide to obtain compound of Formula III;
The reaction is carried out at a temperature range of 10-60 °C for the duration of 19-30 hours. Preferably at a temperature in the range from 15-55 oC for the duration of 22-26 hours.
In step b), reaction of compound of Formula III with ethyl-3-oxobutanoate in presence of isopropanol and calcium oxide to obtain compound of Formula II;

The reaction is carried out at a temperature range of -20-45 °C for the duration of 8-16 hours. Preferably at a temperature in the range from 0-35 oC for the duration of 10-14 hours.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1: Process for the preparation of Benzofurazan-N-oxide (III)

A mixture of sodium hydroxide (140.4 grams, 3.51 mol) and water 500 mL was stirred until the Solid had dissolved. The solution was cooled to 30°C, and 250 grams of PEG-6000 was added into above solution at 25-30°C. Charge 2-Nitro-aniline (500 grams, 3.619 moles) into above solution at 25-30 °C, added slowly sodium hypochlorite solution at 25-40°C and maintain for 24 hours at 25-45 °C. reaction solution becomes light yellow suspension, and TLC tracks to reaction and finishes; Suction filtration; Filter cake wash with water (250 mL) and dried at 35-40°C pale yellow crystals is being Benzofurazan N-Oxide 463 grams. The crude proceeded for the next stage without purification.
Yield: 93.97%.

Example 2: Process for the preparation of 2-Ethoxycarbonyl-3-methylquinoxaline 1,4-Dioxide (II)
A mixture of benzofurazan N- oxide (500 g, 3.673 mol) and calcium oxide (17.5 grams, 0.312 moles) in 1000 mL isopropyl alcohol was stirred at 0-25 °C, add Ethyl acetoacetate (500 grams, 3.842 moles) was added to the solution and the mixture stirred for 12 hours at 0-25°C., a yellow precipitate, which was collected by filtration, washed with chilled isopropyl alcohol (250 mL) and dried at 50-55 °C afforded compound is 2-Ethoxycarbonyl-3-methylquinoxaline 1,4-Dioxide.
Yield: 750 grams (82.2%)

Example 3: Process for the preparation of 2 - [N - (2 - Hydroxy ethyl) carbamoyl]-3-methyl quinoxaline 1,4-Dioxide (I)
A mixture of 2-Ethoxycarbonyl-3-methylquinoxaline 1,4-Dioxide (500 g,2.0142 mol), Mono Ethanol amine (135.33 grams, 2.215 moles) and calcium oxide (13.55g, 0.2416moles) in 1000 mL methanol was stirred at 50-60 °C for 4hours, greenish yellow precipitate , which was collected by filtration, washed with methanol (250 mL) and dried at 55-60°C afforded compound is 2 - [N - (2 - Hydroxy ethyl ) carbamoyl]-3-methyl quinoxaline 1,4-Dioxide Yield: 460 grams (86.89 %).

Advantages of the present invention:
1.The present invention involves usage of pEG600 reagent was employed in stage-1 in a catalytic amount in place of the solvent that was used in stage 1.

2.The present invention has excellent reaction progress and maximum yield, when compared with prior art references wherein, calcium hydroxide is used in stage-2.

3.The present invention use of Calcium oxide & Mono-ethanolamine this combination showed good reaction progress and maximum yield when compared to Ethanolamine and Calcium chloride as reported literature.
, Claims:1.An improved process for the preparation of Olaquindox of Formula -I

Formula I
Which comprises:
a) Oxidation of compound of Formula IV

Formula IV

in presence of sodium hypochlorite and sodium hydroxide to obtain compound of Formula III;

Formula III

b) reaction of compound of Formula III with ethyl-3-oxobutanoate in presence of isopropanol and calcium oxide to obtain compound of Formula II;

Formula II
c) amination of compound of Formula II with Calcium oxide and Mono-ethanolamine in methanol to obtain compound of Formula I.