DESC:FIELD OF THE INVENTION
The present invention relates to an environment friendly preparation method of 6-Methoxypyridazin-3-Amine compound having the Formula I.

BACKGROUND OF THE INVENTION

6-methoxypyridazin-3-amine is an intermediate in the synthesis of prodrugs or pharmaceutically acceptable salts which are potent inhibitors of tubulin, topoisomerase activities such as topoisomerase II dependent conversion of supercoiled DNA to topoisomers and potent activators of caspase cascade and inducers of apoptosis. These are useful for treating diseases and disorders responsive to induction of apoptosis, inhibition of tubulin and inhibition of topoisomerase II.

The process for preparation of 6-methoxypyridazin-3-amine is disclosed in Maes, Bert et al, Journal of Heterocyclic chemistry 2001, 38 (5), 1215- 1218; Moine, Esperance et al, European Journal of Medicinal chemistry (2015), 105, 80-105;
US 2891953A; US20100069383; WO2009029625; WO2013068458A1; Xin, Lei et al, Guangzhou Huagong (2012), 40(9), 121-122;Zhai, xin et al chemical research in Chinese universities (2006), 22(4), 459-464.
The process disclosed in the prior art has draw backs like low yield, high reaction time and usage of high quantities of ammonia, which results in high cost of production and release of high quantity of effluent.

In view of the above, there is a significant need to develop a novel, economically significant, commercially viable, eco-friendly and robust process for the preparation of 6-methoxypyridazin-3-amine.

SUMMARY OF THE INVENTION

The present invention relates to the novel and cost-effective process for manufacturing of 6 methoxypyridazin-3-amine compound of Formula I with higher yield and purity.

In one embodiment, the present invention provides an environment friendly preparation method for manufacturing of 6 methoxypyridazin-3-amine compound of Formula I,

which comprises;
i. amination of 3,6-dichloropyridazin compound of Formula II in presence of aqueous ammonia and water to give 6-chloropyridazin-3-amine compound of Formula III,

ii. conversion of 6-chloropyridazin-3-amine in presence of sodium methoxide and 1,4-dioxane to give 6-methoxypyridazin-3-amine,

iii. purification of 6-chloropyridazin-3-amine in presence of ethyl acetate to give 6-methoxypyridazin-3-amine compound of Formula I.

In another embodiment, the present invention uses ammonia in the range of 2-3 moles equivalents in step i.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a novel and improved method for manufacturing of 6-methoxypyridazin-3-amine compound of Formula I,

The main embodiment of the current invention provides an environment friendly method for the preparation of 6-methoxypyridazin-3-amine compound of Formula I which is outlined in below scheme.

Step i:
Amination of 3,6-dichloropyridazin compound of Formula II in presence of aqueous ammonia and water to give 6-chloro pyridazin-3-amine compound of Formula III,

The quantity of ammonia used in the reaction is in the range of 2-3 moles equivalents.

The reaction is carried out at temperature range of 90- 130 °C for 10-14 hours; preferably at a temperature in the range of 100- 120 °C for 12 hours.

Step ii:
Conversion of 6-chloropyridazin-3-amine in the presence of sodium methoxide and 1,4- dioxane to give 6-methoxypyridazin-3-amine compound of Formula I.

The reaction is carried out at a temperature range of 80-120 °C for 2-8 hours; preferably at a temperature range of 90-100 °C for 3-6 hours.

Step iii:
purification of 6-methoxypyridazin-3-amine using ethyl acetate to give 6-methoxypyridazin-3-amine compound of Formula I.

Purification of the compound is carried out a temperature range of 70-90 °C. Preferably at a range of 80-85 °C.

EXPERIMENTAL PORTION

The details of the invention are given below in the examples provided below, which are given to illustrate the invention only and therefore should not be constructed to limit the scope of the invention.

Preparation 1: Procedure for the preparation of 6-Chloropyridazin-3-amine

A solution of 3, 6-dichloropyridazin (500 grams, 3.35 mol) and aqueous ammonia (25% conc.) (1360 mL, 9.7 mol) were heated to 120°C for 12 hours in an autoclave. Cooled the mass to 30°C, stirred for 1 hour. Filtered the separated solid and washed with water (250 mL), dried at 65°C for 5 hours to obtain 356.6 grams of 6-chloropyridazin-3-amine (Yield: 82%). Purity by HPLC: 99.6%.
Example 1: Procedure for the preparation of 6-Methoxypyridazin-3-amine
A solution of sodium methoxide (144 grams, 2.66 mol) and 1, 4 dioxane (1000 mL) were stirred at an ambient temperature for 15 minutes, added slowly 6-chloropyridazin-3-amine (100 grams, 0.77 mol). Reaction mixture is heated to 100°C for 5-8 Hrs, filtered the mass at 100°C, and distilled off the filtrate Completely under reduced pressure at below 60°C. Cooled the resultant crude material to ambient temperature, Dichloromethane (400 mL) was added to it, stirred for 15 minutes. Heated the mass to 35-40°C to get clear solution, was added activated carbon (10 grams), stirred for 30 min. Filtered the mass through celite and washed the celite bed with hot Dichloromethane (200 mL). Evaporated the filtrate completely at below 40°C under reduced pressure. To the obtained crude, added Ethyl acetate (200 mL), heated to 75-80°C to get clear solution, was added activated carbon (10 grams), stirred for 30 min. Filtered the mass through celite and washed the celite bed with hot Ethyl acetate (25 mL). and stirred for 60 minutes. Cooled the mass to 5-10°C and stirred for 1hour. Filtered the solid and washed with chilled Ethyl acetate (25 mL), dried the material at 60-65°C for 6-8 hours affords 64.0 grams of 6-methoxypyridazin-3-amine (Yield: 66.25%). Purity by HPLC: 99.9%.

Example 2: Procedure for the preparation of 6-Methoxypyridazin-3-amine
6-chloropyridazin-3-amine (300 grams, 2.315 mol) was added slowly to solution of sodium methoxide (312 grams, 5.77 mol) and 1, 4 dioxane (3000 mL) at an ambient temperature. This mixture was heated to 100 °C for 6 hours, filtered the mass at 100 °C, and distilled off the filtrate completely under reduced pressure at below 60 °C. Ethyl acetate (1800 mL) was added to the resultant crude at ambient temperature, stirred for 10 minutes. This mixture was heated to 85 °C to obtain clear solution, was added activated carbon (30 grams), and stirred for 45 minutes. Separated the carbon using celite filtration and washed the celite bed with Ethyl acetate (300 mL). Concentrated the mass at below 40 °C, added Ethyl acetate (300 mL) and heated to 45 °C and stirred for 45 minutes. This mixture was cooled to 0°C and stirred for 45 minutes. Filtered the solid and washed with chilled Ethyl acetate (75 mL), dried the material at 65 °C for 5 hours to obtain 185.0 grams of 6-methoxypyridazin-3-amine (Yield: 63.83%). Purity by HPLC: 99.7%

The present invention has the following advantages:

1. In present invention less volume of ammonia is used in step i compared to prior art.

2. Usage of less volumes of ammonia make this process
a. Eco friendly because less effluent is generated after completion of the reaction.
b. Cost effective as the process involves usage of less quantity of reagent.

3. The present invention reduces the cost of production of intermediates which in turn reduces the cost of API’s.

4. Water is used as solvent in step i which makes this process economical and ecofriendly.

5. In the present invention 1,4 dioxane is used as solvent in step ii of the process which results in higher yield (62%) compared to the yield reported in prior art US 2891953 A (34%) which used methanol as solvent.

6. In prior art the reaction time in step ii is more than 20 hours. In present invention the reaction time is in the range of 4-6 hours which results in low consumption of energy.
,CLAIMS:We Claim:

1. An environment friendly method for preparation of 6-methoxypyridazin-3-amine compound having Formula I,

which comprises:
i. amination of 3,6-dichloropyridazin compound of formula II,

in presence of aqueous ammonia and a solvent to give 6-chloropyridazin-3- amine compound of formula III;

ii. conversion of 6-chloropyridazin-3-amine in the presence of sodium methoxide and 1,4-dioxane to give 6-methoxypyridazin-3-amine compound of Formula I;

iii. purification of 6-methoxypyridazin-3-aminein ethyl acetate to give 6-methoxypyridazin-3-amine compound of Formula I.

2. The process as claimed in step i of claim 1, wherein the amount of ammonia used in the reaction is in the range of 2-3 mole equivalents.