WO2019115019A1

WO2019115019A1 - Process for preparing elagolix

Info

Publication number: WO2019115019A1
Application number: PCT/EP2018/061028
Authority: WO
Inventors: Petr Bartos; Ondrej HYLSE
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2017-12-11
Filing date: 2018-04-30
Publication date: 2019-06-20
Anticipated expiration: 2020-06-11
Also published as: EP3724167A1

Abstract

The application relates to a process for the preparation of compound of formula (1) or a salt thereof (i.e. elagolix): The application also relates to solid crystalline forms of intermediates used in the process.

Description

PROCESS FOR PREPARING ELAGOLIX

BACKGROUND OF THE PRESENT INVENTION

This invention relates to an improved process of preparation of elagolix of formula

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Elagolix, 4-[2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]- 4-methyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydro- 1 -pyrimidinyl]- 1 (R)-phenylethylamino]butyric acid sodium salt, is an oral gonadotropin releasing hormone (GnRH) antagonist of formula

Elagolix is in pre-registration used for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.

Elagolix was first disclosed in W02005007165 application.

W02005007165 describes a process for preparation of elagolix. The process contains chromatographic purification of several intermediates in order to produce the intermediates and consequently the final product in a pure form, since the particular steps are accompanied by formation of a variety of impurities, which cannot be eliminated by crystallization due to their low crystallinity. Chromatographic purification steps are tedious and expensive process steps on an industrial scale. Also the overall yield of the preparation is low (15% of the theoretical yield).

An improved process for preparation of elagolix is disclosed in W02009062087 application. The process is depicted in following scheme:

The described process is limited by using iodine as a leaving group. The other halo leaving groups were not found to be reactive enough in the coupling reaction and are therefore not used in the process. The iodo intermediate is prepared via iodination of starting l-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(lH,3H)-dione with hazardous and expensive iodine monochloride compound. The overall yield of the described process is 35% of the theoretical yield.

Elagolix prior art process yield amorphous elagolix. Amorphous elagolix is difficult to purify and it is therefore necessary to purify individually the process intermediates to obtain the final elagolix in a sufficient purity.

Therefore, there is a need for alternative process that does not comprise

chromatographic purification, does not use hazardous halogenating reagents and provides elagolix in sufficient purity and yield.

SUMMARY OF THE INVENTION

The presented invention relates to a process for preparation of compound of formula

(1):

(1 ) ; or a salt thereof;

comprising isolating of a solid crystalline form of compound (4):

The presented invention also relates to a process for preparation of compound of formula (1):

; or a salt thereof;

comprising isolating of a solid crystalline form of compound (5):

wherein X is Cl or Br or I.

The presented invention further relates to a process comprising:

a. Reacting compound of formula (2) with a compound of formula (3) to provide compound of formula (4):

wherein LG means a leaving group; b. Reacting compound of formula (4) with a halogenating agent to provide compound of formula (5):

wherein X means Cl or Br or I;

c. Reacting compound of formula (5) with a compound of formula (6) to provide compound of formula (7) in a presence of a base and a catalyst:

transforming compound of formula (7) into compound of formula (1) or a salt thereof.

The salt of compound (1) is preferably sodium salt (i.e. elagolix) of formula:

The presented invention also relates to solid crystalline forms of compounds of formulas (4) and (5):

wherein X means Cl or Br or I.

The presented process does not comprise chromatographic purification, does not use hazardous halogenating reagents and provides elagolix in good purity and yield.

DETAILED DESCRIPTION OF THE INVENTION

(1):

; or a salt thereof;

comprising isolating of a solid crystalline form of compound (4):

; or a salt thereof;

comprising isolating of a solid crystalline form of compound (5):

wherein X is Cl or Br or I.

The presented invention further relates to a process comprising:

wherein X means Cl or Br or I

reacting compound of formula (5) with a compound of formula (6) to provide compound of formula (7) in a presence of a base and a catalyst:

The LG group of compound (3) can be for example OH, mesylate, tosylate and other alkyl sulfonate, a perfluoroalkylsulfonate (such as triflate), a halogenide (such as iodine, bromine, chlorine), preferably it is an alkyl sulfonate (such as mesylate os tosylate), more preferably it is mesylate. The reaction step a. can be done in a solvent selected from N,N- dimethyl formamide (DMF) or an alcohol (such as MeOH, 1 ,2-Propanediol, EtOH, n-BuOH, s-BuOH, t-BuOH, i-PrOH, amyl alcohol, tert-amyl alcohol) or nitromethane or acetonitrile or dimethylsulfoxide or N-methyl pyrrolidone or an ketone (such as methyl isobutyl ketone) or an ether (such as dimethyl ether, diethyl ether, methyl-tert-butyl ether) or tetrahydrofurane or 2-methyl-tetrahydrofurane or an acetate (such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate) or l,4-dioxane at a temperature between 40°C and the reflux temperature of used solvent for 1 to 50 hours, preferably for 10 to 30 hours. The

concentration of compound (2) in the solvent can be between 0.05 and 2 g/ml, preferably it is between 0.07 and 1.2 g/ml. The concentration of compound (3) in the solvent can be between 0.08 and 0.3 g/ml, preferably it is between 0.1 and 0.2 g/ml. The molar ratio between compounds (2) and (3) can be between 1 :0.8 and 1 :5 preferably it is between 1 : 1 and 1 :1.5. The reaction is done in a presence of a suitable base. The suitable base is selected from: i. An organic base, such as an amine (for example diethylamine, triethylamine, iso- propyl diethyl amine) or l,8-Diazabicyclo[5.4.0]undec-7-ene or 1,5- Diazabicyclo(4.3.0)non-5-ene or l,4-diazabicyclo[2.2.2]octane or a phosphazene base (such as tert-Butylimino-tris(dimethylamino)phosphorane, tert-Butylimino- tri(pyrrolidino)phosphorane, 2-tert-Butylimino-2-diethylamino-l,3-dimethyl- perhydro- 1 ,3 ,2-diazaphosphorine, 1 -tert-Butyl-4,4,4-tris(dimethylamino)-2,2- bis [tris(dimethylamino)-phosphoranylidenamino] -2l5 ,4l5 - catenadi(phosphazene)) or an organometal (such as MeLi, BuLi, t-BuLi, MeMgBr, EtMgCl, i-PrMgBr, PhMgBr, hexyllithium, octyllithium) or an amide (such as Lithium diisopropylamide, Lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide); or

ii. An inorganic base for example a hydroxide (such as sodium hydroxide or

potassium hydroxide) or a carbonate (such as sodium carbonate, potassium carbonate) or a hydrogencarbonate (such as sodium hydrogencarbonate or potassium hydrogencarbonate). The molar ratio between the compound of formula (2) and the base can be between 1 : 1 and 1 :10, preferably it is between 1 :3 and 1 :8.

The reaction is preferably done under a protective atmosphere, for example under nitrogen or argon atmosphere. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the reaction mixture is mixed with water and a water immiscible solvent, for example an ether (such as methyl tert-butyl ether, diethylether, dimethylether) or a halogenated alkane (such as dichloromethane, chloroform) or toluene. The phases are separated and the water phase can be washed with the water immiscible solvent. The water immiscible solvent phases are mixed together. They can be washed with water and/or a water solution of a base, for example water solution of a hydroxide (such as sodium or potassium hydroxide) or a carbonate (such as sodium, potassium carbonate) or a hydrogencarbonate (such as sodium hydrogencarbonate, potassium hydrogencarbonate). The organic mixture is concentrated, for example to 1/2 or 1/4 or 1/10 or 1/100 of its original volume and to the remaining mixture a suitable antisolvent is added. The antisolvent can be for example n-heptane or hexane or water, preferably it is n-heptane. The antisolvent is added slowly, in the course of for example 10, 20, 30, 40, 50 or 60 minutes and the mixture is stirred for between 10 minutes and 10 hours to precipitate a solid form of compound (4) from the mixture. The solid compound (4) can be isolated by any suitable method, for example by filtration.

We have surprisingly found that the compound (4) can be isolated in a solid form. The solid form is characterized by XRPD pattern having 20 values 5.9°, 11.3°, 17.4°, 17.8° and 18.3° degrees 2 theta ( + 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern having 20 values: 5.9°, 11.3°, 12.3°, 14.3°, 16.5°, 17.4°, 17.9°, 18.3°, 19.5°, 20.4°, 21.3° and 22.1° degrees 2 theta ( + 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern depicted in Figure 1. The solid form of compound formula (4) can also be crystallized by a process comprising dissolving compound (4) in a solvent and seeding the mixture. To this mixture an antisolvent can be optionally added. The solvent can be for example selected from N,N- dimethyl formamide (DMF) or an alcohol (such as methanol, 1 ,2-Propanediol, ethanol, n- butanol, s-butanol, t-butanol, iso-propanol, amyl alcohol, tert-amyl alcohol) or nitromethane or acetonitrile or dimethylsulfoxide or N-methyl pyrrolidone or an ketone (such as methyl isobutyl ketone) or an ether (such as dimethyl ether, diethyl ether, methyl-tert-butyl ether) or tetrahydrofurane or 2-methyl-tetrahydrofurane or an acetate (such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate). The antisolvent can be for example n-heptane or hexane or water, preferably it is n-heptane. The crystalls for seeding can be prepared for example by a procedure described in Example 6.The concentration of compound (4) in the solvent can be between 0.2 g/ml and 0.7 g/ml, preferably it is between 0.3 g/ml and 0.5 g/ml. The ratio between the solvent and the antisolvent can be between 1 : 1 and 1 :3 (vokvol), preferably it is between 1 :1.1 and 1 :1.5 (vokvol).

The mixture of compound (4) in solvent and antisolvent can be optionally cooled to a temperature for example between -l0°C and 25°C and stirred at this temperature for between for example 0.5 and 5 hours.

The solid compound (4) can be isolated by any suitable method, for example by filtration.

Isolated solid form is characterized by XRPD pattern having 20 values 5.9°, 11.5° and

18.7° degrees 2 theta ( + 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern having 20 values: 5.9°, 7.9°, 11.5°, 18. 2° and 18.7° degrees 2 theta ( + 0.2 degrees 2 theta). The solid form can be further characterized by XRPD angles given in following table:

The solid form can be further characterized by XRPD pattern depicted in Figure 3.

In the reaction step b. the compound of formula (4) reacts with a halogenating agent to provide compound of formula (5). The reaction is done in a suitable solvent, for example acetonitrile or water or acetic acid or nitromethane or a halogenated alkanes (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate) or tetrahydrofurane or 2-methyl-tetrahydrofurane or an alcohol (such as methanol, ethanol, butanol, s-butanol, tert-butanol, isopropanol, tert-amyl alcohol, amyl alcohol) or l,4-dioxane. The concentration of compound (4) in the solvent can be between 0.08 and 1 g/ml, preferably it is between 0.15 and 0.4 g/ml. As a halogenating agent for example N-bromo succimide or bromine or HBr or a bromide (such as NH₄Br, NaBr, KBr, CuBr, ZnBr₂) or I₂ or an iodide (such as NH₄I, Nal, KI, Cul, Znl₂) or IC1 or N- Iodosuccinimide or trimethyl silyl iodide or N-Chlorosuceinimide or Trichloroisocyanuric acid can be used. The halogenating reaction can be performed in a presence of another reagent (activator) such as CF₃COOH or AgNTf₂ or H₂S0₄ or H₂0₂ or BF₃.Et₂0 or NaI0₄ or DMSO.

The molar ratio between the compound of formula (4) and the halogenating agent can be between 1 : 1 and 1 :5, preferably it is between 1 :1.1 and 1 :1.7. The reaction is done at a temperature between 20°C and 60°C, preferably at room temperature for 1 to 100 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the reaction mixture is concentrated to between 1/5 and 1/20, preferably to 1/10 of the original volume. The mixture is washed with water, dried (for example using MgS0₄) and filtered. The mixture is concentrated to obtain a rest. We have surprisingly found that the compound of formula (5) can be isolated in a crystalline form.

To prepare a crystalline form of compound (5) the rest is dissolved in a suitable solvent, for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as

methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate) or tetrahydrofurane or 2- methyl-tetrahydrofurane or an alcohol (such as methanol, ethanol, butanol, s-butanol, tert- butanol, isopropanol, tert-amyl alcohol, amyl alcohol) or 1 ,4-dioxane, preferably methyl tert- butyl ether and an antisolvent such as n-heptane or pentane or hexane or petrolether or water, preferably n-heptane is added to precipitate the compound (5) from the mixture. The volume ratio between the solvent and the antisolvent can be between 1 : 1 and 1 :10, preferably between 1 : 1 and 1 :3. The concentration of compound (5) in the solvent can be between 0.2 and 2 g/ml, preferably is it between 0.4 and 1 g/ml. The mixture can be cooled, for example to a temperature between -20°C and the room temperature. The compound (5) is isolated from the mixture by any suitable method, for example by filtration. In the case the compound (5) has the following formula (wherein X means Br):

the solid form is characterized by XRPD pattern having 2Q values 7.4°, 14.4°, 17.0°, 17.8° and 20.9° degrees 2 theta ( + 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern having 2Q values: 7.4°, 14.4°, 17.0°, 17.8°, 20.9°, 22.1° and 22.5° degrees 2 theta ( ± 0.2 degrees 2 theta).

The solid form can be further characterized by XRPD pattern depicted in Figure 2. Compound of formula (5) subsequently reacts with a compound of formula (6) in step c. to provide compound of formula (7) in a presence of a water mixture of a base and a catalyst in a suitable solvent. As a solvent an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate) or tetrahydrofurane or 2-methyl-tetrahydrofurane or an alcohol (such as methanol, ethanol, butanol, s-butanol, tert-butanol, isopropanol, tert-amyl alcohol, amyl alcohol) or 1 ,4-dioxane or a mixture thereof can be used. As a suitable base a carbonate (such as Na₂C0₃, K₂CO₃, Rb₂C0₃, Cs₂C0₃) or a hydroxide (such as NaOH, KOH, CsOH, Ba(OH)₂, TlOH (and their hydrates)) or an alkoxide (such as NaOCH₃, NaOEt, TlOEt, NaO/-Bu, KO/-Bu) or a fluoride (such as NaF, KF, CsF, Bu₄NF) or an acetate (for example AcOK, AcONa) or other inorganic base (such as K₃PO₄) or an amine (such as Et₃N. (/-Pr)₂EtN) can be used. The base is used in a form of a mixture with water. The volume ratio between the solvent and water is between 2 : 1 and 6:1, preferably between 3 : 1 and 5:1. A catalyst:

i. Can be either prepared by mixing a source of Pd with a ligand.

Pd source can be for example Pd(OAc)₂ or Pd(MeCN)₂Cl₂ or Pd₂(dba)₃ or Pd₂(dba)₃-CFlCl₃ or Pd(acac)₂.

A ligand used with the Pd source can be for example PPh₃ or P(t-Bu)₃ or P(t-Bu)₃ HBF₄ or PCy₃ or PCy₃ HBF₄ or P(o-tol)₃ or trifuran-2-yl-phosphane or (4-(N,N- dimethylamino)phenyl)-di-tert-butylphosphine, HPCy₂, P(t-Bu)₂Cl, P(OMe)₃, HPOPh₂, hexamethylphosphorous triamide, monophosphine 1, 2, 3,4,5- pentaphenyl-r-(di-tert-butylphosphino)ferrocene, l,3,5-triaza-7- phosphaadamantane, bis(p-sulfonatophenylphenylphosphine dihydrate dipotassium salt, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), bis[2-(diphenylphosphino)phenyl] ether, 1 , 1 '-bis-(diphenylphosphino)ferrocene, bis-diphenylphosphinomethane, 1 ,2-bis-(diphenylphosphino)ethane, 1 ,3-bis- (diphenylphosphino)propane, 1 ,4-bis-(diphenylphosphino)butane, 1 ,2-bis- (dicyclohexylphosphino)ethane, 1 , 1 '-bis(di-tertbutylphosphino)ferrocene, 2- dicyclohexylphosphino- 1 , 1 '-biphenyl, N-[2'-(dicyclohexylphosphino)-l , 1 '- biphenyl-2-yl]-N,N-dimethylamine, 2-(dicyclohexylphosphino)-3,6-dimethoxy- 2',4',6'-triisopropyl- 1 , 1 '-biphenyl, dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)- phosphane, 2-(dicyclohexylphosphino)-2'-methylbiphenyl, dicyclohexyl-(2',6'- diisopropoxy-[ 1 , 1 '-biphenyl]-2-yl)phosphine, sodium 2'-dicyclohexylphosphino- 2,6-dimethoxy- 1 , 1 '-biphenyl-3 -sulfonate hydrate, biphenyl-2-yl-di-tert-butyl- phosphane.

ii. Or can be a compound selected for example from

(bis(tricyclohexyl)phosphine)palladium(II) dichloride or bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) or (I,G- bis(diphenylphosphino)fenOcene)palladium(II) dichloride or dichloro[l,l'-bis(di- t-butylphosphino)ferrocene]palladium(II) or (2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , G- biphenyl) [2-(2’-amino- 1 , 1’-biphenyl)]palladium(II) methanesulfonate or (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'- biphenyl)[2-(N-methyl-2’-amino-l ,r-biphenyl)]palladium(II) methanesulfonate.

The concentration of compound (5) in the solvent can be between 0.04 and 2 g/ml, preferably it is between 0.05 and 1 g/ml. The molar ratio between compound (5) and the base can be between 1 : 1 and 1 :10. The reaction is done at a temperature between 40°C and the reflux temperature of used solvent for 1 to 10 hours, preferably for 3 to 6 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is concentrated. The rest is mixed with water or water solution of a base, for example water solution of a hydroxide (such as sodium or potassium hydroxide) or a carbonate (such as sodium carbonate or potassium carbonate) or a hydrogencarbonate (such as sodium hydrogencarbonate or potassium hydrogencarbonate) and water immiscible solvent, for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate). The phases are separated. The water phase is washed with the water immiscible solvent. The combined organic mixtures are dried (for example using MgS0₄), filtered and concentrated.

Obtained compound (7) can be transformed into compound (1) for example by a process comprising: a. Deprotecting compound (7) to provide compound (8):

b. Reacting compound (8) with compound (9) to provide compound (10)

wherein LG means a leaving group (such as an alkyl sulfonate (methane sulfonate, ethane sulfonate) or a perfluoroalkylsulfonate (for example triflate) or a halogen) and R means a protecting group (such as Cl -Cl 0 alkyl, alkyl sulfonate (such as methane sulfonate, ethane sulfonate), a perfluoroalkylsulfonate (for example triflate));

c. Deprotecting the compound of formula (10) to provide compound of formula (1) or a salt thereof.

The compound (7) can be deprotected by using for example acidic conditions (using for example trifluoroacetic acid, methanesulfonic acid, HC1, H₂S0₄, HBr, pentafluoropropionic acid, benzenesulfonic acid) in a suitable solvent (for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as

dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate)). The concentration of compound (7) in the solvent is between 0.05 and 1 g/ml, preferably between 0.1 g/ml and 0.5 g/ml. The deprotection is done at a temperature between 40°C and the reflux temperature of the used solvent for 1 to 10 hours. The reaction progress can be monitored by a suitable analytical technique e.g. by HPLC or GC. After the reaction is finished the reaction mixture is mixed with water solution of a base (for example water solution of a hydroxide (such as sodium hydroxide or potassium hydroxide) or a carbonate (such as sodium carbonate, potassium carbonate) or a

hydrogencarbonate (such as sodium hydrogencarbonate, potassium hydrogencarbonate)) to set pH of the mixture to 8 to 10. The phases are separated and the organic phase is concentrated to provide compound (8).

Compound (8) subsequently reacts with a compound of formula (9) in a suitable solvent, for example N,N-dimethylformamide or an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate)), in a presence of a suitable base, for example a carbonate (such as Na₂C0 , K₂C0 , Rb₂C0 , Cs₂C0 ) or a hydroxide (such as NaOH, KOH, CsOH, Ba(OH)₂, TlOH (and their hydrates)) or an alkoxide (such as NaOCH , NaOEt, TlOEt, NaO/-Bu, KO/-Bu) or a fluoride (such as NaF, KF, CsF, Bu₄NF) or an acetate (for example AcOK, AcONa) or other inorganic base (such as K P0₄) or an amine (such as Et N, (7-Pr)₂EtN). The concentration of compound (8) in the solvent can be between 0.5 g/ml and 3 g/ml, preferably it is between 0.7 and 2 g/ml. The concentration of compound (9) in the solvent can be between 0.1 and 5 g/ml, preferably it is between 0.3 and 0.9 g/ml. The reaction is performed at a temperature between 20°C and the reflux temperature of used solvent for 10 to 50 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, water and water immiscible solvent, for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate)) are added. The phases are separated, the organic phase is washed with water and concentrated to obtain compound of formula (10).

Compound of formula (10) is dissolved in a suitable solvent, for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate) or tetrahydrofurane or 2-methyl-tetrahydrofurane or an alcohol (such as methanol, ethanol, butanol, s-butanol, tert-butanol, isopropanol, tert-amyl alcohol, amyl alcohol) or l,4-dioxane and to the mixture a water solution of a base (for example water solution of a hydroxide, such as sodium or potassium hydroxide or a carbonate such as sodium carbonate, potassium carbonate or an hydrogencarbonate, such as sodium

hydrogencarbonate or potassium hydrogencarbonate) or a water solution of an acid (using for example trifluoroacetic acid, methanesulfonic acid, HC1, H₂S0₄, HBr, pentafluoropropionic acid, benzenesulfonic acid) is added. The concentration of compound (10) in the solvent can be between 0.1 and 1 g/ml, preferably between 0.2 and 0.5 g/ml. The water solution of the base or the acid is added slowly, for example in the course of 1, 5, 10, 20, 30, 40 or 50 minutes or dropwise. The molar ratio between compound (10) and the base or the acid can be between 1 : 1 and 1 :10, preferably between 1 :1.5 and 1 :3. The reaction is done at a temperature between 30°C and 60°C, preferably between 35°C and 45°C for 1 to 20 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, a water immiscible solvent, for example an ether (such as dimethyl ether, diethyl ether, methyl tert-butyl ether) or a halogenated alkane (such as dichloromethane, chloroform) or an acetate (such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate)) is added. The mixture is stirred for 10 to 120 minutes and the phases are separated. The water phase is washed with the water immiscible solvent. The organic mixtures are mixed, washed with water and concentrated to provide compound (1) or a salt thereof.

Compound (1) can be optionally transformed into a salt, preferably sodium salt, using a reaction with a sodium base, such as sodium hydroxide or sodium methoxide or sodium hydride or sodium carbonate or sodium hydrogencarbonate.

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

EXAMPLES

Example 1 :

Preparation of tert-butyl (R)-(2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6- dioxo-3 ,6-dihydropyrimidin- 1 (2H)-yl)- 1 -phenylethyl)carbamate (compound (4)) :

6.13 g of l-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2.4(lH,3H)-dione,

10.23 g of (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate and 7 g of potassium carbonate were suspended in 72 ml of DMF under the stream of Argon. The mixture was heated to 50-55 °C. The mixture was stirred at this temperature for 23 hours. To the reaction mixture 100 ml of water and 100 ml of methyl tert-butyl ether were added.

Layers were separated and the aqueous phase was extracted with 2 x 50 ml of methyl tert- butyl ether. The combined organic phases were washed with 70 ml of water and 70 ml 2 M of aqueous NaOH. The organic phase was concentrated to approx. 1/5 of the original volume. To this solution 25 ml of n-heptane was added in the course of 20 minutes. After few minutes the solid started forming. The mixture was stirred for 30 min. 25 ml of heptane was added and the suspension was filtered. The solid was dried under vacuo at room temperature to provide 10.02 g (95% of the theoretical yield) of compound (4) (purity 98.3%. HPLC IN).

The XRPD spectrum of obtained solid corresponds to XRPD spectrum depicted in Figure 1. XRPD spectrum was obtained using the following measurement conditions:

Panalytical Empyrean diffractometer with Q/2Q geometry (transmition mode), equipped with a PixCell 3D detector;

Example 2:

Preparation of tert-butyl (R)-(2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4- methyl-2,6-dioxo-3 ,6-dihydropyrimidin- 1 (2H)-yl)- 1 -phenylethyl)carbamate;

to the mixture of 9.52 g of tert-butyl (R)-(2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-

2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)carbamate in 46 ml of acetonitrile 3.52 g of N-bromosuccinimide was added at 25°C. The mixture was stirred at 25°C for 90 hours. The reaction mixture was concentrated to approx 1/10 of the original volume. 70 ml of methyl tert-butyl ether was added to the mixture and the mixture was washed with 2 x 40 ml of water. The washed organic solution was dried (over MgS0₄) and filtered. The mixture was concentrated. The obtained residue was dissolved in 15 ml of methyl tert-butyl ether. To the solution 20 ml of n-heptane was added. The mixture was cooled at -5°C and was stirred at this temperature for 10 hours. The solid was filtered off and dried to provide 10 g (92% of theoretical yield) of product (98% purity HPLC IN).

The XRPD spectrum of obtained solid corresponds to XRPD spectrum depicted in

Figure 2. XRPD spectrum was obtained using the following measurement conditions:

Bruker-AXS D8 Vario diffractometer with Q/2Q geometry (reflection mode), equipped with a LynxEye detector:

Example 4:

Preparation of tert-butyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3 ,6-dihydropyrimidin- 1 (2H)-yl)- 1 - phenylethyl)carbamate (compound 7):

6 g of tert-butyl (R)-(2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo- 3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)carbamate and 2.2 g of 2-fluoro-3- methoxyphenyl)boronic acid were dissolved in 80 ml of dioxane. To the mixture a solution of 6.36 g of potassium phosphate tribasic in 20 ml of water was added. Obtained clear solution was degassed for 10 min at room temperature. Then, 8.6 mg of Pd-Xphos-G4 was added. The solution was stirred at 70 °C for 3.5 hours. Reaction mixture was cooled down to approx 45 °C and approx 50 ml of the solvent was removed by evaporation. The residue was diluted with 70 ml of ethyl acetate and 70 ml of saturated aqueous solution of NaHCCfi. The phases were separated and the aqueous phase was extracted once more with 70 ml of ethyl acetate. The combined organic extracts were dried over MgS0₄, filtered and concentrated to provide 5.9 g (91% of theoretical yield) of compound (7) (purity 91% HPLC IN).

Example 5 :

Preparation of elagolix sodium:

5.67 g of tert-butyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3 ,6-dihydropyrimidin- 1 (2H)-yl)- 1 - phenylethyl)carbamate was added to 29.3 ml of isopropyl acetate at room temperature. 1.7 ml (26.3 mmol) of methanesulfonic acid was added dropwise at room temperature. The solution was heated to 60 °C and stirred at this temperature for 2 hours. The mixture was cooled down to 20 °C. To the mixture a solution of 6 g of potassium carbonate in 29 ml of water was slowly added. The phases were separated. The organic phase was washed with a solution of 3.01 ml (43.9 mmol) of ortho-phosphoric acid in 50 ml of water. The phases were separated. The aqueous phase was washed with 38 ml of isopropyl acetate. The aqueous phase was treated with a solution of 8.24 g of potassium carbonate in 32 ml of water. 54 ml of isopropyl acetate was added. The biphasic mixture was stirred for 15 min, the phases were separated and the organic phase was filtered. The obtained solution was concentrated to afford 4.25 g (89% of the theoretical yield) of compound (8).

4 g of compound (8) was dissolved in 12.6 ml of isopropyl acetate and 3.8 ml of DMF was added. From the mixture 12.6 ml of the solvent was evaporated at 45°C and 80 mbars (isopropyl acetate was distilled off). To the resulting solution 1.2 ml (8.43 mmol) of ethyl 4- bromobutyrate and 1.7 ml (9.53 mmol) of N,N-diisopropylethylamine at room temperature. The mixture was stirred at 55 °C under Argon for 22 hours. The mixture was cooled down to 20 °C. 23 ml of isopropyl acetate and 20 ml of water were added. The biphasic mixture was stirred for 10 minutes. The phases were separated and the organic phase was washed with 20 ml of water. The organic phase was treated with a solution of 1.3 ml (19.06 mmol) ortho- phosphoric acid in 32 ml of water. On the bottom of the aqueous phase a yellow gel was formed. The phases were separated (the gel was collected together with the aqueous phase) and the organic phase was treated once more with a solution of 0.34 ml (4.91 mmol) ortho- phosphoric acid in 4 ml of water. The phases were separated (the gel was formed, collected with aqueous phase). Aqueous fractions were combined and washed with 4 ml of isopropyl acetate. The aqueous phase was mixed with 23 ml of dichloromethane. A solution of 4.9 g of potassium carbonate in 6.1 ml of water was slowly added. The layers were separated. The organic solution was concentrated to the amount of approx 10 g. This yellow residue was passed through a short (1 cm) pad of silica gel pre-conditioned with DCM, eluted with DCM- EtOH mixture (100:1, 100 ml). Appropriate fractions were combined and the obtained solution was concentrated to afford 3.67 g (76 % of the theoretical yield) of compound (10).

3 g of compound (10) were dissolved in 10 ml of ethanol. A solution of 0.45 g of NaOH in 5 ml of water was added dropwise at room temperature. The solution was stirred at 40°C for 3 hours. The mixture was mixed with 50 ml of water and 75 ml of Methyl Isobutyl Ketone, the biphasic mixture was stirred for 15 minutes. The phases were separated. The aqueous phase was extracted with 2 x 75 ml of methyl isobutyl ketone. The organic phase was washed with 150 ml of brine and concentrated to provide 2.36 g (yield 80% of the theoretical yield) of elagolix sodium.

The overall yield of elagolix sodium preparation was 43 % of the theoretical yield (based on l-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2.4(lH.3H)-dione).

Example 6:

Preparation of crystalline compound (4) - seeding crystals

0.4 g of compound (4) prepared according to Example 1 was dissolved in 5 ml of toluene and 3 ml of n-heptane were added to the mixture at 23°C. 1 ml of the mixture was allowed to stand in a fume hood on a Petri dish overnight. The solvent evaporated to provide crystalline compound (4) that was used for seeding. XRPD spectrum of the obtained solid form corresponds to XRPD spectrum depicted in Figure 3. XRPD spectrum was obtained using the same method as in Example 1. Example 7 :

Preparation of crystalline compound (4)

5.5 g of l-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2.4(lH,3H)-dione, 9.18 g of (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate and 18.86 g of potassium carbonate were suspended in 70 ml of DMF under the stream of Argon. The mixture was heated to 65 °C. The mixture was stirred at this temperature for 23 hours. To the reaction mixture 80 ml of water and 80 ml of methyl tert-butyl ether were added. Three phases system was formed. The organic phase (the top phase) was washed with 55 ml of water and 55 ml 2 M of aqueous NaOH and was concentrated to obtain 26.2 g of the solution. To this solution 25 ml of n-heptane was added in the course of 20 minutes. To the mixture 10 mg of crystalls prepared in Example 6 were added. After few minutes the solid started forming. The mixture was stirred for 30 min. The solid was filtered off and washed with 25 ml of heptane. The solid was dried under vacuo at room temperature to provide 8,43 g (89% of the theoretical yield) of compound (4) (purity 99.2%. HPLC IN). XRPD spectrum of the obtained solid form corresponds to XRPD spectrum depicted in Figure 3. XRPD spectrum was obtained using the same method as in Example 1. Example 8:

Recrystallization of compound (4)

1 g of compound (4) prepared according to Example 1 was dissolved in 17,5 ml of 2- propanol at 85-90°C. The mixture was cooled at -lO°C and 100 mg of crystalls prepared according to Example 6 were added. The mixture was left to stand overnight at -lO°C to provide 0.88 g of solid compound (4). XRPD spectrum of the obtained solid form

corresponds to XRPD spectrum depicted in Figure 3. XRPD spectrum was obtained using the same method as in Example 1.

Claims

1. A process for preparation of compound of formula (1) or a salt thereof:

comprising isolating of solid crystalline form of compound (4):

<⁴>

2. The process according to claim 1 wherein the solid crystalline form is characterized by XRPD pattern having 2Q values 5.9°, 11.3°, 17.4°, 17.8° and 18.3° degrees 2 theta ( + 0.2 degrees 2 theta).

3. The process according to claim 1 wherein the solid crystalline form is characterized by XRPD pattern having 2Q values 5.9°, 11.5° and 18.7° degrees 2 theta ( + 0.2 degrees 2 theta).

4. A process for preparation of compound of formula (1) or a salt thereof:

comprising isolating of a solid crystalline form of compound (5):

wherein X is Cl or Br or I.

5. The process according to claim 4 wherein the compound (5) has a structure:

and the solid crystalline form is characterized by XRPD pattern having 2Q values 7.4°, 14.4°, 17.0°, 17.8° and 20.9° degrees 2 theta ( + 0.2 degrees 2 theta).

6. The process according to anyone of claims 1 to 5 comprising:

wherein LG means a leaving group

b. Isolating solid crystalline form of compound of formula (4)

c. Reacting compound of formula (4) with a halogenating agent to provide

compound of formula (5):

wherein X means Cl or Br or I;

d. Isolating a solid crystalline form of compound of formula (5)

e. Reacting compound of formula (5) with a compound of formula (6) to provide compound of formula (7) in a presence of a base and a catalyst:

f. Transforming compound of formula (7) into compound of formula (1) or a salt thereof.

7. The process according to claim 6 wherein the isolating step b. comprises seeding with the solid crystalline form of compound (4) characterized by XRPD pattern having 2Q values 5.9°, 11.5° and 18.7° degrees 2 theta ( ±0.2 degrees 2 theta).

8. The process according to of claim 6 or 7 wherein the halogenating agent is selected from N-bromosuccimide or bromine or HBr or a bromide or iodine or an iodide or N- Iodosuccinimide or trimethyl silyl iodide or N-Chlorosuccinimide or

Trichloroisocyanuric acid.

9. The process according to anyone of claims 6 to 8 wherein the halogenating agent is N- bromosuccimide .

10. The process according to any of claims 6 to 9 wherein the base is selected from Na₂C03 or K₂C0₃ or Rb₂C0₃ or Cs₂C0₃ or NaOH or KOH or CsOH or Ba(OH)₂ or TlOH or

NaOCH₃ or NaOEt or TlOEt or NaO/-Bu or KO/-B11 or NaF or KF or CsF or Bu₄NF or potassium acetate or sodium acetate or K3PO4 or Et₃N or (7-Pr)₂EtN.

11. The process according to any of claims 6 to 10 wherein the catalyst is selected from a mixture comprising:

1. A Pd source selected from Pd(OAc)₂ or Pd(MeCN)₂Cl₂ or Pd₂(dba)₃ or

Pd₂(dba)vCHCh or Pd(acac)_2; and

11. A ligand selected from PPh₃ or P(t-Bu)3 or P(t-Bu)3 HBF₄ or PCy3 or PCy3 HBF₄ or P(o-tol)3 or trifuran-2-yl-phosphane or (4-(N,N-dimethylamino)phenyl)-di-tert- butylphosphine or HPCy₂ or P(t-Bu)₂Cl or P(OMe)3 or HPOPh₂ or

hexamethylphosphorous triamide or monophosphine l,2,3,4,5-pentaphenyl-l'-(di- tert-butylphosphino)ferrocene or l,3,5-triaza-7-phosphaadamantane or bis(p- sulfonatophenylphenylphosphine dihydrate dipotassium salt or (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphine) or bis[2-(diphenylphosphino)phenyl] ether or 1 , r-bis-(diphenylphosphino)ferrocene or bis-diphenylphosphinomethane or l,2-bis-(diphenylphosphino)ethane or l,3-bis-(diphenylphosphino)propane or 1 ,4-bis-(diphenylphosphino)butane or 1 ,2-bis-(dicyclohexylphosphino)ethane or 1 , 1 '-bis(di-tertbutylphosphino)ferrocene or 2-dicyclohexylphosphino- 1,1'- biphenyl or N-[2'-(dicyclohexylphosphino)- 1 , 1 '-biphenyl-2-yl]-N,N- dimethylamine or 2-(dicyclohexylphosphino)-3 ,6-dimcthoxy-2',4',6'-triisopropyl- l, -biphenyl or dicyclohexyl-(2',6’-dimethoxybiphenyl-2-yl)-phosphane or 2- (dicyclohexylphosphino)-2'-methylbiphenyl or dicyclohcxyl-(2\6'-diisopropoxy- [l, -biphenyl]-2-yl)phosphine or sodium 2'-dicyclohcxylphosphino-2,6- dimethoxy-l, -biphenyl-3 -sulfonate hydrate or biphenyl-2-yl-di-tert-butyl- phosphane.

12. The process according to any of claims 6 to 11 wherein the catalyst is selected from (bis(tricyclohexyl)phosphine)palladium(II) dichloride, bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), ( 1 , G- bis(diphenylphosphino)ferrocene)palladium(II) dichloride, dichloro[ 1 , 1 '-bis(di-t- butylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2',4',6'-triisopropyl- I,G- biphenyl) [2-(2’-amino-l,r-biphenyl)]palladium(II) methanesulfonate, (2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'- biphenyl)[2-(N-methyl-2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate.

13. The process according to any of claims 6 to 12 wherein the compound of formula (7) is transformed by a process comprising: a. Deprotecting compound (7) to provide compound (8):

compound (9) to provide compound (10)

wherein LG means a leaving group and R means a group selected from Ci-Cio alkyl or an alkyl sulfonate or a perfluoroalkylsulfonate;

14. The process according to anyone of claims 1 to 13 wherein the salt of compound (1) is sodium salt of formula:

15. A crystalline compound of formula:

16. The crystalline compound of claim 15 characterized by XRPD pattern having 2Q values 7.4°, 14.4°, 17.0°, 17.8° and 20.9° degrees 2 theta ( ± 0.2 degrees 2 theta).

17. A crystalline compound of formula:

18. The crystalline compound according to claim 17 characterized by XRPD pattern having 2Q values 5.9°, 11.3°, 17.4°, 17.8° and 18.3° degrees 2 theta (+ 0.2 degrees 2 theta).

19. The crystalline compound according to claim 17 characterized by XRPD pattern having 2Q values 5.9°, 11.5° and 18.7° degrees 2 theta (+ 0.2 degrees 2 theta).