ES2802815B2 - 3-[2(R)-AMINO-2-PHENYETHYL]-5-(2-FLUORO-3-METHOXYPHENYL)-1-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL-1H HYDROCHLORIDE SALT -PYRIMIDIN-2,4(1H,3H)-DIONE (I) IN SOLID FORM, PROCEDURE FOR ITS PREPARATION AND USE OF THE SAME IN THE SYNTHESIS OF ELAGOLIX - Google Patents

Description

DESCRIPTION

3-[2(R)-AMINO-2-PHENYETHYL]-5-(2-FLUORO-3-METHOXYPHENYL)-1-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL-1H HYDROCHLORIDE SALT -PYRIMIDIN-2,4(1H,3H)-DIONE (I) IN SOLID FORM, PROCEDURE FOR ITS PREPARATION AND USE OF THE SAME IN THE SYNTHESIS OF ELAGOLIX

field of invention

The present invention relates to a new intermediate useful in the synthesis of elagolix, to a process for obtaining it, to the use of said intermediate for the preparation of elagolix and to a process for the preparation of elagolix that makes use of said intermediate.

Background of the invention

Elagolix (Orilissa®) is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication used in the treatment of pain associated with endometriosis in women. Elagolix is also in development for the treatment of uterine fibroids in women.

(V) Elagolix

Elagolix was approved by the FDA for the treatment of pain associated with endometriosis in the United States on July 23, 2018. It was the first new medication approved by the FDA for the treatment of endometriosis in more than a decade. Elagolix is the first and currently the only commercialized member of a new class of GnRH modulators, described as "second generation" due to its non-peptidic, small molecule nature and oral activity.

Various synthetic routes for the preparation of elagolix have been described (see for example WO 2005/007164 A1, WO 2005/007165 A1, WO 2009/062087 A1, WO 2018/198086 A1 and WO 2019/112968 A1).

Many of the synthetic routes proposed for the preparation of Elagolix use the intermediate 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (MI):

Patent application WO 2019/112968 A1 describes a process for obtaining product (III) that comprises the hydrolysis of product (II):

As described in said application, the product (III) thus obtained is purified by recrystallization from a mixture of isopropyl acetate and heptane to give a product with a purity of 99.8%.

Said purified product is reacted with ethyl 4-bromobutyrate to obtain the product (IVa) which, by basic hydrolysis, provides the product (V) as shown in the following scheme.

The inventors of the present application have reproduced the purification process of compound (III) by recrystallization from a mixture of isopropyl acetate and heptane as described in WO 2019/112968 A1. Starting from a product (III) with a purity of about 95% it was not possible to increase the purity of the product by the described procedure. In addition, the product resulting from recrystallization was a sticky solid that was difficult to handle and isolate.

Therefore, there is a need in the state of the art for alternative procedures for obtaining Elagolix (V) starting from product (III), in particular a product with low purity (preferably less than 96%).

Summary of the invention

The inventors have discovered that a simple way to obtain the product (III) with high purity, preferably greater than 99%, for its subsequent use in the synthesis of elagolix is to generate the hydrochloride salt of said product in solid form (I):

Said salt in solid form (I) can be used in the synthesis of elagolix by a process in which the product (MI) is regenerated, which is subsequently reacted with C1-4 alkyl halobutyrate according to the scheme shown below.

in which R represents a C1-4 alkyl group and X represents a halogen atom.

Description of the figures

Figure 1 shows the heat/temperature curve in a differential scanning calorimetry (DSC) of the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)- 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I). DSC analysis was performed with a perforated closed capsule in a Mettler Toledo 822e instrument with STARe SW15 software with the following parameters: heating range of 30 to 300 °C with a ramp of 20 °C/min and N2 flow of 50 mL/min.

Figure 2 shows the x-ray powder diffractogram (XRPD) of the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2- fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I). The diffractogram was obtained using a Siemens D-500 model X-ray powder diffractometer equipped with a Copper anode. Scan parameters: 4-50 degrees 20, continuous scanning, ratio: 1.2 degrees / minute.

Detailed description of the invention

In a first aspect, the invention refers to the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-( trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) in solid form.

In a preferred embodiment of the first aspect of the invention, the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) is amorphous.

In another preferred embodiment of the first aspect of the invention, the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1Hpyrimidin-2, 4(1H,3H)-dione (I) exhibits a heat/temperature curve in differential scanning calorimetry that has a negative peak at a temperature between 155 and 165 °C, preferably 159.6 ± 0.2 °C . DSC analysis is performed with a perforated closed capsule in a Mettler Toledo 822e instrument with STARe SW15 software with the following parameters: heating range of 30 to 300 °C with a ramp of 20 °C/min and N2 flow of 50 mL/min.

In another preferred embodiment of the first aspect of the invention, the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) presents an X-ray powder diffractogram measured with Cu Ka radiation essentially like that of Figure 2. In said diffractogram 3 broad bands appear at positions of °20 from approximately 3 to 12, 12 to 20 and 20 to 35, more preferably 3 bands at positions 3 ± 0.2 to 12 ± 0.2, 12 ± 0.2 to 20 ± 0.2 and 20 ± 0.2 to 35 ± 0.2. The diffractogram is obtained using a Siemens model D-500 X-ray powder diffractometer equipped with a copper anode. Scan parameters: 4-50 degrees 20, continuous scanning, ratio: 1.2 degrees / minute.

In a second aspect, the invention relates to a process for preparing the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro -6-(trifluoromethyl)benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) in solid form comprising the steps of:

a) contacting the compound of formula (II)

with an acid in the presence of a first solvent to obtain a salt of the compound of formula (III) in solution

b) optionally totally or partially eliminate the solvent present in the solution resulting from step a),

c) neutralizing the product resulting from step a) or the product resulting from step b) with a base to obtain the compound of formula (MI)

d) contacting the product of formula (III) with hydrochloric acid in the presence of a second solvent to obtain the product of formula (I) in solution, e) totally or partially eliminating the solvent to obtain the product of formula (I) in solid form

f) optionally purifying the product of formula (I) in solid form obtained in step e).

In an embodiment of the second aspect of the invention, the acid is an acid of formula AHn, where n is an integer from 1 to 3 and A-n is a mono-, di- or tri-valent anion.

In an embodiment of the second aspect of the invention, the AHn acid used is selected from among protic organic and inorganic acids with a pKa of less than 3. When the acid is polyprotic (n>1), the pKa refers to that of the first proton.

In an embodiment of the second aspect of the invention the anion A-n is selected from the group consisting of chloride, methanesulfonate and trifluoroacetate.

In an embodiment of the second aspect of the invention the HAn acid used is selected from the group consisting of hydrochloric acid, methanesulfonic acid and trifluoroacetic acid.

In an embodiment of the second aspect of the invention, the first solvent used in step a) is selected from the group consisting of acetonitrile, isopropyl acetate, dichloromethane and mixtures of acetonitrile/water, isopropyl acetate/water and dichloromethane/water. .

In an embodiment of the second aspect of the invention, step b) of solvent removal is carried out by distillation at a pressure lower than 101325 Pa.

In an embodiment of the second aspect of the invention, step c) of neutralization is carried out by adding an aqueous solution of a base selected from the group consisting of inorganic hydroxides and carbonates such as hydroxides and carbonates of alkali and alkaline earth metals. , for example NaOH, KOH, Na2CO3 and K2CO3.

In an embodiment of the second aspect of the invention, the product (MI) resulting from step c) is purified before carrying out step d). In a particular embodiment, when step c) has been carried out in aqueous medium, the purification is carried out i) extracting the product (III) from the reaction medium with a solvent that is sparingly soluble in water that is selected from the group consisting of C1-4 alkyl acetates, preferably ethyl acetate or isopropyl acetate, more preferably isopropyl acetate, ii) treating the organic phase of step i) with an acidic aqueous solution, iii) separating said aqueous solution from the organic phase, iv) neutralizing the aqueous solution with a base, v) adding again the same solvent mentioned in step i) and vi) separating the organic phase of said third solvent containing the product (III).

In an embodiment of the second aspect of the invention, the second solvent used in step d) is selected from the group consisting of isopropyl acetate, 2-methyltetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran/water, preferably 2-methyltetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran/water.

In an embodiment of the second aspect of the invention, step d) is carried out at a temperature between 10 °C and 40 °C, preferably between 10 and 30 °C, more preferably 20 °C, maintaining stirring for a time between 15 and 60 minutes, preferably between 15 and 45 minutes, more preferably 30 minutes.

In an embodiment of the second aspect of the invention, step e) of solvent removal is carried out by distillation at a pressure lower than 101325 Pa.

In an embodiment of the second aspect of the invention, step f) of purification is carried out by recrystallization of product (I) using a solvent selected from the group consisting of 2-methyl-tetrahydrofuran, methyl-isobutyl-ketone and C1-alkyl acetates. 4, preferably 2-methyl-tetrahydrofuran.

In a third aspect, the invention relates to a process for the preparation of elagolix (V) comprising the steps of:

a) add a third solvent to 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6 -methyl-1H-pyrimidin-2,4(1H,3H)-dione in solid form (I) to obtain a solution or suspension,

b) contacting the solution or suspension of step a) with a base to generate a solution comprising the product (III),

c) reacting the solution from step b) with C1-4 alkyl 4-halobutyrate to obtain the product of formula (IV)

in which R represents an alkyl C1-4 alkyl group, and

d) hydrolyzing the ester group of the compound of formula (IV) by treatment with NaOH to obtain the product of formula (V) Elagolix.

In one embodiment of the third aspect of the invention the Ci-4 alkyl con 4-halobutyrate is ethyl 4-bromobutyrate.

In an embodiment of the third aspect of the invention, the third solvent used in step a) is selected from the group consisting of dimethylsulfoxide, toluene and dimethylformamide, preferably dimethylformamide.

In an embodiment of the third aspect of the invention, the base used in step b) is selected from the group consisting of diisopropylethylamine, triethylamine, tert-butylamine, diethylamine, preferably diisopropylethylamine.

In an embodiment of the third aspect of the invention, step b) is carried out at a temperature between 20°C and 35°C, preferably between 20 and 25°C.

In an embodiment of the third aspect of the invention, step c) is carried out at a temperature between 70 °C and 100 °C, preferably between 80 and 90 °C, more preferably between 80 and 85 °C, maintaining stirring for a period of time. between 8 and 24 hours, preferably between 8 and 16 hours, more preferably 12 hours.

In an embodiment of the third aspect of the invention, the product (IV) obtained in step c) is purified before carrying out step d). In a particular embodiment, the purification is carried out i) by adding to the reaction medium of stage c) water and a solvent that is sparingly soluble in water, preferably isopropyl acetate, ii) treating the organic phase of stage i) with an aqueous solution acid, iii) separating said aqueous solution from the organic phase, iv) neutralizing the aqueous solution with a base, v) adding the same solvent again mentioned in step i), vi) separating the organic phase from said solvent containing the product (IV) and v) eliminating the solvent to obtain the product (IV).

In an embodiment of the third aspect of the invention, step d) of hydrolysis is carried out in a solvent selected from the group consisting of water, C1-3 alcohol, mixtures of C1-3 alcohol and water, preferably isopropanol or mixture of isopropanol and water.

In an embodiment of the third aspect of the invention, step d) of hydrolysis is carried out using an aqueous solution of NaOH as a base at a temperature between 20 and 50 °C, more preferably between 30 and 40 °C.

In a fourth aspect, the invention relates to the use of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione in solid form (I) in a process for the preparation of Elagolix (V).

In particular embodiments of the fourth aspect of the invention, the use of compound (I) is carried out following the procedure described in the third aspect of the invention.

examples

Example 1: Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H -pyrimidine-2,4-dione (MI)

75.7 g (117.3 mmol) of 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro -6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidin-2,4-dione (II) were dissolved in 450 mL of acetonitrile at the temperature of about 20 °C. In this order, 200 mL of water and 40 mL of a 12 N aqueous solution of HCl (480 mmol) were added, maintaining a temperature of approximately 20 °C. The temperature of the solution obtained was increased to approximately 40°C and it was kept under stirring at said temperature for 2 hours.

Next, the solvent was removed by vacuum distillation and 200 mL of isopropyl acetate was added to the residue obtained and, slowly, a previously prepared solution containing 130 g of K2CO3 in 250 mL of water. The aqueous phase was separated and treated successively with 2 fractions of 200 mL each of isopropyl acetate. The combined organic phases were successively treated with a solution previously prepared containing 30 mL of H3PO4 in 350 mL of H2O and with a previously prepared solution containing 15 mL of H3PO4 in 250 mL of water. The aqueous phase resulting from combining the two washes was successively treated with 2 fractions of 200 mL each of isopropyl acetate. 200 mL of isopropyl acetate and, slowly, 140 g of K2CO3 (pH of the aqueous phase of approximately 8.5) were added to the resulting aqueous phase. The aqueous phase was separated and treated successively with two fractions each of 200 mL of ispopropyl acetate. Solvent was removed from the thus combined organic phases by vacuum distillation to obtain 67.35 g of an orange oil of 94.37% purity by UHPLC comprising 3-((R)-2-amino-2-phenylethyl)- 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (111).

Example 2: Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H -pyrimidine-2,4-dione (MI)

15.1 g (23.45 mmol) of 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro -6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidin-2,4-dione (II) were dissolved in 80 mL of isopropyl acetate at the temperature of about 20 °C. 9 g (93.8 mmol) of methanesulfonic acid were added maintaining a temperature of approximately 20 °C. The temperature of the solution obtained was increased to approximately 60 °C and it was kept under stirring at said temperature for 2 hours.

Next, 40 mL of water and a saturated solution of K2CO3 were added until a pH value of the resulting mixture of approximately 9. The organic phase was separated and 60 mL of H3PO4 and H3PO4 were added to it until a pH value of the resulting mixture of about 1. The aqueous phase was separated and treated successively with 2 fractions of 40 mL each of isopropyl acetate. 40 mL of isopropyl acetate and, slowly, 30 g of K2CO3 (pH of the aqueous phase of approximately 8) were added to the resulting aqueous phase. The aqueous phase was separated and treated successively with two fractions each of 40 mL of ispopropyl acetate. Solvent was removed from the thus combined organic phases by vacuum distillation to obtain 11.56 g of an orange oil of 95.00% purity by UHPLC comprising 3-((R)-2-amino-2-phenylethyl )-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione.

Example 3: Obtaining the hydrochloride salt of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6 -methyl-1H-pyrimidine-2,4-dione (I) in solid form

16.9 g (31 mmol) of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6 -methyl-1H-pyrimidine-2,4-dione (MI) were dissolved in 170 mL of 2-methyltetrahydrofuran at a temperature of about 20 °C. 3 mL (36.5 mmol) of a 12 N aqueous solution of HCl were slowly added, maintaining a temperature of approximately 20 °C and stirring was maintained at said temperature for 30 minutes.

Then, the solvent was removed by distillation under vacuum. 170 mL of 2-methyl-tetrahydrofuran were added and the suspension obtained was heated to reflux temperature, keeping under stirring for 10 minutes. Subsequently, the obtained solution was slowly cooled to a temperature of about 20°C and kept at said temperature for 30 minutes. The resulting solid was isolated by filtration to obtain 14.3 g (yield: 79.1%, purity by UHPLC: 99.97%) of a white solid corresponding to 3-((R)-2-amino hydrochloride salt -2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (I) in solid form.

Example 4: Obtaining the hydrochloride salt of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6 -methyl-1H-pyrimidin-2,4-dione (I)

11.5 g of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H -pyrimidine-2,4-dione (III) (purity by UHPLC: 95.17%) were dissolved in 100 mL of 2-methyl-tetrahydrofuran at the temperature of about 20 °C. 2 mL (24.4 mmol) of a 12 N aqueous solution of HCl were slowly added, maintaining a temperature of approximately 20 °C and stirring was maintained at said temperature for 30 minutes.

Then, the solvent was removed by distillation under vacuum. 100 mL of 2-methyl-tetrahydrofuran were added and the suspension obtained was heated to reflux temperature, keeping under stirring for 10 minutes. Subsequently, the obtained solution was slowly cooled to a temperature of about 20°C and kept at said temperature for 30 minutes. The resulting solid was isolated by filtration to obtain 8.58 g (purity by UHPLC: 99.94%) of a white solid. corresponding to the hydrochloride salt of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl- 1H-pyrimidin-2,4-dione (I) in solid form.

Comparative Example 5: Purification of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl- 1H-pyrimidine-2,4-dione (111)

11.5 g of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H -pyrimidin-2,4-dione (III) (purity by UHPLC: 95.17%) were dissolved in 50 mL of isopropyl acetate at the temperature of about 80 °C. 60 mL of n-heptane were then added slowly, maintaining the temperature above approximately 60 °C. Once the addition was complete, the resulting mixture was slowly cooled to a temperature of approximately 20 °C and kept under stirring at said temperature for 30 minutes.

The mixture was then cooled to 10 °C and the resulting solid was isolated by filtration to obtain 5.13 g (purity by UHPLC: 95.63%) of a yellowish solid corresponding to 3-((R) -2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidin-2,4-dione (III) .

Example 6: Obtaining 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6 acid ethyl ester -dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino)-butyric acid (IVa)

55 g (94.5 mmol) of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1H-pyrimidin-2,4-dione (I) were mixed with 85 mL of dimethylformamide at the temperature of about 20 °C. 45 mL of diisopropylethylamine were slowly added and the mixture obtained was heated to a temperature of 35-40 °C. Maintaining said temperature, 19 mL (132.8 mmol) of ethyl 4-bromobutyrate were added and the resulting mixture was heated to a temperature of 80-85 °C and kept under stirring at said temperature for 12 hours.

Next, 200 mL of isopropyl acetate and 100 mL of water were successively added. The aqueous phase was separated and treated with a 200 mL fraction of isopropyl acetate. The combined organic phases were successively treated with 100 mL of water, an aqueous solution of H3PO4 (78 g in 200 mL) and an aqueous solution of H3PO4 (15 g in 200 mL). The combined aqueous phases were treated with two fractions each. of 200 mL of isopropyl acetate. 300 mL of isopropyl acetate and a saturated aqueous solution of K2CO3 were added to the combined organic phases. The aqueous phase was separated and treated with a 300 mL fraction of isopropyl acetate. The combined organic phases were treated with 200 mL of a saturated aqueous NaHCO3 solution. From the organic phase thus obtained, the solvent was removed by vacuum distillation to obtain 61.72 g of a residue comprising 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)- 3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino)-butyric acid (IVa) (UHPLC: 88 .46%)

Example 7: Obtaining the sodium salt of 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2 acid ,6-dioxo-3,6-dehydro-2H-pyrimidin-1-yl]-1-phenylethylamino)-butyric acid (V)

The residue obtained in the previous example comprising 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl ethyl ester - 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino)-butyric acid (IVa) was dissolved in 120 mL of isopropanol. An aqueous solution previously prepared with 9.5 g of NaOH and 120 mL of water was added to said solution at a temperature of approximately 20 °C. The resulting mixture was heated to a temperature of about 35°C and kept under stirring at said temperature for 2 hours.

Next, 350 mL of water and 200 mL of isopropyl acetate were added. The aqueous phase was separated and treated with two fractions each of 200 mL of isopropyl acetate. 90 g of NaCl were added to the treated aqueous phase and 200 g of methylisobutyketone. The aqueous phase was separated and treated with two fractions each of 200 mL of methyl isobutyl ketone. The combined organic phases were treated with a 200 mL fraction of a 20% NaCl aqueous solution. The solvent of the organic phase was removed by vacuum distillation and the residue obtained was dissolved in 150 mL of ethyl acetate. The mixture obtained was filtered through a filter composed of a layer of diatomaceous earth and a 0.20 micron filter, washing the filter with two fractions each of 30 mL of ethyl acetate. The filtered solution was slowly added to 1000 mL of n-heptane, maintaining the temperature between 5 and 10 °C, keeping the resulting mixture under stirring at the indicated temperature for 60 minutes. The mixture was filtered to obtain a white solid that was dried at 40 °C and vacuum, yielding 41.83 g (yield of the two synthesis steps: 67.7%) of the sodium salt of the acid 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6-dioxo-3,6-dehydro- 2H-pyrimidin-1-yl]1-phenylethylamino)-butyric (V) (elagolix sodium salt), with a purity of 99.87% by UHPLC.

Test conditions

DSC analysis was performed on a Mettler Toledo 822e instrument with STARe SW15 software. Parameters: heating range from 30 to 300 °C with a ramp of 20 °C/min and N2 flow of 50 ml/min. The measurement is made with a perforated closed capsule.

XRPD analysis was performed using a Siemens D-500 model X-ray powder diffractometer equipped with a Copper anode using Cu Ka radiation. Scan parameters: 4-50 degrees 20, continuous scanning, ratio: 1.2 degrees / minute.

The purity of the products obtained was analyzed using the Ultra-High Resolution Liquid Chromatography technique in a Waters brand apparatus, Acquity model, equipped with a photodiode detector and a thermostatic oven for the column. An HSST3 column (2.1 x 100 mm and 1.8 jm) and mobile phases A (50 mM ammonium acetate pH 5.2), B (acetonitrile) and C (water) were used with the following analysis conditions:

Flow rate: (mL/min): 0.3

Ta column (°C): 40

Wavelength (nm): 270 (for elagolix), 210 (for the rest of the compounds) Vol. inj. ( | ^j L): 1

Acquisition time (min): 10

Diluent: acetonitrile/water (1:1)

Gradient:

Claims (14)

1.- 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6- hydrochloride salt methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) in solid form.

2. Salt according to claim 1 characterized by having an amorphous form. 3. Salt according to claim 2, characterized by presenting a heat/temperature curve in a differential scanning calorimetry that has a negative peak at a temperature between 155 and 165°C. 4. Salt according to any of claims 2 and 3, characterized by presenting a diffractogram measured with Cu Ka radiation essentially like that of Figure 2. 5. - A process for preparing the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl )benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione (I) in solid form comprising the steps of: a) contacting the compound of formula (II)

with an acid in the presence of a first solvent to obtain a salt of the compound of formula (111) in solution

b) optionally totally or partially eliminate the solvent present in the solution resulting from step a), c) neutralizing the product resulting from step a) or the product resulting from step b) with a base to obtain the compound of formula (III) d) contacting the product of formula (III) with hydrochloric acid in the presence of a second solvent to obtain the product of formula (I) in solution, e) totally or partially eliminate the solvent to obtain the product of formula (I) in solid form f) optionally purifying the product of formula (I) in solid form obtained in step e). 6. - A method according to claim 5 characterized in that the acid is an acid of formula AHn, n being an integer from 1 to 3 and A-n a mono-, di- or tri-valent anion. 7. - A process according to any of claims 5 to 6, characterized in that the acid is selected from protic organic and inorganic acids with a pKa of less than 3. 8. - A process according to any of claims 5 to 7 in which the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid and trifluoroacetic acid. 9. - A process according to any of claims 5 to 8 characterized in that the product (III) resulting from step c) is purified before performing step d). 10. A process according to any of claims 5 to 9, characterized in that the first solvent used in step a) is selected from the group consisting of acetonitrile, isopropyl acetate, dichloromethane and mixtures of acetonitrile/water, of isopropyl acetate/ water and dichloromethane/water. 11. - A process according to any of claims 5 to 10 characterized in that the second solvent used in step d) is selected from the group consisting of isopropyl acetate, 2-methyl-tetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran / Water. 12. - A process for preparing elagolix (V) comprising the steps of: a) adding a third solvent to the hydrochloride salt of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl )benzyl]-6-methyl-1H-pyrimidin-2,4(1H,3H)-dione in solid form (I) to obtain a solution or suspension, b) contacting the solution or suspension of step a) with a base to generate a solution comprising the product (III), c) reacting the solution from step b) with C1-4 alkyl 4-halobutyrate to obtain the product of formula (IV)

in which R represents an alkyl C1-4 alkyl group, and d) hydrolyzing the ester group of the compound of formula (IV) by treatment with NaOH to obtain the product of formula (V) Elagolix.

13. A process according to claim 12 in which the C1-4 alkyl 4-halobutyrate is ethyl 4-bromobutyrate such that the product obtained in step c) is:

14.- Use of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)bendl hydrochloride salt ]-6-methyl-1H-pmmidin-2,4(1H,3H)-dione in solid form (I) in a process for the preparation of Elagolix (V).