DESC:FIELD OF THE INVENTION:
The present invention relates to process for the purification of norethindrone acetate.
BACKGROUND OF THE INVENTION:
Norethindrone (I) and norethindrone acetate (II) 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 acetate respectively. These are used alone or in combination with ethinyl estradiol as oral contraceptives.

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 2,964,537 describes purification of norethindrone acetate using the mixture of dichloromethane-hexane solvent.
The patent US 3,408,371 describes crystallization of norethindrone acetate from various 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 for the purification of norethindrone acetate (II) from organic solvents or mixture of organic solvents.
DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment there is provided a process for purification of Norethindrone acetate comprising column chromatography using organic solvent or a mixture of organic solvents.
The solvents used for the purification are selected from the group comprising of alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and chlorinated solvents such as dichloromethane, dichloromethane, carbon tetrachloride etc; the most preferred combination of solvents is toluene-ethyl acetate, toluene-dichloromethane or mixtures thereof. The most preferred single organic solvent is toluene.
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:
Preparation of Norethindrone Acetate
Norethindrone (40 g) was added to toluene (480 ml) containing acetic anhydride (320 ml) at 20-30 ºC. To the reaction mass, 4-dimethylamino pyridine (3.27 gm) was added, heated to 50-60 ºC then stirred. After completion of the reaction water (1000 ml) was added and stirred. The organic layer was separated and aqueous layer was extracted with toluene (80 ml). The organic layers were combined then pH adjusted to 5.8 using 5% NaOH. The organic layer was subjected to column chromatography and was eluted with 10% ethyl acetate in toluene. The elute containing the product were concentrated and n-heptane (200 ml) was added and concentrated. The resulting slurry was cooled to 0-5 ºC, stirred, filtered and washed with n-heptane. Yield: 38.15 g (wet cake).
EXAMPLE 2:
Purification of Norethindrone Acetate from ethyl acetate-toluene (1:9):
Norethindrone (20 g) was added to toluene (480 ml) containing acetic anhydride (120 ml) at 20-30 ºC. To the reaction mass, 4-dimethylamino pyridine (1.63 gm) was added, heated to 50-60 ºC then stirred. After completion of the reaction water (1000 ml) was added and stirred. The organic layer was separated and aqueous layer was extracted with toluene (80 ml). The organic layers were combined then pH adjusted to 5.8 using 5% NaOH. The organic layer was subjected to column chromatography and was eluted with 10% ethyl acetate in toluene. The elute containing the product were concentrated and ethyl acetate (5 ml) was added followed by addition of n-heptane (40 ml) and concentrated. The resulting slurry was cooled to 0-5 ºC, stirred, filtered and washed with n-heptane. Yield: 99.83 g (wet cake).
EXAMPLE 3:
Purification of Norethindrone Acetate from toluene :
Norethindrone (20 g) was added to toluene (480 ml) containing acetic anhydride (120 ml) at 20-30 ºC. To the reaction mass, 4-dimethylamino pyridine (1.63 gm) was added, heated to 50-60 ºC then stirred. After completion of the reaction water (500 ml) was added and stirred. The organic layer was separated and aqueous layer was extracted with toluene (40 ml). The organic layers were combined then pH adjusted to 5.8 using 5% NaOH. The organic layer was subjected to column chromatography and was eluted with toluene. The elute containing the product were concentrated and n-heptane (40 ml) was added and concentrated. The resulting slurry was cooled to 0-5 ºC, stirred, filtered and washed with n-heptane. Yield: 17 g (wet cake).
EXAMPLE 4:
Purification of Norethindrone Acetate from dichloromethane-toluene (1:9):
Norethindrone (20 g) was added to toluene (480 ml) containing acetic anhydride (120 ml) at 20-30 ºC. To the reaction mass, 4-dimethylamino pyridine (1.63 gm) was added, heated to 50-60 ºC then stirred. After completion of the reaction water (500 ml) was added and stirred. The organic layer was separated and aqueous layer was extracted with toluene (40 ml). The organic layers were combined then pH adjusted to 5.8 using 5% NaOH. The organic layer was subjected to column chromatography and was eluted with 10% dichloromethane in toluene. The elute containing the product were concentrated and n-heptane (100 ml) was added and concentrated. The resulting slurry was cooled to 0-5 ºC, stirred, filtered and washed with n-heptane. Yield: 18 g (wet cake).
Example 5: Preparation of Pure Norethindrone Acetate without column chromatography purification.
A mixture of Norethindrone (20 gm), acetic anhydride (120 ml) and 4-dimethylaminopyridine (1.63 g) in toluene (480 ml) was heated to 50-60°C. The reaction mixture was stirred at 50-60°C for 6 hrs. After completion of reaction, reaction mass was quenched with water (500 ml) and stirred for 1.5 hours at 25-30°C. The two layers were separated and aqueous layer was extracted with toluene (40 ml). Water (100 ml) was added to the combined organic layer and pH was adjusted to 6.0 with 5% sodium hydroxide solution. The two layers were separated and organic layer was washed with water (100 ml). The organic layer was treated with 2x 60 g of basic alumina in round bottom flask and filtered. The filtrate was concentrated. Heptane (100 ml) was then added into residue and concentrated up to 90 mL residual volume. The suspension was cooled to 0-5°C and stirred for 1 hour at 0-5°C. The solid was filtered and washed the with 2x30 mL of n-heptane. The white solid obtained was dried. Yield : 20 gm.
,CLAIMS:1) A process for purification of norethindrone acetate comprising using organic solvent or a mixture of organic solvents.
2) The process according to claim 1, wherein purification is done using a column chromatography.
3) The process according to claim 1, wherein solvents used for the purification are selected from the group comprising of alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and chlorinated solvents such as dichloromethane, dichloromethane, carbon tetrachloride or mixtures thereof.
4) The process according to claim 3, where in the most preferred solvent mixture is toluene-ethyl acetate and toluene-dichloromethane.
5) The process according to claim 1, wherein the purity the purity of norethindrone acetate is greater than 99%.