The present invention provides a process for preparation of gonadotropin releasing hormone antagonist, elagolix and its intermediates. The invention further relates to amorphous elagolix sodium with low residual solvent content and process for its preparation.
BACKGROUND OF THE INVENTION
Elagolix is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino] butanoic acid. It is approved by USFDA as elagolix sodium, represented as Formula I, for the treatment of pain associated with endometriosis and is under development for the treatment of uterine leiomyoma.

Formula I
U.S. Patent No. 7,056,927 B2 discloses elagolix, its salts and a process for preparation of elagolix sodium salt as given below in Scheme-I:

Scheme 1

The disclosed process for the preparation of elagolix and then elagolix sodium has many disadvantages such as isolation of intermediates using column chromatography which is highly infeasible on industrial scale. The reported process have low yield and more number of impurities in the intermediates which subsequently requires more purifications, which are usually carried out using column chromatography. The process used hazardous solvents/reagents like trifluoroacetic acid and lacked the identification of control/removal of impurities leading to low purity and yield. The final product elagolix sodium is subjected to lyophlilization process which is again highly unsuitable for large scale preparations.
U.S. Patent No. 8,765,948 B2 describes a process for preparation of elagolix sodium in example-1 and 4 as given below Scheme-II:

Scheme II
Further, the U.S. Patent No. 8,765,948 B2 discloses an alternate process for the preparation of compound of formula (1e) as mentioned below Scheme-III:

Scheme III

The disclosed process for the preparation of elagolix involves use of chloroformate which is not preferred for use at large scale application due to its toxic nature. Further, the disclosed process involves use of organic amines which are a source of genotoxic impurities in elagolix, which would attract purification of intermediates and elagolix. The multiple purifications not only generate effluents but also are uneconomical for large scale application.

IN201821030524 discloses a process for the preparation of elagolix as given in Scheme-IV:

Scheme IV
The disclosed process discloses use of acid addition salts of intermediates which implies that the disclosed process provides intermediates which require purification, adding more steps to the process and thus increasing energy consumption and cycle time that makes the process unsuitable for large scale production.
WO2020023459 discloses a process for the preparation of elagolix and its salts, wherein the process provides elagolix in high purity with less than 3 percent of specific impurities. The process disclosed used salicylic acid salts of intermediates of formula 2 and another urea derivative salt of formula 6a, to purify the intermediates and thereby achieve the desired purity of elagolix and its salts thereof. The disclosed process involving salt formation to achieve the purification increases the process steps and also the cycle time of the whole process, which makes the process not favorable for industrial application.

Formula 2

Formula 6a
A process providing an active pharmaceutical ingredient should always have the attributes of being simple, efficient in terms of yield, robust, short cycle time, lesser number of steps, use of greener solvents/reagents, and should always provide control on formation of impurities/efficient removal of impurities so as to form the compound with desired purity and characteristics defined by ICH guidelines or by other regulatory authorities. Elagolix in its sodium salt form is generally used in its amorphous form, thus it has its own challenges of purification at final stage, thus it is highly desirable for the process to have capacity to control impurities to not only give the compound in high purity but also provide the desired morph with stability.

The processes disclosed in prior art fail to contain all the attributes listed above for preparation of elagolix sodium with desirable properties. Consequently, there is a need for an improved process for the preparation of elagolix sodium, which not only overcomes the problems in the prior art processes as mentioned above, but also is environment friendly, economically viable and industrially feasible for the preparation of elagolix sodium.

OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide an improved process for the preparation of elagolix sodium.
It is yet another object of the present invention to provide intermediates of elagolix of Formula III, IV and VI as solid in crystalline or amorphous form.
It is yet another object of the present invention to provide a process for the preparation of elagolix and salts thereof involving use of solid intermediates in crystalline or amorphous form.
It is another object of the present invention to provide a simple, economic and efficient process for the preparation of elagolix and salts thereof with control on formation of impurities including genotoxic impurities.
It is yet another object of the present invention to provide a process for the preparation of stable amorphous elagolix sodium with low residual solvent.
In one embodiment, the present invention relates to compound of Formula III in solid form.

Formula III
In another embodiment, the present invention also relates to a process for the preparation of elagolix sodium using compound of Formula III in solid form.
In one embodiment, the present invention relates to compound of formula IV in solid form.

Formula IV
In another embodiment, the present invention also relates to a process for the preparation of elagolix sodium using compound of Formula IV in solid form.
In yet another embodiment, the present invention relates to compound of formula VI in solid form.

Formula VI
In another embodiment, the present invention also relates to a process for the preparation of elagolix sodium using compound of Formula VI in solid form.
In yet another embodiment, the present invention relates to a process for the preparation of elagolix sodium of Formula I,

Formula I
wherein the process is comprising the steps of:
(i) reacting compound of Formula II with D-BHG to obtain compound of Formula III,

Formula II D-BHG Formula III

(ii) reacting compound of Formula III with 3-MFB to obtain compound of Formula IV with not more than 1.0% of impurity

3-MFB Formula IV
(iii) de-protecting compound of Formula IV to obtain compound of Formula V,

Formula V
(iv) N-alkylation of compound of Formula V using ethyl 4-bromobutanoate to obtain compound of Formula VI,

Formula VI
(v) hydrolysis of compound of Formula VI to obtain elagolix, and
(vi) preparing elagolix sodium.
In yet another embodiment, the present invention relates to a process for the preparation of elagolix sodium of Formula I with low residual solvent wherein the process comprises of drying elagolix sodium in controlled humidity conditions.
DESCRIPTION OF DRAWINGS
Figure 1: X-ray diffraction pattern of compound of Formula III obtained as per present invention
Figure 2: X-ray diffraction pattern of compound of Formula IV obtained as per present invention
Figure 3: X-ray diffraction pattern of compound of Formula VI obtained as per present invention
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
While preparing an active pharmaceutical ingredient meant for human consumption, the purity is the foremost criteria followed by economics of the manufacturing process. The process is efficient at all levels if it can primarily control the formation of impurities at all steps, which not only provides intermediates with higher purity, but also provides a highly pure final compound. The control on formation of impurities also have additional benefits, firstly, the intermediates and the final compound would then require lesser purification, which highly reduce the operations, cycle time, energy consumption and effluent generation, Secondly, the control on formation of impurities allows the compounds to crystallize as solid due to higher purity. The isolation of intermediates as solid provides robustness to the process and also makes the operational handling much easier. Thus, in an attempt to provide a manufacturing process eliminating the limitations of prior art, the inventors of present invention devised the process for the preparation of elagolix sodium with high purity, having control on formation of impurities and preparing intermediates as solid.
The present invention relates to compound of Formula III in solid form.

Formula III
In one embodiment, the compound of Formula III is in crystalline form and has an X-ray powder diffraction pattern comprising one or more peaks at ±0.2 of 7.3, 14.4, 17.0, 17.8, 20.9, 22.1, 22.4, 23.8 and 28.4 °2?, as given in Figure 1.
The present invention also relates to a process for the preparation of elagolix sodium using compound of Formula III in solid form.
The present invention relates to compound of formula IV in solid form.

Formula IV
In one embodiment, the compound of Formula IV is in crystalline form and has an X-ray powder diffraction pattern comprising one or more peaks at ±0.2 of 9.0, 10.3, 11.9, 12.1, 12.4, 14.7, 17.0, 19.3, 21.0, 21.1, 21.8, 22.5, 24.3, 24.8 and 26.4 °2?, as given in Figure 2.
The present invention also relates to a process for the preparation of elagolix sodium using compound of Formula IV in solid form.
The present invention relates to compound of formula VI in solid form.

Formula VI
In one embodiment, the compound of Formula VI is in amorphous form, as given in Figure 3.
The present invention also relates to a process for the preparation of elagolix sodium using compound of Formula VI in solid form.
The present invention relates to a process for the preparation of elagolix sodium as depicted in the following Scheme V:

Scheme V
The process described herein provide simple and efficient process with manufacturability to obtain elagolix and salts thereof, wherein the inventors have identified that control on formation of impurity is important at all steps, but the purity of intermediate of Formula IV is of utmost importance as its purity directly governs the purity of final compound. Thus, the conditions/reagents/solvents used for the preparation of compound of Formula IV are keenly devised to control on formation of desbromo impurity-C thus providing compound of Formula IV having not less than 99% purity, which eventually leads to the high purity of elagolix sodium.
In one embodiment, the process of present invention provides control on genotoxic impurities during the preparation of elagolix sodium.
According to the present invention, the genotoxic impurities are potent carcinogens in animals and probable carcinogens in humans, especially nitrosamines. ICH M7 recommends that these mutagenic carcinogens be controlled at or below the acceptable cancer risk level. Due to their known potent carcinogenic effects, and because it is feasible to limit these impurities by taking reasonable steps to control or eliminate their presence, particularly nitrosamine impurities. The goal is to have no quantifiable nitrosamine impurities or well within the declared limits in elagolix sodium which is safe for human consumption.
The present invention relates to a process for the preparation of elagolix sodium of Formula I,

Formula I
wherein the process is comprising the steps of:
(i) reacting compound of Formula II with D-BHG to obtain compound of Formula III,

Formula II D-BHG Formula III

(ii) reacting compound of Formula III with 3-MFB to obtain compound of Formula IV with not more than 1.0% of impurity,

3-MFB Formula IV
(iii) de-protecting compound of Formula IV to obtain compound of Formula V,

Formula V
(iv) N-alkylation of compound of Formula V using ethyl 4-bromobutanoate to obtain compound of Formula VI,

Formula VI
(v) hydrolysis of compound of Formula VI to obtain elagolix, and
(vi) preparing elagolix sodium.
In one embodiment, the compound of Formula II is reacted with D-BHG in the presence of solvent, triphenylphosphine and azodicarboxylate to obtain compound of Formula III. The solvent used is selected from the group comprising of protic, aprotic solvent or mixture thereof, preferably aprotic solvent, and the solvent is further selected from the group comprising of halogenated hydrocarbons such as dichloromethane, chloroform and the like, esters such as ethyl acetate, isopropyl acetate and the like, nitrile such as acetonitrile and the like, water and mixtures thereof. The azodicarboxylate is selected from the group comprising diisopropylazodicarboxylate. The reaction by-products triphenylphosphineoxide and hydrazine derivative are removed by filtration and the compound of Formula III may have impurity A and impurity B which is/are not more than 0.10%.

Impurity A Impurity B
In one embodiment the compound of Formula III undergoes Suzuki coupling reaction with 3-MFB in presence of palladium catalyst in presence of base and optionally in presence of a ligand to obtain compound of Formula IV. The palladium catalyst is selected from the group comprising of palladium acetate (Pd(OAc)2), tris(dibenzylidene-acetone)palladium(Pd2(dba)3), tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) and the like. The base used is preferably inorganic base which is selected from the group comprising of metal carbonate, metal bicarbonate, metal hydroxide and metal alkoxides wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium, cesium or magnesium. The ligand used is selected from the group comprising of tri-t-butylphosphonium tetrafluoroborate, tri-t-butylphosphine, triphenylphosphine and the like. The ligand is selected from the group comprising of tri-t-butylphosphonium tetrafluoroborate, tri-t-butylphosphine, triphenylphosphine and the like. The reaction is carried out in suitable solvent using water miscible solvents, water and mixtures thereof. The water miscible solvent is selected from the group comprising of ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, tertiary butanol and the like; nitriles such as acetonitrile and the like and ethers such as tetrahydrofuran, methyltetrahydrofuran and the like. The reaction provides compound of Formula IV with not more than 1.0% of impurity, preferably desbromo impurity-C and dimer of 3-MFB.

Impurity-C
In one embodiment, the compound of Formula IV is de-protected to obtain compound of Formula V. The reaction is carried out using the reagent selected from the group comprising of hydrochloric acid in ethyl acetate, sulfuric acid in t-butyl acetate, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid in THF, Lewis acids such as BF3.OEt2, TMSI, TMSOTf, TiCl4, SnCl4, AlCl3, Sn(OTf)2 and ZnBr2 and the like.
In one embodiment, the compound of Formula V is N-alkylated with ethyl 4-bromobutanoate to obtain the compound of formula VI, in presence of a base. The base used is selectively an inorganic base which is used to avoid the formation of genotoxic impurities. The inorganic base is selected from the group comprising of metal carbonate, metal bicarbonate, metal hydroxide and metal alkoxides wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium, cesium or magnesium. The solvent used for the reaction is selected from the group comprising of ketones such as acetone, hydrocarbons such as toluene and the like; nitriles such as acetonitrile and the like; ethers such as tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether; water and mixtures thereof. The reaction provide the compound of Formula VI with impurity D and impurity E not more than 1.0%.

Impurity D Impurity E
In one embodiment, elagolix sodium, the compound formula I is obtained by hydrolysis of the compound of formula V using sodium hydroxide or sodium C1-C4 alkoxide. The sodium C1-C4 alkoxide is selected from the group comprising of sodium methoxide, sodium ethoxide and the like. The solvent used is selected from the group comprising of alcohols, esters, ketones, ethers, hydrocarbons, water and mixtures thereof; particularly methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate, acetone, methyl ethyl ketone, methyl tertiary butyl ether, diisopropyl ether, water or mixtures thereof.
According to the present invention, the intermediates and elagolix sodium are isolated using one or more work-up processes such as extraction, washing, precipitation, filtration and the like. The intermediates used for the preparation of elagolix and elagolix sodium are then optionally crystallized from suitable organic solvent to increase/enhance purity. The suitable organic solvent for crystallization is selected from the group comprising of alcohols, esters, ketones, ethers, hydrocarbons, water and mixtures thereof; particularly methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate, acetone, methyl ethyl ketone, methyl tertiary butyl ether, diisopropyl ether, n-heptane, cyclohexane, hexane, toluene, water and mixtures thereof.
Elagolix as its sodium salt is generally used in its amorphous form. The amorphous polymorphic form need special attributes to be stable as the processes disclosed in prior art fail to provide elagolix sodium in amorphous form having high purity and stability, most importantly, residual solvent limits as desired by ICH guidelines. Elagolix sodium in amorphous form being sensitive to higher temperature cannot be subjected to drying under harsh conditions to achieve desired residual solvent limits, thus there is a need to develop simple and robust conditions for drying of elagolix amorphous to achieve limits along with keeping the high purity requirements of product. The inventors of present invention have very keenly devised a process for achieving the required residual solvent limits in amorphous elagolix sodium.
The present invention relates to a process for the preparation of elagolix sodium with low residual solvent wherein the process comprises of drying elagolix sodium in controlled humidity conditions.
Further, the present invention relates to a process for the preparation of amorphous elagolix sodium with low residual solvent wherein the process comprises of drying elagolix sodium in controlled humidity conditions.
According to the present invention, the controlled humidity drying condition is comprised of humidity drying conditions with relative humidity up to about 100%.
In one embodiment of the present invention, the elagolix sodium of Formula I is subjected to drying to remove solvent under controlled humidity conditions, wherein the relative humidity during drying is up to about 100%. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is controlled by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about 0-80?C, for 1-30 h. The temperature of dryer is increased optionally in stepwise manner, starting from lower temperature range to higher range, by keeping each range of temperature constant for about 1-20 h.
The elagolix sodium of Formula I used herein as starting material may contain solvent wherein the solvent is selected from organic solvent, water and mixtures thereof used during the preparation of elagolix sodium.
In one embodiment of the present invention, elagolix sodium of Formula I used herein can be prepared according to the processes as disclosed in the prior art or by the process of present invention for the preparation of elagolix sodium.
In one embodiment the elgolix sodium obtained as per present invention is having low residual solvent, wherein residual solvent is not more than about 5000 ppm, preferably not more than 2000 ppm and more preferably not more than 1000 ppm.
In one embodiment, the elagolix sodium obtained as per the present invention is having purity not less than 99.0%, preferably not less than 99.5% and more preferably not less than 99.9%.
In one embodiment, the elagolix sodium obtained by process of the present invention being essentially free of impurities, preferably genotoxic impurities, more preferably nitrosamines, is well within the specifications prescribed safe for human consumption, preferably nitrosamine impurity is less than 0.01 ppm, wherein the limit of detection is 0.01 ppm.
The process disclosed in present invention has following advantages:
(a) The process involves use of green reagents and green solvents and avoids the use of hazardous and toxic reagents and solvents, thus is environmentally safe.
(b) The process provides intermediates in solid form which are easy to handle and makes operations simple.
(c) The process is integrated with control on formation of impurities at all steps, wherein it not only avoids cumbersome chromatographic purifications but also avoids the requirement of purification and thereby reduces operations, cycle time and effluent generation and provides product with high purity.
(d) The process provides elagolix sodium with desired pharmacopoeia standards and with low residual solvent making it more stable.
(e) The process provides elagolix sodium essentially free of impurities, preferable genotoxic impurities.
EXAMPLES
Example 1: Preparation of compound of Formula III:
To a solution of compound of Formula II (150 g) in ethyl acetate (1000 ml), added D-BHG (109 g) and triphenylphosphine (140 g). The reaction mixture was stirred and cooled to about 5 °C. To the resulting mixture slowly added diisopropylazodicarboxylate (108 g) solution in ethylacetate. The temperature of reaction mixture was then raised to room temperature and stirred for about 2 hours. On completion of reaction, the solvent from the reaction mass is distilled off. To the residue added toluene (400 ml) and stirred the reaction mixture at about 60 °C, cooled the reaction mixture to about 5 °C and stirred. The solid so obtained was filtered out and solvent from the filtrate was distilled out partially and subsequently cooled to about 50 °C, added methanol (1200 ml). The temperature of reaction mixture is then raised to about 60 °C, slowly added water (400 ml) and stirred for another 1 hour. The resulting reaction mixture is gradually cooled to room temperature and is stirred for about 2 hours. The solid so obtained is filtered, washed with methanol/water solution and dried to obtain compound of Formula III in crystalline form, as given in Figure 1.

Example 2: Preparation of compound of Formula IV:
To a stirred solution of Palladium acetate (0.80 g), tri-tert-butyl phosphonium tetrafluoroborate (1.0 g), aqueous potassium hydroxide solution (29.0 g in 500 ml of water) in acetone (500 ml), added a solution of compound of Formula III (150 g) and 3-MFB (82 g) in acetone (500 ml) at about 30 °C. The temperature of reaction mixture is raised to about 45 °C and stirred for about 1 hour. The solvent from the reaction mixture is distilled out completely, added toluene (500 ml) to the residue, raised the temperature to about 70 °C and stirred for about 45 minutes. On completion of reaction, separated the layers and distilled out solvent from the organic layer. To the residue added methanol (900 ml) and water (180 ml) and heated the resulting reaction mixture to reflux and stirred for about 30 minutes. The reaction mixture is then cooled, the solid so obtained is filtered, washed with mixture of methanol/water and dried to obtain compound of Formula IV in crystalline form, as given in Figure 2.
Des bromo impurity-C: NMT 0.1%
Dimer of 3-MFB: NMT 0.75%

Example 3: Preparation of compound of Formula V:
To a solution of compound of Formula IV (100 g) in ethyl acetate (450 ml), added concentrated hydrochloric acid (64 g) at room temperature. The resulting reaction mixture is stirred for about 5 hours. On completion of reaction, the reaction mixture is cooled to about 10 °C and pH was adjusted to about 7.5 using aqueous sodium carbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent is distilled out to obtain compound of Formula V to be used as such for next step.

Example 4: Preparation of compound of Formula VI:
To a solution of compound of Formula V, prepared in Example 3, in ethyl acetate (50 ml), charged a solution of aqueous potassium carbonate and ethyl 4-bromobutyrate (60 g). The temperature of reaction mixture is raised to about 70 °C and stirred for about 5 hours. On completion of reaction, the reaction mixture is cooled and treated with m-xylene and aqueous phosphoric acid solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled out to obtain compound of Formula VI.
Impurity E: NMT 1.0%

Example 5: Preparation of elagolix sodium:
To a solution of compound of Formula VI (100 g) in ethanol (500 ml), added aqueous sodium hydroxide solution (8.0 g in 500 ml water). The reaction mixture was stirred at room temperature for about 6 hours. On completion of reaction, the pH of reaction mixture is adjusted to about 8.0 using aqueous hydrochloric acid. To the resulting reaction mixture added ethyl acetate (500 ml), stirred for about 20 minutes. The layers were separated and solvent was distilled from organic layer to obtain a residue. The residue was dissolved in ethyl acetate (800 ml) and stirred, slowly added the reaction mixture to methyl tertiary butyl ether (1500 ml) at room temperature and stirred for about 30 minutes. The solid so obtained was filtered and washed with methyl tertiary butyl ether to obtain elagolix sodium. The elagolix sodium is dried under vacuum for about 3 hours at room temperature and is sequentially dried at relative humidity of up to 100% under atmospheric pressure for about 15 hours to obtain elagolix sodium in amorphous form.

We claim:

1.A compound selected from compounds of Formula III, IV and VI in solid form.

Formula III Formula IV

Formula VI
2. The compound of Formula III as claimed in claim 1, characterized by X-ray powder diffraction pattern comprising one or more peaks at ±0.2 of 7.3, 14.4, 17.0, 17.8, 20.9, 22.1, 22.4, 23.8 and 28.4 °2?.
3. The compound of Formula IV as claimed in claim 1, characterized by X-ray powder diffraction pattern comprising one or more peaks at ±0.2 of 9.0, 10.3, 11.9, 12.1, 12.4, 14.7, 17.0, 19.3, 21.0, 21.1, 21.8, 22.5, 24.3, 24.8 and 26.4 °2?.
4. The compound of Formula VI as claimed in claim 1 wherein it is in amorphous form.
5. The process for the preparation of elagolix sodium using any one of compounds of Formula III, IV and VI in solid form as claimed in claim 1.
6. A process for the preparation of elagolix sodium of Formula I,

Formula I
wherein the process comprises the steps of:
(i) reacting compound of Formula II with D-BHG to obtain compound of Formula III,

Formula II D-BHG Formula III

(ii) reacting compound of Formula III with 3-MFB to obtain compound of Formula IV with purity of at least 99%,

3-MFB Formula IV
(iii) de-protecting compound of Formula IV to obtain compound of Formula V,

Formula V
(iv) N-alkylation of compound of Formula V using ethyl 4-bromobutanoate to obtain compound of Formula VI,

Formula VI
(v) hydrolysis of compound of Formula VI to obtain elagolix, and
(vi) preparing elagolix sodium.
7. The process as claimed in claim 6, wherein the elagolix sodium obtained is essentially free of impurities including genotoxic impurities.
8. A process for the preparation of elagolix sodium of Formula I with low residual solvent wherein the process comprises of drying elagolix sodium under controlled humidity conditions.
9. The process as claimed in claim 8, wherein the controlled humidity condition is having relative humidity of up to 100%.
10. The process as claimed in claim 8, wherein elagolix sodium with low residual solvent limit is wherein residual solvent is not more than 5000 ppm, preferably not more than 2500 ppm and more preferably not more than 1000 ppm.