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WO2021009034A1 - 3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix - Google Patents

3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix Download PDF

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Publication number
WO2021009034A1
WO2021009034A1 PCT/EP2020/069529 EP2020069529W WO2021009034A1 WO 2021009034 A1 WO2021009034 A1 WO 2021009034A1 EP 2020069529 W EP2020069529 W EP 2020069529W WO 2021009034 A1 WO2021009034 A1 WO 2021009034A1
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fluoro
product
methyl
formula
methoxyphenyl
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Inventor
Roberto BALLETTE
Oscar Jiménez Alonso
Alicia DOBARRO RODRÍGUEZ
Elena García García
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Moehs Iberica SL
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Moehs Iberica SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones

Definitions

  • the present invention relates to a new intermediate useful in the synthesis of elagolix, to a process for obtaining same, to the use of said intermediate for preparing elagolix, and to a process for preparing elagolix making use of said intermediate.
  • 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 under development for treating uterine myomas in women.
  • GnRH antagonist gonadotropin-releasing hormone antagonist
  • Elagolix was approved by the FDA for treating pain associated with endometriosis in the United States on 23 July 2018. It was the first new medication approved by the FDA for treating endometriosis in over a decade. Elagolix is the first and currently the only marketed member of a new class of GnRH modulators, described as“second generation” due to the non-peptidic small-molecule nature and oral activity thereof.
  • Patent application WO 2019/112968 A1 describes a process of obtaining product (III) comprising the hydrolysis of product (II):
  • product (III) thus obtained is purified by means of recrystallization in a mixture of isopropyl acetate and heptane to yield a product with a purity of 99.8%.
  • the inventors of the present application have reproduced the procedure for purifying compound (III) by means of recrystallization in 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 means of the described procedure. Furthermore, the product resulting from recrystallization was a sticky solid that was hard to handle and isolate.
  • Said salt in solid form (I) may be used in the synthesis of elagolix by a process in which product (III) is regenerated, subsequently being reacted with C 1-4 alkyl halobutyrate according to the scheme shown below.
  • Figure 1 shows the heat/temperature curve in a differential scanning calorimetry (DSC) of 3- [2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I).
  • DSC differential scanning calorimetry
  • DSC analysis was performed with a perforated closed capsule in a Mettler Toledo 822e apparatus 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 diffraction (XRPD) of 3-[2(R)-amino-2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-
  • the invention relates to 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)- dione hydrochloride salt (I) in solid form.
  • the 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1 -[2 -fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2, 4(1 H,3H)-dione hydrochloride salt (I) is amorphous.
  • the 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1 -[2 -fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2, 4(1 H,3H)-dione hydrochloride salt (I) has a heat/temperature curve in a differential scanning calorimetry having a negative peak at a temperature comprised 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 apparatus 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.
  • the 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I) has a diffractogram measured with Cu K a radiation essentially like the one in Figure 2.
  • said diffractogram there are 3 broad bands at °2q positions of about 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 D-500 model X-ray powder diffractometer equipped with a copper anode. Scanning parameters: 4-50 degrees 2Q, continuous scan, ratio: 1.2 degrees/minute.
  • the invention relates to a process for preparing 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I) in solid form comprising the steps of: a) contacting the compound of formula (II)
  • step b) optionally completely or partially removing the solvent present in the solution resulting from step a),
  • the acid is an acid of formula AH n , with n being an integer of 1 to 3 and A -n a mono-, di-, or trivalent anion.
  • the AH n acid used is selected from organic and inorganic protic acids with a pK a of less than 3.
  • pK a refers to that of the first proton.
  • the A -n anion is selected from the group consisting of chloride, methanesulfonate, and trifluoroacetate.
  • the AH n acid used is selected from the group consisting of hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid.
  • 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.
  • step b) of removing the solvent is performed by distillation at a pressure of less than 101325 Pa.
  • step c) of neutralization is performed by addition of an aqueous solution of a base selected from the group consisting of inorganic hydroxides and carbonates, such as the hydroxides and the carbonates of alkaline and alkaline earth metals, for example NaOH, KOH, Na 2 CO 3 , and K 2 CO 3 .
  • a base selected from the group consisting of inorganic hydroxides and carbonates, such as the hydroxides and the carbonates of alkaline and alkaline earth metals, for example NaOH, KOH, Na 2 CO 3 , and K 2 CO 3 .
  • product (III) resulting from step c) is purified before performing step d).
  • the purification is performed by i) extracting product (III) from the reaction medium with a solvent of low solublility in water selected from the group consisting of C 1-4 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 the same solvent mentioned in step i) again, and vi) separating the organic phase from said third solvent containing product (III).
  • a solvent of low solublility in water selected from the group consisting of C 1-4 alkyl acetates, preferably ethyl acetate or isopropyl acetate, more preferably isopropyl
  • 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, preferably 2-methyl-tetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran/water.
  • step d) is performed at a temperature of between 10°C and 40°C, preferably between 10 and 30°C, more preferably 20°C, maintaining stirring for a time comprised between 15 and 60 minutes, preferably between 15 and 45 minutes, more preferably 30 minutes.
  • step e) of removing the solvent is performed by distillation at a pressure of less than 101325 Pa.
  • step f) of purification is performed by recrystallization of product (I) using a solvent selected from the group consisting of 2- methyl-tetrahydrofuran, methyl isobutyl ketone and C 1-4 alkyl acetates, preferably 2-methyl- tetrahydrofuran.
  • the invention relates to a process for preparing elagolix (V) comprising the steps of:
  • step b) contacting the solution or suspension of step a) with a base to generate a solution comprising product (III),
  • step b) reacting the solution of step b) with C 1-4 alkyl 4-halobutyrate to obtain the product of formula (IV)
  • R represents a C 1-4 alkyl group
  • the C 1-4 alkyl 4-halobutyrate is ethyl 4- bromobutyrate.
  • the third solvent used in step a) is selected from the group consisting of dimethylsulfoxide, toluene, and dimethylformamide, preferably dimethylformamide.
  • the base used in step b) is selected from the group consisting of diisopropylethylamine, triethylamine, tert-butylamine, diethylamine, preferably diisopropylethylamine.
  • step b) is performed at a temperature comprised between 20°C and 35°C, preferably between 20 and 25°C.
  • step c) is performed at a temperature comprised between 70°C and 100°C, preferably between 80 and 90°C, more preferably between 80 and 85°C, maintaining stirring for a time comprised between 8 and 24 hours, preferably between 8 and 16 hours, more preferably 12 hours.
  • product (IV) obtained in step c) is purified before performing step d).
  • purification is performed by i) adding to the reaction medium of step c) water and a solvent of low solubility in water, 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 the same solvent mentioned in step i) again, vi) separating the organic phase from said solvent containing product (IV), and v) removing the solvent to obtain product (IV).
  • step d) of hydrolysis is performed in a solvent selected from the group consisting of water, C1 -3 alcohol, mixtures of C1 -3 alcohol and water, preferably isopropanol or a mixture of isopropanol and water.
  • step d) of hydrolysis is performed using as a base an aqueous solution of NaOH at a temperature comprised between 20 and 50°C, more preferably between 30 and 40°C.
  • 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-1 H-pyrimidine- 2,4(1 H,3H)-dione in solid form (I) in a process for preparing Elagolix (V).
  • the aqueous phase resulting from combining the two washes was treated successively with 2 fractions of 200 mL isopropyl acetate each.
  • 200 mL of isopropyl acetate and, slowly, 140 g of K 2 CO 3 (pH of the aqueous phase of about 8.5) were added to the resulting aqueous phase.
  • the aqueous phase was separated and treated successively with two fractions of 200 mL of isopropyl acetate each.
  • Example 3 Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2- fluoro-6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione hydrochloride salt (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-1 H-pyrimidine-2,4-dione (III) were dissolved in 170 mL of 2- methyl-tetrahydrofuran at a temperature of about 20°C. 3 mL (36.5 mmol) of a 12 N aqueous solution of HCI were added slowly, maintaining a temperature of about 20°C, and it was kept under stirring at said temperature for 30 minutes.
  • Comparative example 5 Purification of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3- methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III) 11.5 g of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III) (purity by means of UHPLC: 95.17%) were dissolved in 50 mL of isopropyl acetate at a temperature of about 80°C.
  • Example 6 Obtaining 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 ethyl ester (IVa)
  • the aqueous phase was separated and treated with a fraction of 300 mL of isopropyl acetate.
  • the combined organic phases were treated with 200 mL of a saturated aqueous solution of NaHCO 3 .
  • the solvent was removed from the organic phase thus obtained by means of 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-phenylethyllamino)-butyric acid ethyl ester (IVa) (UHPLC: 88.46%).
  • Example 7 Obtaining 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 acid sodium salt (V)
  • the obtained mixture was filtered through a filter made up of a layer of diatomaceous earth and a 0.20 micra filter, the filter being washed with two fractions 30 mL of ethyl acetate each.
  • the filtered solution was slowly added to 1000 mL of n-heptane, maintaining the temperature between 5 and 10°C, the resulting mixture being maintained under stirring at the indicated temperature for 60 minutes.
  • DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software. Parameters: heating range of 30 to 300°C with a ramp of 20°C/min and N2 flow of 50 ml/min. The measurement is taken 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 K a radiation. Scanning parameters: 4-50 degrees 2Q, continuous scan, ratio: 1.2 degrees/minute.
  • the purity of the obtained products was analyzed by means of the ultra-high-performance liquid chromatography technique in a Waters Acquity model apparatus, provided with a photodiode detector and thermostated oven for the column.
  • the column used is an HSST3 column (2.1 x 100 mm and 1.8 mm) 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

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Abstract

The present invention relates to a new intermediate useful in the synthesis of elagolix, to a process for obtaining same, to the use of said intermediate for preparing elagolix, and to a process for preparing elagolix making use of said intermediate.

Description

3-[2(R)-AMINO-2-PHENYLETHYL]-5-(2-FLUORO-3-METHOXYPHENYL)-1-[2-FLUORO-6- (TRIFLUOROMETHYL)BENZYL]-6-METHYL-1 H-PYRIMIDINE-2,4(1 H,3H)-DIONE HYDROCHLORIDE SALT (I) IN SOLID FORM, PROCESS FOR PREPARING SAME, AND
USE THEREOF IN THE SYNTHESIS OF ELAGOLIX.
DESCRIPTION
Field of the Invention
The present invention relates to a new intermediate useful in the synthesis of elagolix, to a process for obtaining same, to the use of said intermediate for preparing elagolix, and to a process for preparing elagolix making 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 under development for treating uterine myomas in women.
Figure imgf000002_0001
Elagolix was approved by the FDA for treating pain associated with endometriosis in the United States on 23 July 2018. It was the first new medication approved by the FDA for treating endometriosis in over a decade. Elagolix is the first and currently the only marketed member of a new class of GnRH modulators, described as“second generation” due to the non-peptidic small-molecule nature and oral activity thereof.
Several synthetic routes for preparing 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 pathways proposed for preparing Elagolix use the intermediate 3-[2(R)- amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-1 H-pyrimidine-2,4(1H,3H)-dione (III):
Figure imgf000003_0002
Patent application WO 2019/112968 A1 describes a process of obtaining product (III) comprising the hydrolysis of product (II):
Figure imgf000003_0001
As described in said application, product (III) thus obtained is purified by means of recrystallization in a mixture of isopropyl acetate and heptane to yield a product with a purity of 99.8%.
Said purified product is reacted with ethyl 4-bromobutyrate to obtain product (IVa) which, by basic hydrolysis, provides product (V) as shown in the following scheme.
Figure imgf000004_0001
The inventors of the present application have reproduced the procedure for purifying compound (III) by means of recrystallization in 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 means of the described procedure. Furthermore, the product resulting from recrystallization was a sticky solid that was hard to handle and isolate.
Therefore, there is a need in the state of the art for alternative processes for obtaining Elagolix (V) starting from product (III), in particular from a product with low purity (preferably less than 96%).
Summary of the Invention The inventors have discovered that a simple way to obtain product (III) with a high purity, preferably greater than 99%, for subsequent use in the synthesis of elagolix is to generate the hydrochloride salt of said product in solid form (I):
Figure imgf000005_0002
Said salt in solid form (I) may be used in the synthesis of elagolix by a process in which product (III) is regenerated, subsequently being reacted with C1-4 alkyl halobutyrate according to the scheme shown below.
Figure imgf000005_0001
wherein 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 3- [2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I). DSC analysis was performed with a perforated closed capsule in a Mettler Toledo 822e apparatus 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 diffraction (XRPD) of 3-[2(R)-amino-2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-
2,4(1 H,3H)-dione hydrochloride salt (I). The diffractogram was obtained using a Siemens D- 500 model X-ray powder diffractometer equipped with a copper anode. Scanning parameters: 4-50 degrees 2Q, continuous scan, ratio: 1.2 degrees/minute. Detailed Description of the Invention
In a first aspect, the invention relates to 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)- dione hydrochloride salt (I) in solid form.
Figure imgf000006_0001
In a preferred embodiment of the first aspect of the invention, the 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1 -[2 -fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2, 4(1 H,3H)-dione hydrochloride salt (I) is amorphous.
In another preferred embodiment of the first aspect of the invention, the 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1 -[2 -fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2, 4(1 H,3H)-dione hydrochloride salt (I) has a heat/temperature curve in a differential scanning calorimetry having a negative peak at a temperature comprised 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 apparatus 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 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I) has a diffractogram measured with Cu Ka radiation essentially like the one in Figure 2. In said diffractogram, there are 3 broad bands at °2q positions of about 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 D-500 model X-ray powder diffractometer equipped with a copper anode. Scanning parameters: 4-50 degrees 2Q, continuous scan, ratio: 1.2 degrees/minute.
In a second aspect, the invention relates to a process for preparing 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H- pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I) in solid form comprising the steps of: a) contacting the compound of formula (II)
Figure imgf000007_0001
with an acid in the presence of a first solvent to obtain a salt of the compound of formula (III) in solution
Figure imgf000008_0002
b) optionally completely or partially removing 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)
Figure imgf000008_0001
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) completely or partially removing the solvent to obtain the product of formula (I) in solid form, and
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, with n being an integer of 1 to 3 and A-n a mono-, di-, or trivalent anion.
In an embodiment of the second aspect of the invention, the AHn acid used is selected from organic and inorganic protic acids with a pKa of less than 3. When the acid is polyprotic (n>1), pKa refers to that of the first proton. In an embodiment of the second aspect of the invention, the A-n anion is selected from the group consisting of chloride, methanesulfonate, and trifluoroacetate.
In an embodiment of the second aspect of the invention, the AHn 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 removing the solvent is performed by distillation at a pressure of less than 101325 Pa.
In an embodiment of the second aspect of the invention, step c) of neutralization is performed by addition of an aqueous solution of a base selected from the group consisting of inorganic hydroxides and carbonates, such as the hydroxides and the carbonates of alkaline and alkaline earth metals, for example NaOH, KOH, Na2CO3, and K2CO3.
In an embodiment of the second aspect of the invention, product (III) resulting from step c) is purified before performing step d). In a particular embodiment, when step c) has been carried out in aqueous medium, the purification is performed by i) extracting product (III) from the reaction medium with a solvent of low solublility in water 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 the same solvent mentioned in step i) again, and vi) separating the organic phase from said third solvent containing 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-methyl-tetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran/water, preferably 2-methyl-tetrahydrofuran and mixtures of 2-methyl-tetrahydrofuran/water.
In an embodiment of the second aspect of the invention, step d) is performed at a temperature of between 10°C and 40°C, preferably between 10 and 30°C, more preferably 20°C, maintaining stirring for a time comprised 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 removing the solvent is performed by distillation at a pressure of less than 101325 Pa.
In an embodiment of the second aspect of the invention, step f) of purification is performed by recrystallization of product (I) using a solvent selected from the group consisting of 2- methyl-tetrahydrofuran, methyl isobutyl ketone and C1-4 alkyl acetates, preferably 2-methyl- tetrahydrofuran.
In a third aspect, the invention relates to a process for preparing elagolix (V) comprising the steps of:
a) adding a third solvent to 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-
2,4(1 H,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 product (III),
c) reacting the solution of step b) with C1-4 alkyl 4-halobutyrate to obtain the product of formula (IV)
Figure imgf000010_0001
wherein R represents a C1-4 alkyl group, and
d) hydrolyzing the ester group of the compound of formula (IV) by means of treatment with NaOH to obtain the product of formula (V) Elagolix.
Figure imgf000011_0001
In an embodiment of the third aspect of the invention, the C1-4 alkyl 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 performed at a temperature comprised 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 performed at a temperature comprised between 70°C and 100°C, preferably between 80 and 90°C, more preferably between 80 and 85°C, maintaining stirring for a time comprised 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, product (IV) obtained in step c) is purified before performing step d). In a particular embodiment, purification is performed by i) adding to the reaction medium of step c) water and a solvent of low solubility in water, 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 the same solvent mentioned in step i) again, vi) separating the organic phase from said solvent containing product (IV), and v) removing the solvent to obtain product (IV).
In an embodiment of the third aspect of the invention, step d) of hydrolysis is performed in a solvent selected from the group consisting of water, C1 -3 alcohol, mixtures of C1 -3 alcohol and water, preferably isopropanol or a mixture of isopropanol and water.
In an embodiment of the third aspect of the invention, step d) of hydrolysis is performed using as a base an aqueous solution of NaOH at a temperature comprised 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-1 H-pyrimidine- 2,4(1 H,3H)-dione in solid form (I) in a process for preparing Elagolix (V).
In particular embodiments of the fourth aspect of the invention, the use of compound (I) is performed following the process 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-1 H-pyrimidine-2,4-dione (III)
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-1 H-pyrimidine-2,4-dione (II) were dissolved in 450 mL of acetonitrile at a temperature of about 20°C. 200 mL of water and 40 mL of a 12 N aqueous solution of HCI (480 mmol) were added, in this order, maintaining a temperature of about 20°C. The temperature of the obtained solution was increased to about 40°C, and it was kept under stirring at said temperature for 2 hours.
After keeping under stirring, the solvent was removed by means of vacuum distillation, and 200 mL of isopropyl acetate, and, slowly, a previously prepared solution containing 130 g of K2CO3 in 250 mL of water were added to the obtained residue. The aqueous phase was separated and treated successively with 2 fractions of 200 mL isopropyl acetate each. The combined organic phases were treated successively with a previously prepared solution 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 treated successively with 2 fractions of 200 mL isopropyl acetate each. 200 mL of isopropyl acetate and, slowly, 140 g of K2CO3 (pH of the aqueous phase of about 8.5) were added to the resulting aqueous phase. The aqueous phase was separated and treated successively with two fractions of 200 mL of isopropyl acetate each. The solvent was removed from the thus combined organic phases by means of vacuum distillation to obtain 67.35 g of an orange colored oil with a purity of 94.37% by means of UHPLC, comprising 3- ((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III).
Example 2: Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2- fluoro-6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III)
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-1 H-pyrimidine-2,4-dione (II) were dissolved in 80 mL of isopropyl acetate at a temperature of about 20°C. 9 g (93.8 mmol) of methanesulfonic acid were added, maintaining a temperature of about 20°C. The temperature of the obtained solution was increased to about 60°C, and it was kept under stirring at said temperature for 2 hours.
After keeping under stirring, 40 mL of water and a saturated solution of K2CO3 were added until a pH value of the resulting mixture of about 9. The organic phase was separated and 60 mL of water and H3PO4 was added 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 isopropyl acetate each. 40 mL of isopropyl acetate and, slowly, 30 g of K2CO3 were added to the resulting aqueous phase (pH of the aqueous phase of about 8). The aqueous phase was separated and treated successively with two fractions of 40 mL of isopropyl acetate each. The solvent was removed from the thus combined organic phases by means of vacuum distillation to obtain 11.56 g of an orange colored oil with a purity of 95.00% by means of UHPLC, comprising 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro- 6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione.
Example 3: Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2- fluoro-6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione hydrochloride salt (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-1 H-pyrimidine-2,4-dione (III) were dissolved in 170 mL of 2- methyl-tetrahydrofuran at a temperature of about 20°C. 3 mL (36.5 mmol) of a 12 N aqueous solution of HCI were added slowly, maintaining a temperature of about 20°C, and it was kept under stirring at said temperature for 30 minutes.
After keeping under stirring, the solvent was removed by means of vacuum distillation. 170 mL of 2-methyl-tetrahydrofuran were added, and the obtained suspension was heated at the reflux temperature, being maintained under stirring for 10 minutes. Subsequently, the obtained solution was slowly cooled to a temperature of about 20°C, and said temperature was maintained for 30 minutes. The resulting solid was isolated by means of filtration to obtain 14.3 g (yield: 79.1%, purity by means of UHPLC: 99.97%) of a white solid corresponding to 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione hydrochloride salt (I) in solid form.
Example 4: Obtaining 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2- fluoro-6-trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione hydrochloride salt (I)
11.5 g of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III) (purity by means of UHPLC: 95.17%) were dissolved in 100 mL of 2-methyl-tetrahydrofuran at a temperature of about 20°C. 2 mL (24.4 mmol) of a 12 N aqueous solution of HCI were added slowly, maintaining a temperature of about 20°C, and it was kept under stirring at said temperature for 30 minutes.
After keeping under stirring, the solvent was removed by means of vacuum distillation. 100 mL of 2-methyl-tetrahydrofuran were added, and the obtained suspension was heated at the reflux temperature, being maintained under stirring for 10 minutes. Subsequently, the obtained solution was slowly cooled to a temperature of about 20°C, and said temperature was maintained for 30 minutes. The resulting solid was isolated by means of filtration to obtain 8.58 g (purity by means of UHPLC: 99.94%) of a white solid corresponding to 3-((R)- 2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6- methyl-1 H-pyrimidine-2,4-dione hydrochloride salt (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-1 H-pyrimidine-2,4-dione (III) 11.5 g of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- trifluoromethylbenzyl)-6-methyl-1 H-pyrimidine-2,4-dione (III) (purity by means of UHPLC: 95.17%) were dissolved in 50 mL of isopropyl acetate at a temperature of about 80°C. Then 60 mL of n-heptane were slowly added, maintaining the temperature above about 60°C. Once this addition was finished, the resulting mixture was slowly cooled at a temperature of about 20°C, and it was kept under stirring at said temperature for 30 minutes.
After keeping under stirring, the mixture was cooled to a temperature of 10°C, and the resulting solid was isolated by means of filtration to obtain 5.13 g (purity by means of 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-1 H-pyrimidine-2,4- dione (III).
Example 6: Obtaining 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 ethyl ester (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-1 H-pyrimidine-2,4-dione hydrochloride salt (I) were mixed with 85 mL of dimethylformamide at a temperature of about 20°C. 45 mL of diisopropylethylamine were slowly added, and the obtained mixture was heated at 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 at a temperature of 80- 85°C, and it was kept under stirring at said temperature for 12 hours.
After keeping under stirring, 200 mL of isopropyl acetate and 100 mL of water were added successively. The aqueous phase was separated and treated with a fraction of 200 mL of isopropyl acetate. The combined organic phases were treated successively 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 200 mL of isopropyl acetate each. 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 fraction of 300 mL of isopropyl acetate. The combined organic phases were treated with 200 mL of a saturated aqueous solution of NaHCO3. The solvent was removed from the organic phase thus obtained by means of 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-phenylethyllamino)-butyric acid ethyl ester (IVa) (UHPLC: 88.46%).
Example 7: Obtaining 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 acid sodium salt (V)
The residue obtained in the preceding example 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 ethyl ester (IVa) was dissolved in 120 mL of isopropanol. A previously prepared aqueous solution with 9.5 g of NaOH and 120 mL of water was added to said solution at a temperature of about 20°C. The resulting mixture was heated at a temperature of about 35°C, and it was kept under stirring at said temperature for 2 hours.
After keeping under stirring, 350 mL of water and 200 mL of isopropyl acetate were added. The aqueous phase was separated and treated with two 200 mL of isopropyl acetate each. 90 g of NaCI and 200 of methyl isobutyl ketone were added to the treated aqueous phase. The aqueous phase was separated and treated with two fractions of 200 mL of methyl isobutyl ketone each. The combined organic phases were treated with a fraction of 200 mL of an aqueous solution of 20% NaCI. The solvent was removed from the organic phase by means of vacuum distillation, and the obtained residue was dissolved in 150 mL of ethyl acetate. The obtained mixture was filtered through a filter made up of a layer of diatomaceous earth and a 0.20 micra filter, the filter being washed with two fractions 30 mL of ethyl acetate each. The filtered solution was slowly added to 1000 mL of n-heptane, maintaining the temperature between 5 and 10°C, the resulting mixture being maintained under stirring at the indicated temperature for 60 minutes. The mixture was filtered to obtain a white solid which was dried at 40°C and under vacuum, yielding 41.83 g (yield of the two synthesis steps: 67.7%) of 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 acid sodium salt (V) (elagolix sodium salt), with a purity of 99.87% by means of UHPLC.
Assay conditions DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software. Parameters: heating range of 30 to 300°C with a ramp of 20°C/min and N2 flow of 50 ml/min. The measurement is taken 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. Scanning parameters: 4-50 degrees 2Q, continuous scan, ratio: 1.2 degrees/minute.
The purity of the obtained products was analyzed by means of the ultra-high-performance liquid chromatography technique in a Waters Acquity model apparatus, provided with a photodiode detector and thermostated oven for the column. The column used is an HSST3 column (2.1 x 100 mm and 1.8 mm) 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
Column temperature (°C): 40
Wavelength (nm): 270 (for elagolix), 210 (for the remaining compounds)
Inj. vol. (mL): 1
Acquisition time (min): 10
Diluent: acetonitrile/water (1 :1)
Gradient:
Figure imgf000017_0001

Claims

1. 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-
(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)-dione hydrochloride salt (I) in solid form.
Figure imgf000018_0001
2. Salt according to claim 1 , characterized by presenting an amorphous form.
3. Salt according to claim 2, characterized by presenting a heat/temperature curve in a differential scanning calorimetry having a negative peak at a temperature comprised 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 the one in Figure 2.
5. A process for preparing 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2- fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1 H,3H)-dione hydrochloride salt (I) in solid form comprising the steps of: a) contacting the compound of formula (II)
Figure imgf000019_0003
with an acid in the presence of a first solvent to obtain a salt of the compound of formula (III) in solution
Figure imgf000019_0001
b) optionally completely or partially removing 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)
Figure imgf000019_0002
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) completely or partially removing the solvent to obtain the product of formula (I) in solid form, and
f) optionally purifying the product of formula (I) in solid form obtained in step e).
6. A process according to claim 5, characterized in that the acid is an acid of formula AHn, with n being an integer of 1 to 3 and A-n a mono-, di-, or trivalent anion.
7. A process according to any of claims 5 to 6, characterized in that the acid is selected from organic and inorganic protic acids with a pKa of less than 3.
8. A process according to any of claims 5 to 7, wherein 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 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, 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 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2- fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-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 product (III),
c) reacting the solution of step b) with C1-4 alkyl 4-halobutyrate to obtain the product of formula (IV)
Figure imgf000021_0003
wherein R represents a C1-4 alkyl group, and
d) hydrolyzing the ester group of the compound of formula (IV) by means of treatment with NaOH to obtain the product of formula (V) Elagolix.
Figure imgf000021_0001
13. A process according to claim 12, wherein the C1-4 alkyl 4-halobutyrate is ethyl 4- bromobutyrate, such that the product obtained in step c) is:
Figure imgf000021_0002
14. Use of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-1 H-pyrimidine-2,4(1H,3H)-dione in solid form (I) in a process for preparing Elagolix (V).
PCT/EP2020/069529 2019-07-12 2020-07-10 3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix Ceased WO2021009034A1 (en)

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