FIELD OF THE INVENTION: The present invention relates to process for the purification of norethindrone and norethindroneacetate.

BACKGROUND OF THE INVENTION:

Norethindrone (I) and norethindrone acetate (Il)are first-generation progestin, chemically known as 17-hydroxy-19-nor-17a-pregn-4-en-20-yn-3-one and 17-hydroxy-19-nor-17a- pregn-4-en-20-yn-3-one acetaterespectively. These are used alone or in combination with ethinylestradiolasoral contraceptives.

(I) (Π)

The methods for the purification of norethindrone and norethindrone acetate in the prior art documents are discussed below.

The patent US 2,744, 122 describes purification of norethindrone by recrystallization from ethyl acetate.

Another patent US 3,759,961 describes crystallisation of norethindrone from acetone.

The patent US 2,964,537describespurification of norethindrone acetate using the mixture of dichloromethane-hexane solvent.

The patent US 3,408, 371describescrystallization of norethindrone acetate from solvents such as ethyl acetate and dichloromethane. The patent US 3,409,643 describes purification of norethindrone acetate from methanol containing a drop of pyridine.

SUMMARY OF THE INVENTION:

The present invention provides a process forthe purification of norethindrone (I) from mixture of dimethyl formamide-water. The present invention further provides two processes for purification of norethindrone acetate (II):

Process A: It involves purification from mixture of dichloromethane- n-heptane and

Process B : It involves purification from mixture of methanol-water.

DETAILED DESCRIPTION OF THE INVENTION: In one embodiment there is provided a process for the purification of norethindrone comprising; i) dissolution of norethindrone in dimethyl formamide by heating, ii) addition of water, iii) cooling, and iv) isolation.

Norethindrone is dissolved in dimethyl formamide by heating at reflux temperature, preferably 55-60 °C.

Slurry obtained after addition of water cooled to -10 to 30 °C, preferably 20-25°C.

The ratio of dimethyl formamide-water isl: 100 to 100: 1, preferably 20: 1 to 1 :20, more preferably 10:1 to 5: 1 (volume/volume).

The quantity of dimethyl formamide-water with respect to norethindrone (I) is 1-20 times (weight/volume) preferably 5-10 times (weight/volume).

The purity of norethindrone (I) obtained by the present invention is greater than 99%. In another embodiment there is provided two processes for purification of norethindrone acetate (II):

Process A: Process for the purification of norethindrone acetate (II) comprising a) stirring of norethindrone acetate in dichloromethane, b) addition of n-heptane, c) cooling, and d) isolation.

The solvent n-heptane addedto norethindrone acetate in dichloromethane at 10-40 °C, preferably 20-30 °C. Slurry obtained after addition of n-heptane cooled to -20 to 15 °C, preferably 0-5 °C.

The ratio of dichloromethane and n-heptane is 1 : 10 to 10: 1, preferably 1:5 to 5:1 (volume/volume) .

The quantity of dichloromethane and n-heptane with respect to norethindrone acetate (II) is 1-10 times (weight/volume) preferably 2-5 times (weight/volume) Process B: Process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in mixture of ethanol-water and b) isolation.

Stirring of norethindrone acetate in mixture of ethanol-water mixture is carried out in the temperature range of 10-70 °C, preferably 20-50 °C, more preferably 30-35 °C. Norethindrone acetate in ethanol-water mixture is stirred for 30 minutes to 10 hours, preferably 1-5 hours, more preferably 1-2 hours.

The ratio of ethanol-water is 1 : 10 to 10: 1, preferably 1: 1 to 1 :4 (volume/volume).

The purity of norethindrone acetate (II) obtained by the purification process of present invention is greater than 99%. The pure compounds according to the present invention can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.

The products dried using different techniques of drying like tray trying and rotatory drying techniques with or without application of vacuum and/or under inert condition. The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

EXAMPLE 1:

Purification of Norethindrone:

Norethindrone (4.5 g)was added to dimethyl formamide (27 ml) at 25-30 °C. The slurry was heated to 55-60 °C. To the solution water (23.5 ml) was added and stirred for 45 minutes at 55-60°C. The slurry cooled to 20-25°C and stirred for 3 hrs. Filtered, washed with water and dried under vacuum. HPLC Purity :99.01

EXAMPLE 2:

Preparation of Norethindrone Acetate Norethindrone (50 g) was added to toluene (1.55 litres) containing acetic anhydride (400 ml) at 20-30 °C. To the reaction mass, 4-dimethylamino pyridine (4 g)was added,heated to 80-90°C then stirred for 3 hours and cooled to 10-25 °C then water (1.25 litres) was added. The reaction mass further cooled to 10-15°C then pH adjusted to 5.5 to 6.5 using 5% NaOH. The organic layer was separated and cyclohexane (500 ml) was added to it. The product was chromatographed on 300 g of alumina column and eluted with toluene/cyclohexane mixture. The elute containing the product were concentrated and passed through 0.45 micron membrane filter then n-heptane (250 ml) was added. The resulting slurry was cooled to 0-5°C, stirred, filtered and washed with n-heptane. Yield: 31 g (wet cake). Purification of Norethindrone Acetate from dichloromethane- n-heptane:

Crude norethindrone acetate (31 g) obtained above was added to dichloromethane (250 ml) at 20-30 °C. To the solution, n-heptane (100 ml) was added, stirring continued at 20- 30 °Cfor 1 ½ hour and cooled to 0-5°C. Filtered it. Purification of Norethindrone Acetate from ethanol-water:

The wet solid obtained from dichloromethane-n-heptane was stirred in mixture of ethanol (125 ml) and water (225 ml)at 30-35 °C for an hour. Solid filtered, washed with water and dried. Yield: 19.5 g. HPLCPurity:99.86

Second crop (8.5 g) was obtained from filtrate by cooling to 0-5 °C.