FIELD OF THE INVENTION

The present invention provides a process for the preparation of norsteroids. In particular, the present invention provides a process for the preparation of 19-norsteroids.

BACKGROUND OF THE INVENTION

Norsteroids are pharmacologically active compounds or important intermediate for pharmacologically active compounds. These have been known as xenobiotics with androgenic and anabolic properties and obligatory endogenous intermediates in the biosynthesis of estrogens from androgens in all species, including mammals.

Norsteroids have been found to exhibit potent progestational activities, antiestrogenic activities, and estrogenic responses in the estrogen-deficient state. Besides, depending on the specific compound produced, there are several other effects also associated with that compound such as pregnancy-maintenance, anti-estrogenic, ovulation- suppressing, androgenic and anti-androgenic activities.

Accordingly, processes for producing norsteroids compounds are of immense interest and various methods have been disclosed in the prior arts for preparation of Norsteroids and specific compounds thereof such as 19-norsteroids and more particularly 19-norethisterone.

For instance, US 2774777 discloses a process wherein, the starting material, 19-Norandrostene- 3, 17-dione is first protected with ethyl orthoformate to form enol-ether at the C-3 position as intermediate. Then, this intermediate is purified through solvent purification. Further base mediated acetylene is introduced at C-17 position followed by deprotection at the C-3 position. To obtain the final product, multiple purifications with ethyl acetate are conducted. The disadvantage of this process is protection at C-3, then deprotection in the last stage and multiple purifications at each stage to get the pure product with low yield. Therefore, due to multiple steps process with multiple purification steps and also low yield, this process is not commercially viable.

US 2744122 discloses a process wherein A— 19-nor-androsten-17p-ol-3-one compound, a lower alkyl ether of estrone with an alkali metal in liquid ammonia followed by hydrolysis with a mineral acid and oxidation with chromic acid to form A -19-norandrosten-3, 17-dione, selectively forming a 3-enol ether of said dione and treating said ether with acetylene in the presence of an alkali metal alkoxide, followed by hydrolysis with a mineral acid. Therefore, due to multiple steps process and also low yield, this process is not commercially viable.

US3655649 discloses a process wherein 9-hydroxy-3-keto-A-steroid is reacted with a secondary amine to form the corresponding 19-nor-3, 5-diene-3-amine. In this process, C-3 keto group is protected through secondary amine and column chromatography is used for purification which makes the process is more complex and commercially not viable.

Therefore, the commercial production and purification of 19-norethisterone have heretofore been accomplished by a relatively complicated process comprising multiple steps and complex purification followed by filtration and repeated crystallization. Further, the recovery of pure product attained according to these processes is very low and not suited for the processing of large amounts of 19-norethisterone with high yields.

Hence, there is a need to prepare 19-norethisterone by a process which leads to the production of 19-norethisterone with high yield and high purity which is simple, economical, user- friendly and commercially viable.

OBJECT OF THE TNVRNTTON

An object of the present invention is to provide a process for the preparation of 19- Norethisterone of Formula-I that addresses one or more deficiencies mentioned in the prior art documents.

SUMMARY OF THE TNVENTTON

Accordingly, the present invention provides a one-pot process for the preparation of 19- Norethisterone of Formula-I with high yield and high purity. The one-pot process is simple, economical, user-friendly and commercially viable.

Formula-I: In a non-limiting embodiment of the invention, the process for the preparation of 19- Norethisterone of Formula-I comprises the step of:

(i) reacting 19-Norandostene-3,17-dione of Formula-II with a solution comprising a metal acetylide and an acid to obtain 19- Norethisterone of Formula-I; and

(ii) purifying the 19- Norethisterone of Formula-I thus obtained by refluxing and subsequently washing with an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a single pot process for the preparation of 19- Norethisterone of Formula-I, comprising the ste s of:

Formula-I

(i) reacting 19-Norandostene-3,17-dione of Formula-II with a solution comprising a metal acetylide and an acid to obtain 19- Norethisterone of Formula-I; and

(ii) purifying the 19- Norethisterone of Formula-I thus obtained by refluxing and subsequently washing with an organic solvent.

The process of the present invention may be suitably started from the compound of formula II, known by its IUPAC name (8R,9S,10R,13S,14S)-13-methyl-l,2,6,7,8,9,10,l 1,12,13, 14,15,16- dodecahydro-lH-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione and hereinafter referred to as 19-Norandrostenedione (formula II) and leads to formation of 19 -Norethisterone of Formula-I known by its IUPAC name (8R,9S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl- 6,7,8,9,10,11,12, 14, 15, 16-dodecahydro-lH-cyclopenta[a]phenanthren-3(2H)-one.

In the present invention a solution comprising 19-Norandrostenedione of Formula II may be contacted with the solution comprising metal acetylide at temperature not exceeding 5°C, preferably between -5°C to 5°C, more preferably 0°C + 2°C, and most preferably 0°C + 1°C, to get a first stage reaction solution comprising 19-Norethisterone of Formula I and free metal.

In a non-limiting embodiment of the invention, the solution of 19-Norandrostenedione of Formula II comprises a solvent selected from a group consisting of tetrahydrofuran (THF), toluene, and dioxane; with tetrahydrofuran being the preferred choice.

In another non-limiting embodiment, the solution comprising metal acetylide is obtained by dissolving the metal acetylide in a solvent selected from a group consisting of tetrahydrofuran, toluene, and dioxane; with tetrahydrofuran being the preferred choice.

In a further non-limiting embodiment, the solution comprising metal acetylide is obtained by in- situ reaction of the first base with an acetylene yielding stream.

In a further non-limiting embodiment, the first base is taken in form of a solution comprising a solvent selected from a group consisting of tetrahydrofuran, toluene and dioxane; with tetrahydrofuran being the preferred choice; and the first base is selected from the group consisting of potassium t-butoxide, potassium hydroxide, lithium hydroxide, sodium t-butoxide and sodium hydroxide; with potassium t-butoxide being the preferred choice.

In a further non-limiting embodiment, the acetylene yielding stream is acetylene. In an embodiment of the invention, the method further comprising adding an acetylene yielding stream to the first stage reaction solution to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19-Norandrostenedione to form 19- norethisterone of Formula-I.

In an embodiment of the invention, the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added.

Thereafter, an acid is added to the first stage reaction solution to obtain a second stage reaction solution. The acid is added to the first stage reaction solution at a temperature of not exceeding 20°C, preferably between 10°C to 20°C, more preferably 15°C + 3°C, and most preferably 15°C + 1°C. The temperature of the second stage reaction solution is increased to a temperature not exceeding 45°C, preferably between 35°C to 45°C, more preferably 40°C + 2°C, and most preferably 40°C + 1°C.

In a non-limiting embodiment, the acid is selected from a group consisting of hydrochloric acid, acetic acid, and trifluoro acetic acid. Preferably, hydrochloric acid is the acid.

The extraction of 19-Norethisterone of Formula I is done from the second stage reaction solution by use of an organic solvent selected from the group consisting of methyl isobutyl ketone, dichloromethane (DCM), ethyl acetate and toluene. Preferably, the organic solvent is preferably methyl isobutyl ketone. While extracting 19-Norethisterone of Formula I from the second stage reaction solution, a pH value of mother liquor (that comprises the second stage reaction solution and the organic solvent) is maintained between 6 and 7. For the purposes of maintaining the pH of the mother liquor, a second base may be used. By way of non-limiting example, the second base may be selected from a group consisting of sodium bicarbonate, potassium bicarbonate, potassium carbonate and sodium carbonate. Preferably, sodium bicarbonate is the second base.

In an embodiment of the invention, wherein in step (ii), the purification of 19- Norethisterone of Formula-I is performed in presence of an organic solvent selected from a group consisting of methanol, ethanol and isopropanol; with methanol being the preferred organic solvent. The compound of formula I may be used as important starting material/ intermediate for the synthesis of active materials.

The compound of formula I may be optionally purified to obtain a pure compound. Such purification may be done by means of refluxing and subsequently washing with alcohol.

In an embodiment of the present invention, single pot process for the preparation of 19- norethisterone of Formula-I comprises of:

(i) reacting 19-Norandostene-3,17-dione of Formula-II with potassium t-butoxide, acetylene gas/solution and Hydrochloric acid to obtain a reaction solution comprising 19- norethisterone of Formula-I;

Formula-II Formula-I

(ii) adding methyl isobutyl ketone to the reaction solution of (i) for extraction of 19- norethisterone of Formula-I from the reaction solution; and

(iii) optionally, purifying 19-norethisterone of Formula-I by refluxing and subsequently washing with an alcohol.

In another embodiment of the present invention, the process for the preparation of 19- Norethisterone of Formula-I comprises of sequential steps of:

(i) adding the first base to a solvent to obtain a solution;

(ii) cooling the solution of (i) to a temperature not exceeding 5°C;

(iii) adding an acetylene yielding stream to the solution of step (ii) to form metal acetylide therein;

(iv) adding 19-Norandrostenedione to the solution of step (iii) while maintaining the temperature at not more than 5°C such that 19-Norandrostenedione reacts with the metal acetylide to form 19-norethisterone of Formula-I and free metal;

(v) adding an acetylene yielding stream to the solution of step (iv) to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19- Norandrostenedione to form 19-norethisterone of Formula-I, the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added;

(vi) gradually adding acid to a solution of step (v) and raising the temperature to not more than 45°C;

(vii) adding an organic solvent to a solution of step (vi), stir and separate an organic layer thus formed; and

(viii) filtration of the organic layer to obtain a compound of Formula I.

In another embodiment of the present invention, the process for the preparation of 19- Norethisterone of Formula- 1 comprises of sequential steps of:

(i) adding 19-Norandrostenedione to a solution comprising a metal acetylide while maintaining the temperature at not more than 5°C such that 19-Norandrostenedione reacts with the metal acetylide to form 19-norethisterone of Formula-I and free metal;

(ii) adding an acetylene yielding stream to the solution of step (i) to convert the free metal thus formed to further metal acetylide, wherein the further metal acetylide reacts with 19- Norandrostenedione to form 19-norethisterone of Formula-I, the addition of acetylene yielding stream is carried out until 19-Norandrostenedione gets depleted to at least 50%, preferably gets depleted to at least 75%, more preferably gets depleted to at least 90%, most preferably gets depleted to at least 99.5% of the original amount added;

(iii) gradually adding acid to a solution of step (ii) and raising the temperature to not more than 45°C;

(iv) adding an organic solvent to a solution of step (iii), stir and separate an organic layer thus formed; and

(v) filtration of the organic layer to obtain a compound of Formula I.

It can be observed can be observed that when metal acetylide reacts with 19-Norandrostenedione, it produces the compound of formula I and free metal. Thus, over a period of time, the amount of metal acetylide available reduces and the amount of free metal increases. Because of the addition of the acetylene yielding stream at the intermediate stage, the free metal gets converted to metal acetylide. Thus, addition of the acetylene yielding stream at the intermediate stage results in increasing the amount of metal acetylide available for reaction with 19-Norandrostenedione for the production of the compound of formula I. Thus, if the process uses metal acetylide as a starting material, the amount of metal acetylide needed can be substantially lesser than the stoichimetric amount needed for conversion of 19-Norandrostenedione to the compound of formula I. Likewise, if the process uses first base as a starting material (for the in-situ production of metal acetylide), the amount of the first base needed can be substantially lesser than the stoichiometric ratio needed for conversion of 19-Norandrostenedione to the compound of formula I.

Advantages of the present invention:

1. The process of the present invention is single pot and avoids multiple steps.

2. The process of the present invention involves th e use of economic and environment- friendly reagents that will give highly pure material and cost-effective process.

3. The process of the present invention leads to the synthesis of product with high yield and high purity.

4. The process yields the final product which can be used as important starting material/intermediate for other active material.

The invention will be further illustrated by non-limiting examples.

Example-1: Process for the preparation of Norethisterone of Formula-1

Charge 170L of tetrahydro furan (17.0 volume), 15.0kg of potassium-t-butoxide(133.68mol) in SS Reactor under nitrogen atmosphere, cool to 0°C(+5°C), start acetylene gas purging and continue for 105min.(+5min.), add 19-Norandrostenedione solution ((10kg.l9-Nor [36.7 lmol])) in 50L of THF(5 volume)at same temperature, continue acetylene gas purging for 105min.(+5min.).

In-process check by TLC, 19-Norandrostenedione should be less than 0.50%, added 10L of purified water at 5°C+ (5°C), added 30L of hydrochloric acid at 15°C+ (5°C), raised the temperature up to 40°C+ (5°C), stir for 30min., added 100L of methyl isobutyl ketone (10 volume) and 100L of purified water(10 volume), stir and separate organic layer. Organic layer is wash with 10% sodium bicarbonate aqueous solution (2.0kg in 18L of purified water), check pH, should be 6-7, added carbon and filter through hyflow bed, collect the filtrate in a SS Reactor and distilled under vacuum till thick mass, cool to 20°C+ (2°C), stir for 12 hours at 20°C+ (2°C), filter and wash with 10L of methyl isobutyl ketone. Wet material is dry at 65°C (+5°C) till moisture content less than 0.50%. This example provides a compound of Formula-I with Yield=9.0kg (82.15%) and HPLC Purity=98.00%

Purification

Charge 27.0L of methanol (3.0 volume), 9.0kg of Norethi sterone crude (30.16mol) in SS-Reactor, heated to reflux and reflux for 60min.(+10min.), cool to 20°C(+2°C), stir for 06hrs (+30min.) at the same temperature, filter and wash with 5.0L of methanol. Wet material is dry at 65° (±5°c) till moisture content less than 0.50%. This example provides a compound of Formula- 1 with Yield=8.50kg and HPLC Purity=99.8%.