EP3724167A1 - Process for preparing elagolix - Google Patents
Process for preparing elagolixInfo
- Publication number
- EP3724167A1 EP3724167A1 EP18720272.6A EP18720272A EP3724167A1 EP 3724167 A1 EP3724167 A1 EP 3724167A1 EP 18720272 A EP18720272 A EP 18720272A EP 3724167 A1 EP3724167 A1 EP 3724167A1
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- European Patent Office
- Prior art keywords
- compound
- formula
- bis
- theta
- degrees
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
-
- 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
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Definitions
- This invention relates to an improved process of preparation of elagolix of formula
- 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.
- 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).
- 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.
- the presented invention relates to a process for preparation of compound of formula
- the presented invention also relates to a process for preparation of compound of formula (1):
- X is Cl or Br or I.
- the presented invention further relates to a process comprising:
- X means Cl or Br or I
- 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):
- 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.
- the presented invention relates to a process for preparation of compound of formula
- the presented invention also relates to a process for preparation of compound of formula (1):
- X is Cl or Br or I.
- the presented invention further relates to a process comprising:
- 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 is 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.
- 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
- 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.
- 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
- An inorganic base for example a hydroxide (such as sodium hydroxide or
- 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.
- 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.
- 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.
- 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).
- a hydroxide such as sodium or potassium hydroxide
- a carbonate such as sodium, potassium carbonate
- 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.
- 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.
- 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 eth
- 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
- 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.
- the compound of formula (4) reacts with a halogenating agent to provide compound of formula (5).
- 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.
- a suitable solvent for example acetonitrile or water or acetic acid or nitromethane or a halogenated alkanes (such as dichloromethane,
- 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.
- a halogenating agent for example N-bromo succimide or bromine or HBr or a bromide (such as NH 4 Br, NaBr, KBr, CuBr, ZnBr 2 ) or I 2 or an iodide (such as NH 4 I, Nal, KI, Cul, Znl 2 ) 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 CF 3 COOH or AgNTf 2 or H 2 S0 4 or H 2 0 2 or BF 3 .Et 2 0 or NaI0 4 or DMSO.
- activator such as CF 3 COOH or AgNTf 2 or H 2 S0 4 or H 2 0 2 or BF 3 .Et 2 0 or NaI0 4 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.
- 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 MgS0 4 ) 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.
- 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
- an alcohol such as methanol, ethanol, butanol, s-butanol, tert- butanol, isopropanol, tert-amyl alcohol, amyl alcohol
- 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.
- an ether such as dimethyl ether, diethyl ether, methyl tert-butyl ether
- a halogenated alkane such as dichloromethane, chloroform
- an acetate such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate
- tetrahydrofurane or 2-methyl-tetrahydrofurane or an alcohol such as methanol, ethanol, butanol, s-butanol, tert-butanol, isopropanol, tert-amyl alcohol, amyl alcohol
- 1 ,4-dioxane or a mixture thereof can be used.
- a carbonate such as Na 2 C0 3 , K 2 CO 3 , Rb 2 C0 3 , Cs 2 C0 3
- a hydroxide such as NaOH, KOH, CsOH, Ba(OH) 2 , TlOH (and their hydrates)
- an alkoxide such as NaOCH 3 , NaOEt, TlOEt, NaO/-Bu, KO/-Bu
- a fluoride such as NaF, KF, CsF, Bu 4 NF
- an acetate for example AcOK, AcONa
- other inorganic base such as K 3 PO 4
- an amine such as Et 3 N. (/-Pr) 2 EtN
- 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 such as Na 2 C0 3 , K 2 CO 3 , Rb 2 C0 3 , Cs 2 C0
- 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) 2 Cl 2 or Pd 2 (dba) 3 or Pd 2 (dba) 3 -CFlCl 3 or Pd(acac) 2 .
- a ligand used with the Pd source can be for example PPh 3 or P(t-Bu) 3 or P(t-Bu) 3 HBF 4 or PCy 3 or PCy 3 HBF 4 or P(o-tol) 3 or trifuran-2-yl-phosphane or (4-(N,N- dimethylamino)phenyl)-di-tert-butylphosphine, HPCy 2 , P(t-Bu) 2 Cl, P(OMe) 3 , HPOPh 2 , 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(dip
- ii can be a compound selected for example from
- 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).
- 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
- Obtained compound (7) can be transformed into compound (1) for example by a process comprising: a. Deprotecting compound (7) to provide compound (8):
- 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));
- the compound (7) can be deprotected by using for example acidic conditions (using for example trifluoroacetic acid, methanesulfonic acid, HC1, H 2 S0 4 , 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
- 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.
- 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
- 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 Na 2 C0 , K 2 C0 , Rb 2 C0 , Cs 2 C0 ) 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
- 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.
- 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.
- ether such as dimethyl ether, diethyl ether, methyl tert-butyl ether
- a halogenated alkane such as dichloromethane, chloroform
- an acetate such as methylacetate, ethyl acetate, isopropyl acetate, iso-butyl acetate
- 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
- 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.
- 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.
- a sodium base such as sodium hydroxide or sodium methoxide or sodium hydride or sodium carbonate or sodium hydrogencarbonate.
- XRPD spectrum of obtained solid corresponds to XRPD spectrum depicted in Figure 1.
- XRPD spectrum was obtained using the following measurement conditions:
- 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).
- 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 7 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 Example 7 :
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EP17206428 | 2017-12-11 | ||
PCT/EP2018/061028 WO2019115019A1 (en) | 2017-12-11 | 2018-04-30 | Process for preparing elagolix |
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EP3724167A1 true EP3724167A1 (en) | 2020-10-21 |
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Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2802815B2 (en) * | 2019-07-12 | 2022-03-14 | Moehs Iberica Sl | 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 |
CN110372609B (en) * | 2019-07-25 | 2021-04-09 | 奥锐特药业股份有限公司 | Purification method of oxalagogri sodium salt |
CN112300081A (en) * | 2019-07-31 | 2021-02-02 | 上海度德医药科技有限公司 | Intermediate of oxadegril and preparation method and application thereof |
US11840519B2 (en) * | 2019-09-03 | 2023-12-12 | Industriale Chimica S.R.L. | Process for the synthesis of the sodium salt of 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)-phenyl]methyl]-3,6-dihydro-4-methyl-2.6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-butanoic acid (elagolix sodium salt) and intermediates of said process |
TWI755055B (en) * | 2019-09-18 | 2022-02-11 | 台灣神隆股份有限公司 | Process for preparing elagolix sodium and intermediates thereof |
WO2021064561A1 (en) * | 2019-10-03 | 2021-04-08 | Neuland Laboratories Limited | An improved process for the preparation of elagolix sodium |
ES2822398B2 (en) | 2019-10-30 | 2022-03-02 | Moehs Iberica Sl | 3-((R)-2-(Amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidin-2,4-dione or a salt of the same, procedure for its preparation and its use in the synthesis of elagolix |
CN115160584B (en) * | 2022-07-06 | 2024-03-22 | 西北工业大学 | Heterogeneous pore supermolecule organic framework constructed based on synergistic effect of cations-pi and static electricity and preparation method |
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EP1646389B1 (en) | 2003-07-07 | 2008-09-10 | Neurocrine Biosciences, Inc. | Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
CA2531507C (en) * | 2003-07-07 | 2013-10-01 | Neurocrine Biosciences, Inc. | Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
ATE557007T1 (en) * | 2003-07-07 | 2012-05-15 | Neurocrine Biosciences Inc | ARYLPYRIMIDINE SUITABLE FOR TREATING SEXUAL HORMONE RELATED CONDITIONS SUCH AS ENDOMETRIOSIS, PROSTATE CANCER AND THE LIKE |
WO2009062087A1 (en) | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
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