WO2020194115A1 - Process for the preparation of elagolix sodium and intermediates thereof - Google Patents

Process for the preparation of elagolix sodium and intermediates thereof Download PDF

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Publication number
WO2020194115A1
WO2020194115A1 PCT/IB2020/052344 IB2020052344W WO2020194115A1 WO 2020194115 A1 WO2020194115 A1 WO 2020194115A1 IB 2020052344 W IB2020052344 W IB 2020052344W WO 2020194115 A1 WO2020194115 A1 WO 2020194115A1
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Prior art keywords
formula
compound
elagolix
sodium
salt
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PCT/IB2020/052344
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French (fr)
Inventor
Shelen Thakur
Sonu Kumar
Bhuwan BHASHKAR
Sagar TATAR
Lovleen PANKAJ
Kamal Chand SHARMA
Jigar BHAVSAR
Ajay Kumar
Anil Kumar
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Mankind Pharma Ltd.
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Publication of WO2020194115A1 publication Critical patent/WO2020194115A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings

Definitions

  • Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist approved for the management of moderate to severe pain associated with endometriosis.
  • GnRH gonadotropin-releasing hormone
  • Elagolix is chemically known as 4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6- (trifluoromethy l)phenyl] methyl] -3, 6-dihydro-4-methyl-2,6-dioxo-l(2H)-pyrimidinyl]-l- phenylethyl] amino] butanoic acid and is represented by Figure la and its sodium salt is represented by Formula I:
  • WO 2005/007165 A1 discloses pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists.
  • WO’ 165 discloses process for preparing elagolix free acid and sodium salt thereof, wherein said salt is prepared by using ethyl acetate as a solvent followed by lyophilization. Above said application requires strong cation-exchange column for purification. Further, W0’165 discloses the process for preparation elagolix sodium as mentioned in the Scheme- 1 below:
  • WO 2009/062087 A1 describes a process for the preparation of elagolix sodium as mentioned in the Scheme-2, by using iodo intermediate of Formula X.
  • WO’087 further discloses multiple step purification process for obtaining off-white solid of elagolix and its sodium salt.
  • Formula I WO 2018/189212 A1 describes crystalline non-deliquescent acid addition salts of elagolix with strong acids having the pka values ⁇ 3, and their use as intermediates for the purification of elagolix sodium.
  • WO 2018/224063 A2 describes the crystalline solid forms of acid addition salts of elagolix prepared by reacting elagolix ester with strong acids having the pka values ⁇ 1 and their use in purification of the elagolix sodium salt.
  • the present invention provides a process for preparing pure Elagolix sodium and intermediates, which is economical and commercially viable.
  • the main object of present invention is to provide compounds of Formula A, isomers, polymorphs and process of preparation thereof.
  • Another object of the present invention is to provide a process for the preparation of Elagolix and pharmaceutically acceptable salts thereof, by using compounds of Formula A.
  • Another object of the present invention is to provide a process for the preparation of pure Elagolix and its sodium salt of Formula I.
  • Another object of the present invention is to provide conversion of elagolix of Formula la to elagolix sodium of Formula I.
  • the present invention provide compounds of Formula A, isomers, and polymorphs thereof,
  • S is a pharmaceutically acceptable salt
  • R is selected from hydrogen or C 1 -C 3 alkyl group substituted with R 4 , wherein R 4 is selected from -CN, -COR 5 wherein R 5 is selected from NR 6 R 7 , -ORs; wherein R 6 and R 7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group.
  • the present invention provide compounds of Formula A, wherein R is hydrogen, and is represented as Formula Vila,
  • S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide and fluoride salts.
  • the present invention provides compound of Formula Vila, wherein S is pamoate salt, and is represented as compound of Formula Vila'
  • the present invention provide compounds of Formula A, wherein R is selected from C 3 -alkyl substituted with R 4 , and is represented as Formula Villa,
  • S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide and fluoride salts, and
  • R 4 is selected from -CN, -COR 5 wherein R 5 is selected from NR 6 R 7 , -ORs; wherein R6 and R 7 are selected from hydrogen, straight or branched chain alkyl group, and Rx is selected from straight or branched chain alkyl group.
  • the present invention provides compound of Formula A, wherein R is C 3 - alkyl substituted with -CN, S is pamoate salt, and is represented as compound of Formula X',
  • Formula X' in another aspect, the present invention provides compound of Formula Vila' characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 9.40, and 15.59 ⁇ 0.2°q.
  • the present invention provides compound of Formula X' characterized by XRPD having peaks at diffraction angles 2-theta of 4.20, 7.63, 14.17, and 22.38 ⁇ 0.2°q.
  • the present invention provides a process for the preparation of compounds of Formula A,
  • PG is an amine protecting group
  • Ri and R2 are independently selected from hydrogen, saturated or unsaturated Ci- 6 alkyl, branched or straight chain Ci- 6 alkyl, or Ri and R2 together form substituted or unsubstituted cyclic ring optionally comprising of one or more hetero atoms and / or one or more double bonds; and
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
  • S is pharmaceutically acceptable salt
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
  • Another aspect of the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
  • the present invention provides use of compound of Formula A in the preparation of elagolix of Formula I or its salts.
  • the present invention provides triethylamine, morpholine and dicyclohexyl amine salt of elagolix of Formula la; wherein said salts are represented as Formulae la', la" and la'" respectively;
  • Fig. 1 represents the X-ray (powder) diffraction (XRPD) pattern of the Pamoic acid salt of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoro methyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula Vila.
  • XRPD X-ray (powder) diffraction
  • Fig. 2 represents the X-ray (powder) diffraction (XRPD) pattern of the Pamoic acid salt of 3-[2(R)- ⁇ 3-cyanopropyl-amino ⁇ -2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro- 6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula X.
  • XRPD X-ray (powder) diffraction
  • Fig. 3 represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of Elagolix sodium of Formula I.
  • Fig. 4 represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of Elagolix sodium of Formula I after 4 months.
  • “Pharmaceutically acceptable salts” or“salts” as used in the context of the present invention includes, but are not limited to pamoate, 2,3-dibenzoyl-tartarate (in particular (+)-2,3- dibenzoyl-D-tartarate), hydrochloride, hydrobromide, sulphate, phosphate salt; formate, acetate, diphenyl acetate, triphenylacetate, caprylic acid salt, dichloroacetate, trifluoro acetate, propionate, butyrate, lactate, citrate, gluconic acid salt, mandelate, tartarate, malic acid salt, adipic acid salt, aspartate, fumarate, glutamate, maleate, malonic acid salt, succinate, benzoate, p-chlorobenzoate, nicotinate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxy- naphthalene-2-carboxylate, hydro xyna
  • Suitable acid or“acids” as used in the context of the present invention refers to reagents selected from, but not limited to, pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)- 2,3-dibenzoyl-D-tartaric acid), hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloro acetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, oxalic acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, succinic acid, benzoic acid, p-chlorobenzoic acid, nicotinic acid,
  • Protecting group refers to compounds that has a purpose of temporarily masking the functionality of the site to which it is attached on a molecule. Prior to the use of the molecule in a subsequent analysis or application, the protecting group may or may not be removed.
  • the protecting groups are selected from any carbon, sulfur and silyl containing moiety such as tert-butyloxycarbonyl (BOC), acetyl, benzoyl, benzyl, tosyl, carbobenzyloxy(Cbz), carbamate group and the like.
  • “Leaving group” as used in the context of the present invention refers to compounds/groups that are replaceable and can easily depart the compound to which they are attached.
  • the leaving groups are selected from hydroxyl, tosylate (OTs), mesylate(OMs), silyl, triflate, iodide, bromide, chloride, fluoride, thioether, (un) substituted carboxylate and the like.
  • Suitable solvent refers to solvents selected from, but not limited to, the group comprising of alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like.
  • the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4- dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, acetamide
  • Suitable Base as used in context of the present invention are selected from, but not limited to, selected from organic and inorganic base such as pyridine, triethyl amine, diisopropyl ethyl amine, dimethyl amino pyridine, morpholine, dicyclohexyl amine, carbonates, hydroxides, bicarbonates and the like.
  • the base is selected from, but not limited to, the group comprising of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium bicarbonates, cesium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, and mixture thereof.
  • “Pharmaceutically acceptable excipient” as used in the context of the present invention may include, but not limited to an inorganic oxide such as silicon dioxide, titanium dioxide, zinc oxide, zinc dioxide, aluminium dioxide and zeolite; and organic polymers such as polyvinyl pyrrolidinone, cross linked cellulose acetate phthalate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethyle/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, povidone, povidone K-30, povidone K-60, Povidone K-90, Co-povidone, polyvinyl pyrrolidone vinyl acetate, polyvinyl alcohol, polysorbate 80, polyethylene glycol, methyl cellulose, Eudragit S-100, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelucire 44/14, ethyl cellulose, D-alphatocopheryl polyethylene glycol 1000 succinate
  • the present invention provide compounds of Formula A, isomers, and polymorphs thereof,
  • S is a pharmaceutically acceptable salt
  • R is selected from hydrogen or C1-C3 alkyl group substituted with R4, wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R 6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group.
  • the compounds of Formula A may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein.
  • the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula A as defined above wherein S is pharmaceutically acceptable acid addition salt (according to an embodiment defined below).
  • the present invention provide compounds of Formula A, wherein said compound is represented as compound of Formula Vila, and Villa;
  • S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide, and fluoride salts; and R4 is as defined above.
  • the present invention provides compounds of Formula A wherein said compounds are represented as Formulae Vila', and X';
  • the compound of Formula Vila' is characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 9.40, and 15.59 ⁇ 0.2°q.
  • the compound of Formula Vila' is characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 8.64, 9.16, 9.40, 10.31, 11.07, 11.46, 12.90, 15.23, 15.59, 16.60, 18.94, 19.31, 23.16, 25.03, 26.27, 29.91 and 33.88 ⁇ 0.2°q and as depicted in FIG-1.
  • the compound of Formula X' is characterized by XRPD having peaks at diffraction angles 2-theta of 4.20, 7.63, 14.17, and 22.38 ⁇ 0.2°q.
  • compound of Formula X' is characterized by its XRPD its XRPD having peaks at diffraction angles 2-theta of 4.20, 7.20, 7.63, 8.41, 9.17, 9.47, 10.51, 90.94,
  • the present invention provides a process for the preparation of compounds of Formula A, wherein said process comprises the steps of:
  • triarylphosphine catalyst such as triphenyl phosphine
  • azodicarboxylates catalyst such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD
  • said suitable solvent is selected from tetrahydrofuran, acetonitrile and toluene to obtain the compound of Formula III,
  • R 3 is a suitable leaving group selected from the group of halogen, hydroxyl, tosylate, mesylate or triflate and,
  • PG is amine protecting group selected from tert-butyloxycarbonyl (BOC), acetyl, benzoyl, tosyl or carbenzyloxy;
  • deprotecting agent selected from trifluoro acetic acid, cone. HC1, methanolic HC1, ethanolic HC1, IPA.HC1, ethyl acetate HC1, and 1,4-Dioxane HC1,
  • the present invention provides a process for the preparation of compounds of Formula A,
  • PG is an amine protecting group
  • X is selected from halogen and R 3 is selected from any suitable leaving group
  • Ri and R2 are independently selected from hydrogen, saturated or unsaturated Ci- 6 alkyl, branched or straight chain Ci- 6 alkyl, or Ri and R2 together form substituted or unsubstituted cyclic ring optionally comprising of one or more hetero atoms and / or one or more double bonds; and
  • the cross coupling reaction of compound of Formula II with boron derivative of Formula IV is carried out in presence of the suitable catalyst selected from any palladium or copper containing catalyst.
  • the suitable catalyst is selected from, but not limited to, the group comprising of palladium acetate and o-(di-tert-butylphosphino)biphenyl, tetrakis(triphenylphosphine)palladium(0), palladium acetate, bis(triphenylphosphine) palladium(II) dichloride, [l,r-bis(diphenylphosphino)ferrocene] palladium(II) dichloride and mixture thereof.
  • cross coupling of compound of Formula II with boron derivative of Formula IV is optionally carried out in presence of base which are as defined above.
  • R3 is selected from any leaving atom or group that is detached from the rest of a compound of Formula V and VI respectively, during a reaction of compound of Formula VI with compound of Formula V.
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of: a) deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable solvent to obtain compound of Formula VII,
  • S is pharmaceutically acceptable salt
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
  • deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable solvent to obtain compound of Formula VII, wherein said deprotecting agent is selected from the group comprising of trifluoro acetic acid, cone. HC1, methanolic HC1, ethanolic HC1, IPA.HC1, ethyl acetate HC1, and 1,4-Dioxane HC1;
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
  • the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
  • the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
  • the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
  • the present invention provides amorphous form of elagolix sodium as represented in Fig. 3.
  • the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
  • step c) treating either the reaction mass of step a) or the solution of step b) with aqueous solution of suitable base followed by addition of solvent to get a biphasic solution;
  • the suitable acid is selected from formic acid, oxalic acid and tartaric acid.
  • the process for the preparation of elagolix includes preparation of intermediates wherein said intermediates may optionally be not isolated, or may be converted to suitable salts before proceeding to next step.
  • the process for the preparation of elagolix includes preparation of intermediates wherein said intermediates may optionally be isolated as its pharmaceutically acceptable salts.
  • the compound of Formula A is converted to elagolix of Formula la or its sodium salt of Formula I by any known conventional method or by a process of the present invention.
  • the elagolix sodium of Formula A may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction, evaporation and lyophilization.
  • the present invention provides salts of elagolix of Formula B , wherein said salts (Base + ) are selected from, but not limited to, triethylamine, DMAP, pyridine, diisopropyl amine, DIPEA, dicyclohexyl amine, N-methyl morpholine, methyl amine and dicyclohexylamine.
  • the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
  • the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
  • the present invention provides a substantially pure elagolix sodium of Formula I, wherein said elagolix sodium is free from the compound of Formula A.
  • the present invention provides a substantially pure compound of Formula A, wherein said compound is free of impurity of Formula P and Q, preferably each impurity is less than about 0.3%w/w and wherein total impurity is less than about 1.0% w/w,
  • the present invention provides pure elagolix sodium of Formula I, wherein said elagolix sodium of Formula I is substantially free of impurities of Formula C to Y; wherein each impurity is less than about 0.3% w/w or total impurity less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;
  • the present invention provides pure elagolix sodium of Formula I, wherein said elagolix sodium is characterized by purity of 99.0% and above.
  • the present invention provides a substantially pure amorphous form of compound of Formula I, wherein said compound is free of intermediates of Formula VII and X, wherein said elagolix sodium is characterized by purity of 99.0% and above.
  • the amorphous form of elagolix sodium of present application is stable on storage as shown in Table- 1 as measured by Karl Fischer method, wherein the amorphous elagolix sodium does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about four months and more.
  • Table 1 Table 1:
  • the present invention provides amorphous solid dispersion of elagolix, comprising the steps of: a) adding elagolix of Formula la in a suitable solvent to get a solution; b) treating the solution of step a) with pharmaceutically acceptable carrier; and c) removing the solvent to get amorphous solid dispersion of elgolix.
  • present invention provides elagolix sodium of Formula I, having particle size distribution D90 less than about 200pm.
  • present invention provides a composition comprising elagolix sodium of Formula I, with atleast one or more pharmaceutically acceptable excipients.
  • Example-3 Synthesis of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l- [2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII: The 3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2, 4 (1H,3H)- dione of Formula III (15 g) was dissolved in methylene dichloride (75 ml) at room temperature and cool to 0-5°C then slowly added trifluoroacatic acid (15 ml) at 0-5°C within 30-45 minutes.
  • methylene dichloride 75 ml
  • trifluoroacatic acid
  • Example-4 Synthesis of Pamoic acid salt of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro- 3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula Vila (wherein S is pamoic acid salt): To a stirred solution of 3- [2(R)-amino-2-phenyl-ethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl] -6-methyl-pyrimidine-2, 4 (lH,3H)-dione of Formula VII (12.0 g) in 120 ml methanol at room temperature, followed by addition of pamoic acid (5.12 g) in methanol (25 ml).
  • Example-5 Synthesis of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l- [2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII: Pamoic acid salt of 3-[2(R)-amino-2-phenyl-ethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (1H,3H)- dione of Formula Vila 18.0 g was dissolved in 180 ml dichloromethane.
  • Example-6 Synthesis of 3-[2(R)- ⁇ 3-cyanopropyl-amino ⁇ -2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione: The 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2- fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula VII (10 g) was dissolved in acetonitrile (100 ml) and added 4-bromobutyronitrile (13.5 g) and triethylamine (3.7 g ).
  • Example-7 Synthesis of Pamoic acid salt of 3-[2(R)- ⁇ 3-cyanopropyl-amino ⁇ -2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-pyrimidine-2,4(lH,3H)-dione of Formula X': To a stirred solution of 3-[2(R)- ⁇ 3- cyanopropyl-amino ⁇ -2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula X 5.0 g in methanol (50 ml) was added pamoic acid solution (1.90 g pamoic acid solution in 15 ml methanol) and stirred at 60-65°C
  • Example-9 Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: To 3-[2(R)- ⁇ 3-cyanopropyl-amino ⁇ - 2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-pyrimidine-2,4(lH,3H)-dione (3.0 g) was added cone.
  • reaction mass was heated to 60-65°C for 6-10 hours. Then the reaction mass was cooled to 10-15°C and added aqueous solution of sodium hydroxide (0.41 gm in 12 ml DM water). Reaction mass was stirred at 25-30°C. To this charged MIBK (15.0 ml) and heated to 55-60°C for 15- 20 minute and layer was separated. Charged the aqueous layer and added MIBK (15.0 ml). To this added aqueous sodium hydroxide solution (1.96 g dissolved in 3.0 ml DM water) at 25-30°C. Reaction mass was stirred for 10-15 minute and layer was separated out at 25-30°C.
  • TPP tetrakis
  • the reaction mixture was cooled to 25-30°C and filtered through celite bed at 25-30°C. The solvent was removed under vacuum and residue was dissolved in ethyl acetate. Organic layer was washed with DM water and then with saturated brine solution. The organic layer was evaporated under vacuum to get residue. Residue was dissolved in dichloromethane (500 ml) at room temperature and cooled to 0-5°C then slowly added trifluoro acetic acid (50 ml) at 0-5°C within 30-45 minutes. The reaction mixture was stirred for 8-10 hours at 20-30°C.
  • TPP tetrakis
  • Example-11 Synthesis of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula VII: Dissolved 49.0 g Pamoate salt of 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl]-6- methyl-pyrimidine-2,4-(lH,3H)-dione of Formula Vila in 500 ml MDC meanwhile prepared saturated sodium bicarbonate solution (500 ml).
  • Example-12 Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I:
  • the 3-[2(R)-amino-2-phenylethyl]-5- (2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl] -6-methyl-pyrimidine- 2,4-(lH,3H)-dione of Formula VII (15.0 g) was charged in acetonitrile (30.0 ml) and then added ethyl 4-bromobutyrate (10.7 g) and triethylamine (8.3 g) were added.
  • the reaction mass was heated to 50-80°C and stirred for 20-30 hours at same temperature.
  • the reaction mass was cooled to 50-55°C and solvent was removed by evaporating under vacuum.
  • 2-Methyl tetrahydrofuran (75.0 ml) and water (75.0 ml) were charged to the residue, stirred and allowed to settle and then separated the layers.
  • the organic layer was washed again with water (75.0 ml).
  • the organic layer was separated and then washed 3-4 times with 10% w/v aq. solution of L-(+) -tartaric acid (3 x 75 ml). All aq.
  • tartaric acid layers were separated and combined, and washed twice with methyl tert-butyl ether (2 x 30 ml), and separated again.
  • the pH of aq. layer was adjusted with sodium carbonate to >7.0, and extracted twice with dichloro methane (2 x 75.0 ml).
  • Dichloromethane layers were combined and distilled off under vacuum. Residue was dissolved in tetrahydrofuran (30 mL).
  • Aq. sodium hydroxide solution [sodium hydroxide (2.20 g) in water (60.0 ml)] was added. The resulting mixture was stirred at 20- 60°C for 6-10 hours.
  • the reaction mass was concentrated under vacuum to remove tetrahydrofuran and then DM water (60 ml) and 2-methyl tetrahydrofuran (75.0 mL) were charged.
  • the reaction mixture was agitated at 20-40°C, allowed to settle and the layers were separated.
  • Aq. layer was further washed 2-3 times with 2-methyl tetrahydrofuran (2 X 60 mL).
  • the aq. layer was charged with aq. sodium hydroxide solution [sodium hydroxide (14.0 g) in DM water (15 ml)] and 2-methyl tetrahydrofuran (75.0 ml).
  • the mixture was agitated at 20-40°C, allowed to settle and the layers were separated.
  • Aqueous layer was again extracted with 2-methyl tetrahydrofuran (75.0 ml), allowed to settle and the layers were separated.
  • the combined organic layer was washed with saturated brine solution (50 ml) at 25-30°C.
  • the final organic layer was treated with activated carbon, and filtered over hyflo bed, followed by filtration through 0.45 micron paper. Filtrate was concentrated under vacuum to 10-20% of original volume.
  • Methyl tert-butyl ether (150.0 ml) was charged in another round bottom flask and cooled to 10-20°C. The former solution of 2-methyl tetrahydrofuran was added slowly to cold solution of methyl tert-butyl ether and stirred for 2-3 hour at 10-20°C.
  • Example-13 Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I:
  • Compound of Formula I can be prepared by following the process of example 14 by replacing tartaric acid with formic acid. Yield 45%, Purity > 99%
  • Example-14 Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: 3-[2(R)-amino-2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4- (lH,3H)-dione of Formula VII (15.0 g) was charged in acetonitrile (30.0 ml) and then Ethyl 4-bromobutyrate (10.7 g) and triethylamine (8.3 g) were added.
  • the reaction mass was heated to 50-80°C and stirred for 20-30 hours at same temperature.
  • the reaction mass was cooled to 50-55°C and solvent was removed by evaporating under vacuum.
  • MTBE (75.0 ml) and water (75.0 ml) were charged to the residue, stirred and allowed to settle and separated.
  • the organic layer was washed again with water (75.0 ml).
  • the organic layer was separated and then washed 3-4 times with 10% w/v aq. solution of oxalic acid (3 X 75 ml). All aq. oxalic acid layers were separated and combined, and washed twice with MTBE (2 X 30 ml), and separated again.

Abstract

The present invention relates to compounds of Formula A, isomers, polymorphs and process of preparation thereof, wherein, S is a pharmaceutically acceptable salt, R is selected from hydrogen or C1-C3 alkyl group substituted with R4; wherein R4 is selected from -CN, -COR5; wherein R5 is selected from NR6R7, -OR8; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and R8 is selected from straight or branched chain alkyl group. The present invention further provides a process for the preparation of elagolix or pharmaceutical acceptable salt by using compounds of Formula A.

Description

PROCESS FOR THE PREPARATION OF ELAGOLIX SODIUM AND INTERMEDIATES THEREOF
BACKGROUND OF THE INVENTION
Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist approved for the management of moderate to severe pain associated with endometriosis.
Elagolix is chemically known as 4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6- (trifluoromethy l)phenyl] methyl] -3, 6-dihydro-4-methyl-2,6-dioxo-l(2H)-pyrimidinyl]-l- phenylethyl] amino] butanoic acid and is represented by Figure la and its sodium salt is represented by Formula I:
Figure imgf000002_0001
WO 2005/007165 A1 discloses pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists. WO’ 165 discloses process for preparing elagolix free acid and sodium salt thereof, wherein said salt is prepared by using ethyl acetate as a solvent followed by lyophilization. Above said application requires strong cation-exchange column for purification. Further, W0’165 discloses the process for preparation elagolix sodium as mentioned in the Scheme- 1 below:
Scheme 1
Figure imgf000003_0001
Formula I
WO 2009/062087 A1 describes a process for the preparation of elagolix sodium as mentioned in the Scheme-2, by using iodo intermediate of Formula X. WO’087 further discloses multiple step purification process for obtaining off-white solid of elagolix and its sodium salt.
Scheme 2
Figure imgf000003_0002
Formula I WO 2018/189212 A1 describes crystalline non-deliquescent acid addition salts of elagolix with strong acids having the pka values <3, and their use as intermediates for the purification of elagolix sodium.
WO 2018/224063 A2, describes the crystalline solid forms of acid addition salts of elagolix prepared by reacting elagolix ester with strong acids having the pka values <1 and their use in purification of the elagolix sodium salt.
Although there are certain processes known in the published references for the preparation of elagolix sodium salt and its intermediates, however, the known published literature suffers from the drawback such as involvement of the purification of intermediates or Elagolix free acid by using column chromatography which is commercially not feasible. Therefore, the present invention provides a process for preparing pure Elagolix sodium and intermediates, which is economical and commercially viable.
OBJECT OF THE INVENTION
The main object of present invention is to provide compounds of Formula A, isomers, polymorphs and process of preparation thereof.
Another object of the present invention is to provide a process for the preparation of Elagolix and pharmaceutically acceptable salts thereof, by using compounds of Formula A.
Another object of the present invention is to provide a process for the preparation of pure Elagolix and its sodium salt of Formula I.
Another object of the present invention is to provide conversion of elagolix of Formula la to elagolix sodium of Formula I.
SUMMARY OF THE INVENTION
In main aspect, the present invention provide compounds of Formula A, isomers, and polymorphs thereof,
Figure imgf000005_0001
Formula A
wherein,
S is a pharmaceutically acceptable salt;
R is selected from hydrogen or C1-C3 alkyl group substituted with R4, wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group.
In another aspect, the present invention provide compounds of Formula A, wherein R is hydrogen, and is represented as Formula Vila,
Figure imgf000005_0002
Formula Vila
wherein,
S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide and fluoride salts.
In another aspect, the present invention provides compound of Formula Vila, wherein S is pamoate salt, and is represented as compound of Formula Vila'
Figure imgf000006_0001
Formula Vila'
In another aspect, the present invention provide compounds of Formula A, wherein R is selected from C3-alkyl substituted with R4, and is represented as Formula Villa,
Figure imgf000006_0002
Formula Villa wherein,
S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide and fluoride salts, and
R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rx is selected from straight or branched chain alkyl group.
In another aspect, the present invention provides compound of Formula A, wherein R is C3- alkyl substituted with -CN, S is pamoate salt, and is represented as compound of Formula X',
Figure imgf000006_0003
Formula X' In another aspect, the present invention provides compound of Formula Vila' characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 9.40, and 15.59 ± 0.2°q.
In another aspect, the present invention provides compound of Formula X' characterized by XRPD having peaks at diffraction angles 2-theta of 4.20, 7.63, 14.17, and 22.38 ±0.2°q.
In another aspect, the present invention provides a process for the preparation of compounds of Formula A,
Figure imgf000007_0001
Formula A
wherein, S and R are as defined above,
wherein said process comprises the steps of:
a) reacting compound of Formula V with compound of Formula VI or its salt in a suitable organic solvent to obtain compound of Formula II or salt thereof,
Figure imgf000007_0002
Formula V Formula VI Formula II
wherein, PG is an amine protecting group,
wherein, X is selected from halogen and R3 is selected from any suitable leaving group; b) reacting the compound of Formula II or its salt with compound of Formula IV to give compound of Formula III or salt thereof,
Figure imgf000008_0001
wherein,
PG and X are as defined above;
Ri and R2 are independently selected from hydrogen, saturated or unsaturated Ci-6 alkyl, branched or straight chain Ci-6 alkyl, or Ri and R2 together form substituted or unsubstituted cyclic ring optionally comprising of one or more hetero atoms and / or one or more double bonds; and
c) converting compound of Formula III or its salt to compound of Formula A. In another aspect, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable solvent to obtain compound of Formula VII,
Figure imgf000008_0002
b) treating the compound of Formula VII with suitable acid to obtain a compound of Formula Vila,
Figure imgf000009_0001
wherein, S is pharmaceutically acceptable salt; and
c) converting the compound of Formula Vila to elagolix of Formula la and its sodium salt. In another aspect, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) reacting compound of Formula VII or its salts with compound of Formula IX in a suitable solvent to obtain compound of Formula VIII;
Figure imgf000009_0002
wherein Y is a suitable leaving group, and R4 is as defined above;
b) treating compound of Formula VIII with suitable acid to obtain a compound of Formula Villa,
Figure imgf000009_0003
wherein S and R4 are as defined above; and
c) hydrolyzing the compound of Formula Villa to get compound of Formula VIII and converting to elagolix of Formula la and its sodium salt. Another aspect of the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
a) treating compound of Formula A or elagolix free acid of Formula la with sodium source in a suitable solvent; and
b) isolating elagolix sodium.
In another aspect, the present invention provides use of compound of Formula A in the preparation of elagolix of Formula I or its salts. In another aspect, the present invention provides triethylamine, morpholine and dicyclohexyl amine salt of elagolix of Formula la; wherein said salts are represented as Formulae la', la" and la'" respectively;
Figure imgf000010_0001
DETAILED DESCRIPTION
Brief Description of the accompanying drawing
Fig. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the Pamoic acid salt of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoro methyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula Vila.
Fig. 2, represents the X-ray (powder) diffraction (XRPD) pattern of the Pamoic acid salt of 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro- 6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula X.
Fig. 3, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of Elagolix sodium of Formula I.
Fig. 4, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of Elagolix sodium of Formula I after 4 months. Definitions:
“Pharmaceutically acceptable salts” or“salts” as used in the context of the present invention includes, but are not limited to pamoate, 2,3-dibenzoyl-tartarate (in particular (+)-2,3- dibenzoyl-D-tartarate), hydrochloride, hydrobromide, sulphate, phosphate salt; formate, acetate, diphenyl acetate, triphenylacetate, caprylic acid salt, dichloroacetate, trifluoro acetate, propionate, butyrate, lactate, citrate, gluconic acid salt, mandelate, tartarate, malic acid salt, adipic acid salt, aspartate, fumarate, glutamate, maleate, malonic acid salt, succinate, benzoate, p-chlorobenzoate, nicotinate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxy- naphthalene-2-carboxylate, hydro xynaphthalene-2-carboxy late, ethanesulfonate, ethane- 1,2- disulfonate, 2-hydro xyethane sulfonate, methanesulfonate, (+)-camphor- 10- sulfonate, benzenesulfonate, naphthalene-2-sulfonate, p-toluenesulfonate; pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium, barium or zinc salts, ammonium salts; and the like.
“Suitable acid” or“acids” as used in the context of the present invention refers to reagents selected from, but not limited to, pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)- 2,3-dibenzoyl-D-tartaric acid), hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloro acetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, oxalic acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, succinic acid, benzoic acid, p-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p- hydroxybenzoic acid, 1 -hydro xy-naphthalene-2-carboxy lie acid, hydro xynaphthalene-2- carboxylic acid, ethanesulfonic acid, ethane- 1,2-disulfonic acid, 2-hydro xyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, and p-toluenesulfonic acid.
“Protecting group” as used in the context of the present invention refers to compounds that has a purpose of temporarily masking the functionality of the site to which it is attached on a molecule. Prior to the use of the molecule in a subsequent analysis or application, the protecting group may or may not be removed. The protecting groups are selected from any carbon, sulfur and silyl containing moiety such as tert-butyloxycarbonyl (BOC), acetyl, benzoyl, benzyl, tosyl, carbobenzyloxy(Cbz), carbamate group and the like. “Leaving group” as used in the context of the present invention refers to compounds/groups that are replaceable and can easily depart the compound to which they are attached. The leaving groups are selected from hydroxyl, tosylate (OTs), mesylate(OMs), silyl, triflate, iodide, bromide, chloride, fluoride, thioether, (un) substituted carboxylate and the like.
“Suitable solvent” as used in the context of the present invention refers to solvents selected from, but not limited to, the group comprising of alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4- dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, n-heptane, water and mixture thereof.
“Suitable Base” as used in context of the present invention are selected from, but not limited to, selected from organic and inorganic base such as pyridine, triethyl amine, diisopropyl ethyl amine, dimethyl amino pyridine, morpholine, dicyclohexyl amine, carbonates, hydroxides, bicarbonates and the like. Specifically the base is selected from, but not limited to, the group comprising of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium bicarbonates, cesium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, and mixture thereof.
“Pharmaceutically acceptable excipient” as used in the context of the present invention, may include, but not limited to an inorganic oxide such as silicon dioxide, titanium dioxide, zinc oxide, zinc dioxide, aluminium dioxide and zeolite; and organic polymers such as polyvinyl pyrrolidinone, cross linked cellulose acetate phthalate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethyle/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, povidone, povidone K-30, povidone K-60, Povidone K-90, Co-povidone, polyvinyl pyrrolidone vinyl acetate, polyvinyl alcohol, polysorbate 80, polyethylene glycol, methyl cellulose, Eudragit S-100, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelucire 44/14, ethyl cellulose, D-alphatocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose derivatives; polyethylene glycol, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like
The present invention provide compounds of Formula A, isomers, and polymorphs thereof,
Figure imgf000013_0001
Formula A
wherein,
S is a pharmaceutically acceptable salt;
R is selected from hydrogen or C1-C3 alkyl group substituted with R4, wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group. The compounds of Formula A may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula A as defined above wherein S is pharmaceutically acceptable acid addition salt (according to an embodiment defined below). In one another embodiment, the present invention provide compounds of Formula A, wherein said compound is represented as compound of Formula Vila, and Villa;
Figure imgf000014_0001
Formula Vila anfj Formula Villa
wherein, S is selected from the benzoate, p-toluene sulfonic acid, acetate, pamoate, citrate, oxalate, maleate, chloride, bromide, iodide, and fluoride salts; and R4 is as defined above.
In another embodiment, the present invention provides compounds of Formula A wherein said compounds are represented as Formulae Vila', and X';
Figure imgf000014_0002
Formula Vila' an(j Formula X'
In one another embodiment, the compound of Formula Vila' is characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 9.40, and 15.59 ± 0.2°q.
In one another embodiment, the compound of Formula Vila' is characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 8.64, 9.16, 9.40, 10.31, 11.07, 11.46, 12.90, 15.23, 15.59, 16.60, 18.94, 19.31, 23.16, 25.03, 26.27, 29.91 and 33.88 ±0.2°q and as depicted in FIG-1.
In one another embodiment, the compound of Formula X' is characterized by XRPD having peaks at diffraction angles 2-theta of 4.20, 7.63, 14.17, and 22.38 ±0.2°q. In one another embodiment compound of Formula X' is characterized by its XRPD its XRPD having peaks at diffraction angles 2-theta of 4.20, 7.20, 7.63, 8.41, 9.17, 9.47, 10.51, 90.94,
11.11, 12.77, 14.17, 14.51, 15.07, 15.27, 15.65, 16.76, 17.26, 17.51, 18.07, 18.45, 19.34,
19.91, 20.66, 21.16, 21.58, 21.76, 21.95, 22.38, 23.53, 24.40, 25.00, 25.46, 25.88, 26.28, 27.11, 27.60, 28.05, 28.36, 28.72, 29.19, 29.95, 30.37, 31.64, 32.51, 33.27, 33.95, 34.18,
35.66, 36.71, 37.53 and 38.88 ±0.2°q and as depicted in Fig. -2.
In one another embodiment, the present invention provides a process for the preparation of compounds of Formula A, wherein said process comprises the steps of:
a) reacting 5-(2-fluoro-3-methoxyphenyl)-l-(2-fluoro-6-(trifluoromethyl)benzyl)-6- methylpyrimidine-2,4(lH,3H)-dione of Formula IX with compound of Formula VI in presence of suitable reagent in a suitable solvent, wherein said suitable reagent is selected from the group comprising of triarylphosphine catalyst such as triphenyl phosphine, and azodicarboxylates catalyst such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD), and
wherein said suitable solvent is selected from tetrahydrofuran, acetonitrile and toluene to obtain the compound of Formula III,
Figure imgf000015_0001
Formula IX Formula VI Formula IP wherein,
R3 is a suitable leaving group selected from the group of halogen, hydroxyl, tosylate, mesylate or triflate and,
PG is amine protecting group selected from tert-butyloxycarbonyl (BOC), acetyl, benzoyl, tosyl or carbenzyloxy;
b) deprotecting the compound of Formula III in presence of deprotecting agent to give compound of Formula VII, wherein said deprotecting agent is selected from trifluoro acetic acid, cone. HC1, methanolic HC1, ethanolic HC1, IPA.HC1, ethyl acetate HC1, and 1,4-Dioxane HC1,
Figure imgf000016_0001
c) converting the compound of Formula VII to compounds of Formula A.
In another embodiment, the present invention provides a process for the preparation of compounds of Formula A,
Figure imgf000016_0002
wherein, S and R are as defined above,
wherein said process comprises the steps of:
a) reacting compound of Formula V with compound of Formula VI or its salt in a suitable organic solvent to obtain compound of Formula II or salt thereof,
Figure imgf000016_0003
Formula V Formula VI Formula II
wherein, PG is an amine protecting group,
X is selected from halogen and R3 is selected from any suitable leaving group;
b) reacting the compound of Formula II or its salt with boron derivative of Formula IV to give compound of Formula III or salt thereof,
Figure imgf000017_0001
wherein,
PG and X are as defined above;
Ri and R2 are independently selected from hydrogen, saturated or unsaturated Ci-6 alkyl, branched or straight chain Ci-6 alkyl, or Ri and R2 together form substituted or unsubstituted cyclic ring optionally comprising of one or more hetero atoms and / or one or more double bonds; and
c) converting the compound of Formula III or its salt to compounds of Formula A. In another embodiment, the cross coupling reaction of compound of Formula II with boron derivative of Formula IV is carried out in presence of the suitable catalyst selected from any palladium or copper containing catalyst. The suitable catalyst is selected from, but not limited to, the group comprising of palladium acetate and o-(di-tert-butylphosphino)biphenyl, tetrakis(triphenylphosphine)palladium(0), palladium acetate, bis(triphenylphosphine) palladium(II) dichloride, [l,r-bis(diphenylphosphino)ferrocene] palladium(II) dichloride and mixture thereof.
In another embodiment, the cross coupling of compound of Formula II with boron derivative of Formula IV is optionally carried out in presence of base which are as defined above.
In another embodiment, R3 is selected from any leaving atom or group that is detached from the rest of a compound of Formula V and VI respectively, during a reaction of compound of Formula VI with compound of Formula V. In another embodiment, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of: a) deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable solvent to obtain compound of Formula VII,
Figure imgf000018_0001
b) treating the compound of Formula VII with suitable acid to obtain a compound of Formula Vila,
Figure imgf000018_0002
wherein, S is pharmaceutically acceptable salt; and
c) converting the compound of Formula Vila to elagolix of Formula la and its sodium salt. In specific embodiment, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable solvent to obtain compound of Formula VII, wherein said deprotecting agent is selected from the group comprising of trifluoro acetic acid, cone. HC1, methanolic HC1, ethanolic HC1, IPA.HC1, ethyl acetate HC1, and 1,4-Dioxane HC1;
Figure imgf000018_0003
b) treating the compound of Formula VII with pamoic acid to obtain a compound of Formula Vila',
Figure imgf000019_0001
c) hydrolysing compound of Formula Vila' to get compound of Formula VII, and converting the compound of Formula Vila to elagolix of Formula la and its sodium salt.
In another embodiment, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) reacting compound of Formula VII or its salts with compound of Formula IX in a suitable solvent to obtain compound of Formula VIII;
Figure imgf000019_0002
wherein Y is a suitable leaving group, and R4 is as defined above;
b) treating the compound of Formula VIII with suitable acid to obtain a compound of Formula Villa,
Figure imgf000019_0003
wherein S and R4 are as defined above; and c) hydrolyzing the compound of Formula Villa to get compound of Formula VIII and converting to elagolix of Formula la and its sodium salt.
In specific embodiment, the present invention provides a process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) reacting compound of Formula VII or its salts with compound of Formula IX in a suitable solvent to obtain compound of Formula VIII;
Figure imgf000020_0001
wherein, R4 = -CN
wherein Y is halogen, and R4 is -CN;
b) treating the compound of Formula VIII with pamoic acid to obtain a compound of Formula X',
Figure imgf000020_0002
Formula VIII
wherein R4 = -CN Formula X'
; and c) hydrolyzing the compound of Formula X' and converting to Elagolix of Formula la or its sodium salt.
In one another embodiment, the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
a) treating compound of Formula A or elagolix free acid of Formula la with sodium source in a suitable solvent; and
b) isolating elagolix sodium of Formula I. In another embodiment, the present invention provides a process for the preparation of elagolix sodium salt of Formula I, comprising the steps of:
a) treating compound of Formula A or elagolix free acid of Formula la with sodium source in a suitable solvent, wherein said sodium source is selected from sodium hydroxide, sodium methoxide and sodium ethyl hexanoate; and
b) isolating elagolix sodium of Formula I.
In another embodiment, the present invention provides amorphous form of elagolix sodium as represented in Fig. 3.
In another embodiment, the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
a) reacting compound of Formula VIII with suitable acid in a suitable solvent to get a reaction mass comprising compound of Formula Villa;
b) optionally heating the reaction mass to get a solution;
c) treating either the reaction mass of step a) or the solution of step b) with aqueous solution of suitable base followed by addition of solvent to get a biphasic solution;
d) adding the suitable sodium source to the biphasic solution;
e) separating aqueous layer from the biphasic solution;
f) treating the aqueous layer with 2-methyl tetrahydrofuran or tetrahydrofuran; and g) isolating the compound of Formula I by treating with solvent selected from cyclohexane, methyl tert-butyl ether.
In preferred embodiment, the suitable acid is selected from formic acid, oxalic acid and tartaric acid.
In another embodiment, the process for the preparation of elagolix includes preparation of intermediates wherein said intermediates may optionally be not isolated, or may be converted to suitable salts before proceeding to next step.
In another embodiment, the process for the preparation of elagolix includes preparation of intermediates wherein said intermediates may optionally be isolated as its pharmaceutically acceptable salts. In another embodiment, the compound of Formula A is converted to elagolix of Formula la or its sodium salt of Formula I by any known conventional method or by a process of the present invention.
In a preferred embodiment, the elagolix sodium of Formula A may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction, evaporation and lyophilization. In another embodiment, the present invention provides salts of elagolix of Formula B , wherein said salts (Base+) are selected from, but not limited to, triethylamine, DMAP, pyridine, diisopropyl amine, DIPEA, dicyclohexyl amine, N-methyl morpholine, methyl amine and dicyclohexylamine.
Figure imgf000022_0001
Formula B
In another embodiment, the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
a) hydrolyzing elagolix salt of Formula B with suitable acid in a solvent to give elagolix of
Formula la,
Figure imgf000022_0002
Formula B Formula la
b) treating the elagolix of Formula la with sodium source; and c) isolating elagolix sodium salt of Formula I.
In one another embodiment, the present invention provides a process for the preparation of elagolix sodium of Formula I, comprising the steps of:
a) hydrolyzing dicyclo hexyl amine salt of elagolix of Formula B'" with suitable acid in a solvent to give elagolix of Formula la, wherein said acid is selected from acetic acid, and hydrochloric acid,
Figure imgf000023_0001
b) treating the elagolix of Formula la with sodium source selected from sodium hydroxide, sodium methoxide and sodium ethyl hexanoate; and
c) isolating elagolix sodium salt of Formula I.
In further embodiment, the present invention provides a substantially pure elagolix sodium of Formula I, wherein said elagolix sodium is free from the compound of Formula A.
In further embodiment, the present invention provides a substantially pure compound of Formula A, wherein said compound is free of impurity of Formula P and Q, preferably each impurity is less than about 0.3%w/w and wherein total impurity is less than about 1.0% w/w,
Figure imgf000023_0002
In furthermore embodiment, the present invention provides pure elagolix sodium of Formula I, wherein said elagolix sodium of Formula I is substantially free of impurities of Formula C to Y; wherein each impurity is less than about 0.3% w/w or total impurity less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;
In another embodiment, the present invention provides pure elagolix sodium of Formula I, wherein said elagolix sodium is characterized by purity of 99.0% and above. In further embodiment, the present invention provides a substantially pure amorphous form of compound of Formula I, wherein said compound is free of intermediates of Formula VII and X, wherein said elagolix sodium is characterized by purity of 99.0% and above.
In another embodiment, the amorphous form of elagolix sodium of present application is stable on storage as shown in Table- 1 as measured by Karl Fischer method, wherein the amorphous elagolix sodium does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about four months and more. Table 1:
Figure imgf000025_0001
In another embodiment, the present invention provides amorphous solid dispersion of elagolix, comprising the steps of: a) adding elagolix of Formula la in a suitable solvent to get a solution; b) treating the solution of step a) with pharmaceutically acceptable carrier; and c) removing the solvent to get amorphous solid dispersion of elgolix.
In another embodiment, present invention provides elagolix sodium of Formula I, having particle size distribution D90 less than about 200pm.
In another embodiment, present invention provides a composition comprising elagolix sodium of Formula I, with atleast one or more pharmaceutically acceptable excipients.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.
EXAMPLES
Example 1: Synthesis of 5-bromo-l-[2-fluoro-6-(trifluoromethyl) benzyl] -6-methyl-3- [2(R)-tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4-(lH,3H)-dione of Formula II: To a stirred solution of 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2,4(lH,3H)-dione of Formula V (25 g) in toluene (275 ml) were added N- t-Boc-D-phenylglycinol of Formula VI (R3=OH, PG=Boc) (19.5 g) and triphenylphosphine (25.6 g) followed by slow addition of di tert-butyl azodicarboxylate in toluene solution (22.5 g in 100 ml) at 5-10°C and stirred at RT for overnight. The resulting mixture was concentrated under vacuum to get 5-bromo-l-[2-fluoro-6-(trifluoromethyl) benzyl]-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4-(lH,3H)-dione which was crystallised in methanol: water (175 ml: 50 ml) to get pure compound of Formula II (27.5g, 70% yield).
Example-2: Synthesis of 3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-5-(2-fluoro- 3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2, 4 (lH,3H)-dione of Formula III: The 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-3-[2(R)-tert-butoxy carbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione of Formula II (X=Br) (30 g) was dissolved in 1,4-dioxane (360ml): water (90ml) at room temperature and added 2-Fluoro-3-methoxy phenyl boronic acid of Formula IV (Ri, R2=OH) (17.09g) then added sodium carbonate (26.09g) and degassed for 15 minute, then added tetrakis (TPP) palladium (5.72 g). The resultant suspension was stirred for 10-12 hours at 95°C. The solvent was removed under vacuum and residue was dissolved in ethyl acetate. Organic layer was washed with DM water and then with saturated brine solution. The organic layer was evaporated under vacuum to get light brown oil (20.9 g) which was crystallised in IPA (30 ml) to get 3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2, 4 (1H,3H)- dione of Formula III (16.8g, 52% yield).
Example-3: Synthesis of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l- [2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII: The 3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2, 4 (1H,3H)- dione of Formula III (15 g) was dissolved in methylene dichloride (75 ml) at room temperature and cool to 0-5°C then slowly added trifluoroacatic acid (15 ml) at 0-5°C within 30-45 minutes. Stirred for 4-5 hours at 25-30°C. After reaction completion, solvent was evaporated under vacuum and added dichloro methane (75 ml), washed with saturated sodium bicarbonate / sodium carbonate solution (75 ml) at room temperature. Organic layer was washed with DM water (45 ml). The organic layer was dried over sodium sulphate and evaporated under vacuum to get desired compound of Formula VII (12 g, 95% yield). HPLC purity 90.71%
Example-4: Synthesis of Pamoic acid salt of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro- 3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula Vila (wherein S is pamoic acid salt): To a stirred solution of 3- [2(R)-amino-2-phenyl-ethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl] -6-methyl-pyrimidine-2, 4 (lH,3H)-dione of Formula VII (12.0 g) in 120 ml methanol at room temperature, followed by addition of pamoic acid (5.12 g) in methanol (25 ml). Then the resultant suspension was stirred for 2-3 hours at 60-65°C, followed by cooling to 25-30°C for 12-14 hours. The mixture was then further cooled to 0-5°C and stirred for 1-2 hours. The resultant suspension was then filtered and washed the material with methanol. Solid so obtained was dried under vacuum at 45°C for 4-5 hours to get Pamoic acid salt of 3-[2(R)- Amino-2-phenyl-ethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione 18.0 g of Formula Vila (18.68g, 90% yield). HPLC purity >98.0%.
Example-5: Synthesis of 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l- [2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII: Pamoic acid salt of 3-[2(R)-amino-2-phenyl-ethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (1H,3H)- dione of Formula Vila 18.0 g was dissolved in 180 ml dichloromethane. Added saturated sodium bicarbonate solution (200 ml) slowly to the above solution at 10-15°C, then raised temperature to 25-30°C. Reaction mixture was stirred at 25-30°C for 1 hour and layers were separated. The organic layer was washed with DM water (90 ml) and stirred at 25-30°C for 30 minutes. Organic layers were separated, dried over sodium sulphate and evaporated under vacuum to get 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6- (trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII (10.4 g, 98% yield). HPLC purity>98.0%.
Example-6: Synthesis of 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione: The 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2- fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula VII (10 g) was dissolved in acetonitrile (100 ml) and added 4-bromobutyronitrile (13.5 g) and triethylamine (3.7 g ). Then the resultant reaction mixture was heated to reflux and stirred for 5-7 hours at same temperature. Then the resultant reaction mixture was cooled to 50-55°C and solvent was removed by evaporating under vacuum. The residue was dissolved in methylene dichloride and washed with water two times. Organic layer was dried over sodium sulphate and concentrated under vacuum to 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione as light yellow oil (10.5g, 91% yield).
Example-7: Synthesis of Pamoic acid salt of 3-[2(R)-{3-cyanopropyl-amino}-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-pyrimidine-2,4(lH,3H)-dione of Formula X': To a stirred solution of 3-[2(R)-{3- cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione of Formula X 5.0 g in methanol (50 ml) was added pamoic acid solution (1.90 g pamoic acid solution in 15 ml methanol) and stirred at 60-65°C for 3 hours. Cooled to 5-10°C and filtered the solids. Washed the solid so obtanied with methanol. The resultant solid was dried under vacuum at 45°C for 4-5 hours to get Pamoic acid salt of 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)- 1 - [2-fluoro-6-(trifluoromethyl)benzyl] -6-methyl-pyrimidine- 2,4(lH,3H)-dione of Formula X’ (7.12 g, 87% yield). HPLC purity >98.0%.
Example-8: Synthesis of 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione of Formula VIII (R4=CN): The Pamoic acid salt of 3-[2(R)-{3- cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6- (trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione 7.0 g of Formula X was dissolved in 70 ml dichloromethane and added saturated sodium bicarbonate solution (100 ml) at 10-15°C. The temperature was raised to 25-30°C and stirred at 25-30°C for 1 hour. The layers were separated. The organic layer was washed with DM water (35 ml), stirred at 25- 30°C for 30 minutes and separated. Organic layer was dried over sodium sulphate and evaporated under vacuum to get 3-[2(R)-{3-cyanopropyl-amino}-2-phenylethyl]-5-(2-fluoro- 3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(lH,3H)- dione (4.20 g, 98% yield). Chromatographic purity> 98.0%.
Example-9: Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: To 3-[2(R)-{3-cyanopropyl-amino}- 2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methyl-pyrimidine-2,4(lH,3H)-dione (3.0 g) was added cone. HC1 (30.0 ml). The resulting mixture was heated to 60-65°C for 6-10 hours. Then the reaction mass was cooled to 10-15°C and added aqueous solution of sodium hydroxide (0.41 gm in 12 ml DM water). Reaction mass was stirred at 25-30°C. To this charged MIBK (15.0 ml) and heated to 55-60°C for 15- 20 minute and layer was separated. Charged the aqueous layer and added MIBK (15.0 ml). To this added aqueous sodium hydroxide solution (1.96 g dissolved in 3.0 ml DM water) at 25-30°C. Reaction mass was stirred for 10-15 minute and layer was separated out at 25-30°C. The organic layer was washed with saturated sodium chloride solution (30.0 ml), then organic layer was distilled out 2-3 volume and filtered through 0.45 micron at 25-30°C. Charged 30 ml of n-heptane in round bottom flask and cooled to 15-20°C, then slowly added solution of MIBK containing mass at 15-20°C. The reaction mass was stirred for 2-3 hours at same temperature and filtered the solid material. Washed the solid so obtained with n-heptane (3.0 ml) to get 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4- methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin- 1-yl]- l-phenyl-ethylamino)-butyric acid sodium salt of Formula I (2.0 g, yield 64%).
Example-10: Synthesis of Pamoic acid salt of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4 (lH,3H)-dione of Formula Vila: The 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]- 6-methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione of Formula II (X=Br) (50.0 g) was dissolved in 1,4-dioxane (300.0 ml) and water (100.0 ml) at room temperature and added 2-fluoro-3-methoxy phenyl boronic acid of Formula IV (Ri, R2=OH) ( (28.3 g) then added sodium carbonate (43.5 g) and degassed for 15 minute. Added tetrakis (TPP) palladium (9.6 g), stirred for 10-12 hours at 95-100°C. The reaction mixture was cooled to 25-30°C and filtered through celite bed at 25-30°C. The solvent was removed under vacuum and residue was dissolved in ethyl acetate. Organic layer was washed with DM water and then with saturated brine solution. The organic layer was evaporated under vacuum to get residue. Residue was dissolved in dichloromethane (500 ml) at room temperature and cooled to 0-5°C then slowly added trifluoro acetic acid (50 ml) at 0-5°C within 30-45 minutes. The reaction mixture was stirred for 8-10 hours at 20-30°C. After reaction completion, 10% w/v aq. sodium carbonate solution (500 ml) was added slowly at room temperature. Reaction mixture was stirred, allowed to stand, and layers were separated. Organic layer was washed with DM water (150 ml). The organic layer was evaporated under vacuum, chased with methanol (50 ml) under vacuum to get residue. Residue was dissolved in methanol (500 ml), added activated carbon (5.0 g), stirred and filtered over hyflo bed.
Pamoic acid (17.8 g) was charged into above filtrate, stirred at 60-65°C for 3 hours then cooled to 5-10°C, filtered and washed with methanol. Wet solid was purified by recrystallization in acetone: water mixture (70:30) (500 ml). Purified material was dried under vacuum at 50°C for 4-5 hours (49.0 g, 90% yield). HPLC purity > 98.0%. Example-11: Synthesis of 3-[2(R)-Amino-2-phenyl-ethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4 (lH,3H)-dione of Formula VII: Dissolved 49.0 g Pamoate salt of 3-[2(R)-amino-2- phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl]-6- methyl-pyrimidine-2,4-(lH,3H)-dione of Formula Vila in 500 ml MDC meanwhile prepared saturated sodium bicarbonate solution (500 ml). Slowly added sodium bicarbonate / sodium carbonate solution in above solution at 10-15°C, then raised temperature to 25-30°C. The reaction mixture was stirred at 25-30°C for 1 hour and then layers were separated. The organic layer was washed with DM water (90 ml), stirred at 25-30°C for 30 minutes and separated the layers. Organic layer was dried over sodium sulphate and evaporated under vacuum to get 3- [2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl]-6-methyl-pyrimidine-2,4-(lH,3H)-dione of Formula VII (10.4 g, 98% yield). HPLC purity >98.0%.
Example-12: Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: The 3-[2(R)-amino-2-phenylethyl]-5- (2-fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl) benzyl] -6-methyl-pyrimidine- 2,4-(lH,3H)-dione of Formula VII (15.0 g) was charged in acetonitrile (30.0 ml) and then added ethyl 4-bromobutyrate (10.7 g) and triethylamine (8.3 g) were added. The reaction mass was heated to 50-80°C and stirred for 20-30 hours at same temperature. The reaction mass was cooled to 50-55°C and solvent was removed by evaporating under vacuum. 2-Methyl tetrahydrofuran (75.0 ml) and water (75.0 ml) were charged to the residue, stirred and allowed to settle and then separated the layers. The organic layer was washed again with water (75.0 ml). The organic layer was separated and then washed 3-4 times with 10% w/v aq. solution of L-(+) -tartaric acid (3 x 75 ml). All aq. tartaric acid layers were separated and combined, and washed twice with methyl tert-butyl ether (2 x 30 ml), and separated again. The pH of aq. layer was adjusted with sodium carbonate to >7.0, and extracted twice with dichloro methane (2 x 75.0 ml). Dichloromethane layers were combined and distilled off under vacuum. Residue was dissolved in tetrahydrofuran (30 mL). Aq. sodium hydroxide solution [sodium hydroxide (2.20 g) in water (60.0 ml)] was added. The resulting mixture was stirred at 20- 60°C for 6-10 hours. The reaction mass was concentrated under vacuum to remove tetrahydrofuran and then DM water (60 ml) and 2-methyl tetrahydrofuran (75.0 mL) were charged. The reaction mixture was agitated at 20-40°C, allowed to settle and the layers were separated. Aq. layer was further washed 2-3 times with 2-methyl tetrahydrofuran (2 X 60 mL). The aq. layer was charged with aq. sodium hydroxide solution [sodium hydroxide (14.0 g) in DM water (15 ml)] and 2-methyl tetrahydrofuran (75.0 ml). The mixture was agitated at 20-40°C, allowed to settle and the layers were separated. Aqueous layer was again extracted with 2-methyl tetrahydrofuran (75.0 ml), allowed to settle and the layers were separated. The combined organic layer was washed with saturated brine solution (50 ml) at 25-30°C. The final organic layer was treated with activated carbon, and filtered over hyflo bed, followed by filtration through 0.45 micron paper. Filtrate was concentrated under vacuum to 10-20% of original volume. Methyl tert-butyl ether (150.0 ml) was charged in another round bottom flask and cooled to 10-20°C. The former solution of 2-methyl tetrahydrofuran was added slowly to cold solution of methyl tert-butyl ether and stirred for 2-3 hour at 10-20°C. Filtered and washed with methyl tert-butyl ether (30.0 ml) to get 4-((R)-2-[5-(2-fluoro-3-methoxy- phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H- pyrimidin-l-yl]-l-phenyl-ethylamino)-butyric acid sodium salt of Formula I (7.6 g, yield 50%, Purity > 99%)
Example-13: Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: Compound of Formula I can be prepared by following the process of example 14 by replacing tartaric acid with formic acid. Yield 45%, Purity > 99%
Example-14: Synthesis of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6- trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l-phenyl- ethylamino)-butyric acid sodium salt of Formula I: 3-[2(R)-amino-2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4- (lH,3H)-dione of Formula VII (15.0 g) was charged in acetonitrile (30.0 ml) and then Ethyl 4-bromobutyrate (10.7 g) and triethylamine (8.3 g) were added. The reaction mass was heated to 50-80°C and stirred for 20-30 hours at same temperature. The reaction mass was cooled to 50-55°C and solvent was removed by evaporating under vacuum. MTBE (75.0 ml) and water (75.0 ml) were charged to the residue, stirred and allowed to settle and separated. The organic layer was washed again with water (75.0 ml). The organic layer was separated and then washed 3-4 times with 10% w/v aq. solution of oxalic acid (3 X 75 ml). All aq. oxalic acid layers were separated and combined, and washed twice with MTBE (2 X 30 ml), and separated again. The pH of aq. layer was adjusted with sodium carbonate to >7.0, and extracted twice with Toluene (2 X 75.0 ml). Toluene layers were combined and distilled under vacuum. Residue was dissolved in THF (30 mL). Aq. sodium hydroxide solution [sodium hydroxide (2.20 g) in water (60.0 ml)] was added. The resulting mixture was stirred at 20- 60°C for 6-10 hours. The reaction mass was concentrated under vacuum to remove THF and then DM water (60 ml) and 2-methyl tetrahydrofuran (75.0 mL) were charged. The mixture was agitated at 20-40°C, allowed to settle and the layers were separated. Aq. layer was further washed 2-3 times with 2-methyl tetrahydrofuran (2 X 60 mL). The aq. layer was charged with aq. sodium hydroxide solution [sodium hydroxide (14.0 g) in DM water (15 ml)] and 2- methyl tetrahydrofuran (75.0 ml). The mixture was agitated at 20-40°C, allowed to settle and the layers were separated. Aqueous layer was again extracted with 2-methyl tetrahydrofuran (75.0 ml), allowed to settle and the layers were separated. The combined organic layer was washed with saturated brine solution (50 ml) at 25-30°C. The final organic layer was treated with activated carbon, and filtered over hyflo bed, followed by filtration through 0.45 micron paper. Filtrate was concentrated under vacuum to 10-20% of original volume. Cyclohexane (150.0 ml) was charged in another round bottom flask and cooled to 10-20°C. Then, 2-methyl tetrahydrofuran solution containing mass was added slowly at 10-20°C, stirred for 2-3 hours at same temperature, filtered and washed with Cyclohexane (30.0 ml) to get 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6- dihydro-2H-pyrimidin-l-yl]-l-phenyl-ethylamino)-butyric acid sodium salt of Formula I (7.3 g, yield 48%, Purity > 99%).

Claims

CLAIMS:
1. Compounds of Formula A, isomers, and polymorphs thereof,
Figure imgf000034_0001
Formula A
wherein,
S is a pharmaceutically acceptable salt;
R is selected from hydrogen or C1-C3 alkyl group substituted with R4, wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group.
2. The compounds as claimed in claim 1, wherein said compounds are represented as compounds of Formula Vila, and Villa,
Figure imgf000034_0002
Formula Vila Formula Villa
wherein, S and R4 are as defined in claim 1.
3. A process for the preparation of compounds of Formula A,
Figure imgf000035_0001
wherein,
S is a pharmaceutically acceptable salt,
R is selected from hydrogen or C1-C3 alkyl group substituted with R4 wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group,
wherein said process comprises the steps of:
a) reacting compound of Formula V with compound of Formula VI or its salt in a suitable organic solvent to obtain compound of Formula II or salt thereof,
Figure imgf000035_0002
Formula V Formula VI Formula II wherein, PG is an amine protecting group,
X is selected from halogen and R3 is independently selected from any suitable leaving group;
b) reacting the compound of Formula II or its salt with boron derivative of Formula IV to give compound of Formula III or salt thereof,
Figure imgf000036_0001
Formula II Formula III
wherein;
PG and X are as defined above;
Ri and R2 are independently selected from hydrogen, saturated or unsaturated Ci-6 alkyl, branched or straight chain Ci-6 alkyl, or Ri and R2 together form substituted or unsubstituted cyclic ring optionally comprising of one or more hetero atoms and / or one or more double bonds;
c) converting compound of Formula III or its salt to compounds of Formula A; and d) optionally converting compound of Formula A to elagolix and its sodium salt.
4. The process as claimed in claim 3, wherein said amine protecting group are selected from carbon, sulfur and silyl containing moiety, and wherein said leaving group is selected from hydroxyl, tosylate (OTs), mesylate(OMs), silyl, triflate, iodide, bromide, chloride, fluoride, thioether, and (un) substituted carboxylate.
5. A process for the preparation of compounds of Formula A,
Figure imgf000036_0002
Formula A
wherein,
S is a pharmaceutically acceptable salt,
R is selected from hydrogen or C1-C3 alkyl group substituted with R4 wherein R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group,
wherein said process comprises the steps of:
a) reacting 5-(2-fluoro-3-methoxyphenyl)- l-(2-fluoro-6-(trifluoromethyl)benzyl)-6- methylpyrimidine-2,4(lH,3H)-dione of Formula IX with compound of Formula VI in presence of suitable reagent in a suitable solvent to obtain the compound of Formula III,
Figure imgf000037_0001
Formula IX Formula VI Formula III wherein, R3 is a suitable leaving group and PG is an amine protecting group;
b) deprotecting the compound of Formula III in presence of deprotecting agent to give compound of Formula VII,
Figure imgf000037_0002
c) converting the compound of Formula VII to compounds of Formula A; and
d) optionally converting compound of Formula A to elagolix and its sodium salt.
6. The process as claimed in claim 5, wherein said step a) is carried out in presence of catalyst selected from triphenyl phosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD).
7. A process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of: a) deprotecting compound of Formula III or its salts in presence of deprotecting agent and suitable organic solvent to obtain compound of Formula VII,
Figure imgf000038_0001
b) treating the compound of Formula VII with suitable acid to obtain a compound of Formula Vila,
Figure imgf000038_0002
wherein, S is pharmaceutically acceptable salt; and
c) converting the compound of Formula Vila to elagolix of Formula la and its sodium salt.
8. A process for the preparation of elagolix of Formula la and its sodium salt, comprising the steps of:
a) reacting compound of Formula VII or its salts with compound of Formula IX in a suitable solvent to obtain compound of Formula VIII;
Figure imgf000038_0003
wherein Y is a suitable leaving group, and R4 is selected from -CN, -COR5 wherein R5 is selected from NR6R7, -ORs; wherein R6 and R7 are selected from hydrogen, straight or branched chain alkyl group, and Rs is selected from straight or branched chain alkyl group;
b) treating the compound of Formula VIII with suitable acid to obtain a compound of Formula Villa,
Figure imgf000039_0001
Formula VIII Formula Villa
wherein S is a pharmaceutically acceptable salt, and R4 is as defined above; and c) hydrolyzing the compound of Formula Villa to get compound of Formula VIII and converting to Elagolix of Formula la and its sodium salt.
9. A Stable amorphous form of elagolix sodium, wherein the amorphous elagolix sodium is stable when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about four months and more.
10. A process for the preparation of elagolix sodium of Formula I, comprising the steps of: a) hydrolyzing elagolix salt of Formula B with suitable acid in a solvent to give elagolix of Formula la,
Figure imgf000039_0002
Formula B Formula la
b) treating the elagolix of Formula la with sodium source; and
c) isolating elagolix sodium salt of Formula I.
11. The process as claimed in claim 10, wherein said salt of compound of Formula B are selected from triethyl amine, DMAP, pyridine, diisopropyl amine, DIPEA, dicyclohexyl amine, N-methyl morpholine, methyl amine and dicyclohexylamine.
12. Compound of Formula Vila'
Figure imgf000040_0001
Formula Vila’
and compound of Formula X'
Figure imgf000040_0002
wherein said compounds of Formula Vila' and X' are used in preparing elagolix sodium.
13. The compound of Formula Vila' as claimed in claim 12, wherein said compound is characterized by XRPD having peaks at diffraction angles 2-theta of 7.92, 9.40, and 15.59 ± 0.2°q.
14. The compound of Formula X' as claimed in claim 12, wherein said compound is characterized by XRPD having peaks at diffraction angles 2-theta of 4.20, 7.63, 14.17, and 22.38 ±0.2°q.
15. A process for the preparation of elagolix sodium, comprising the steps of:
a) treating compound of Formula X' or elagolix free acid of Formula la with sodium source in a suitable solvent; and b) isolating elagolix sodium.
16. The process as claimed in claim 15, wherein said sodium source is selected from sodium hydroxide, sodium alkoxide and sodium ethyl hexanoate.
17. A process for preparing amorphous solid dispersion of elagolix, comprising the steps of: a) adding elagolix of formula la in a suitable solvent to get a solution;
b) treating the solution of step a) with pharmaceutically acceptable carrier; and
c) removing the solvent to get amorphous solid dispersion of elgolix.
18. Elagolix sodium as obtained in any of the preceding claim is characterized by particle size distribution D90 less than about 200pm.
19. A composition comprising elagolix sodium of Formula I as obtained in any of the preceding claim, along with atleast one or more pharmaceutically acceptable excipients.
20. Substantially pure elagolix sodium of Formula I as obtained in any of the preceding claim is characterized by purity of 99.0% and above.
21. A process for the preparation of elagolix sodium of Formula I, comprising the steps of: a) reacting compound of Formula VIII with suitable acid in a suitable solvent to get a reaction mass comprising compound of Formula Villa, wherein said acid is selected from oxalic acid, formic acid and tartaric acid;
b) optionally heating the reaction mass to get a solution;
c) treating either the reaction mass of step a) or the solution of step b) with aqueous solution of suitable base followed by addition of solvent to get a biphasic solution;
d) adding the suitable sodium source to the biphasic solution;
e) separating aqueous layer from the biphasic solution;
f) treating the aqueous layer with 2-methyl tetrahydrofuran or tetrahydrofuran; and g) isolating the compound of Formula I by treating with solvent selected from cyclohexane, methyl tert-butyl ether.
PCT/IB2020/052344 2019-03-25 2020-03-14 Process for the preparation of elagolix sodium and intermediates thereof WO2020194115A1 (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN114814038A (en) * 2022-05-23 2022-07-29 常州制药厂有限公司 HPLC detection method for ilagox sodium raw material medicine and related substances thereof
CN114835650A (en) * 2021-02-01 2022-08-02 上海漠澳浩医药科技有限公司 Salt and crystal of oxalagogri intermediate, and preparation method and application thereof
CN115340498A (en) * 2021-05-12 2022-11-15 成都倍特药业股份有限公司 Oxagolide nitrogen oxide impurity and preparation method thereof

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WO2018198086A1 (en) * 2017-04-28 2018-11-01 Lupin Limited Process for the preparation of elagolix and pharmaceutically acceptable salts thereof

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2018198086A1 (en) * 2017-04-28 2018-11-01 Lupin Limited Process for the preparation of elagolix and pharmaceutically acceptable salts thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835650A (en) * 2021-02-01 2022-08-02 上海漠澳浩医药科技有限公司 Salt and crystal of oxalagogri intermediate, and preparation method and application thereof
CN115340498A (en) * 2021-05-12 2022-11-15 成都倍特药业股份有限公司 Oxagolide nitrogen oxide impurity and preparation method thereof
CN114814038A (en) * 2022-05-23 2022-07-29 常州制药厂有限公司 HPLC detection method for ilagox sodium raw material medicine and related substances thereof

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