WO2014060639A1 - A process for the preparation of ospemifene - Google Patents

A process for the preparation of ospemifene Download PDF

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Publication number
WO2014060639A1
WO2014060639A1 PCT/FI2013/000039 FI2013000039W WO2014060639A1 WO 2014060639 A1 WO2014060639 A1 WO 2014060639A1 FI 2013000039 W FI2013000039 W FI 2013000039W WO 2014060639 A1 WO2014060639 A1 WO 2014060639A1
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WIPO (PCT)
Prior art keywords
compound
formula
process according
butyl
trimethylphenyl
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Ceased
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PCT/FI2013/000039
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English (en)
French (fr)
Inventor
Jan Tois
Ainoliisa PIHKO
Arne Grumann
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Fermion Oy
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Fermion Oy
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Priority to JP2015537313A priority Critical patent/JP6174156B2/ja
Priority to US14/436,706 priority patent/US9321712B2/en
Priority to EP13789369.9A priority patent/EP2909164A1/en
Publication of WO2014060639A1 publication Critical patent/WO2014060639A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/753—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of polycyclic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention is related to a process for the preparation ospemifene and to intermediate compounds used in the process.
  • Ospemifene or (Z)-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol is represented by formula (I):
  • Ospemifene is an estrogen receptor agonist/antagonist currently investigated e.g. for the treatment of vulvar and vaginal atrophy due to menopause.
  • the present invention provides a process for the preparation of a compound of formula (I)
  • R is a protecting group tolerant to Grignard or other organometallic reagents, with phenylmagnesium halide to produce a compound of formula (IV)
  • the present invention provides a process for the preparation of a compound of formula (I) comprising the step of treating the compound of formula (IV), wherein R is a protecting group tolerant to Grignard or other organometallic reagents, with hydrochloric acid to produce a compound of formula (V), and cleaving the ester bond of a compound of formula (V) to give a compound of formula (I). , .
  • the invention is also directed to novel compounds of formula ( ⁇ ) and (IV) wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.
  • lower alcohol means Pi ⁇ .alcpholj.preierably.Pi ⁇ .alcQbol.
  • Representative examples include methanol, ethanol, isopropanol and butanol.
  • Particularly preferred is methanol and ⁇ thanol. .
  • the above reaction is based on the nucleophilic addition of a phenyl- magnesium halide (Grignard reagent), such as phenylmagnesium chloride or phenyl- magnesium bromide, to the carbonyl group of the compound of formula ( ⁇ ).
  • a phenyl- magnesium halide such as phenylmagnesium chloride or phenyl- magnesium bromide
  • the reaction is carried out in suitable solvent, such as diethyl ether or THF, under nitrogen atmosphere.
  • the reagents are suitably added at room temperature and the mixture is heated, for example to about 60 °C.
  • the reaction is typically completed within about 2-3 hours.
  • the reaction can be quenched e.g. with addition of saturated NH 4 Cl-solution.
  • Phenylmagnesium halide reagent is at typically used in molar excess, e.g. in 1.5 - 2 molar equivalents per compound of formula ( ⁇ ).
  • aqueous HCl solution such as 30 % HCl solution.
  • the reaction is suitably carried out at room temperature: The reaction is typically completed within less than one hour.
  • the resulting ester of formula (V) is particularly suitable for being isolated and purified by crystallization before its use in the next reaction step.
  • the reaction mixture can be poured on saturated NaHC0 3 solution and the organic phase is recovered.
  • the organic phase is preferably evaporated and the crystallization solvent is added.
  • Suitable crystallization solvents include plain lower alcohols, such as methanol and ethanol.
  • Particularly suitable crystallization, solvents are methanol or ethanol essentially in the absence of water, thereby giving the ester of formula (V) in high yield and purity.
  • the mixture of crystallization solvent and crude ester of formula (V) is stirred and suitably heated to achieve dissolution.
  • the mixture may then be cooled to about 40 °C and seeded with the desired Z-isomer. Cooling is continued over a period of time (preferably slowly, e.g. over more than one hour) to room temperature or below, e.g. below 15 °C, in order to achieve crystallization.
  • the mixture is suitably stirred in this temperature for more than 3 hours, e.g. for 12 hours.
  • the crystalline ester of formula (V) is filtered, washed and dried preferably under reduced pressure.
  • the chemical purity of the crystallized compound of formula (V) is at this stage typically higher than 92 % and the amount of E-isomer less than 5 %.
  • the end product may be .. further recrystallized if desired.
  • compound of formula ( ⁇ ) can be suitably prepared by reacting a compound of formula (II)
  • X 1 -CH 2 -CH 2 -X 2 a compound of formula X 1 -CH 2 -CH 2 -X 2 , wherein Xi and X 2 is a leaving group and R is a protecting group tolerant to Grignard or other organometallic - , . reagents.
  • Suitable leaving groups and X 2 include, but are not limited to, halogens, para-toluenesulfonate (CH3C6H 4 SO O-), methanesulfonate (CH 3 S0 2 0-) and trifluoromethanesulfonate (CF 3 S0 2 O-) groups.
  • and X 2 are halogens, in particular X] is Br and X 2 is CI.
  • phase transfer catalyst such as quaternary ammonium or phosphonium salts.
  • phase transfer catalyst include tetrabutylammonium hydrogensulfate (TBAHS), benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide.
  • TAAHS tetrabutylammonium hydrogensulfate
  • benzyltrimethylammonium chloride hexadecyltributylphosphonium bromide.
  • phase transfer catalyst such as TB AHS and aqueous NaOH solution (e.g. 50 % NaOH solution)
  • reaction between the compound of formula (II) and the compound of formula Xi-CH 2 -CH 2 -X 2 can be carried out in an organic solvent, such as DMSO, DMF or THF, in the presence of a base such as NaH, K-, Na- or LiOBu-t, or corresponding carbonates.
  • organic solvent such as DMSO, DMF or THF
  • a base such as NaH, K-, Na- or LiOBu-t, or corresponding carbonates.
  • compound of formula (II) can be suitably prepared by reacting a compound of formula (VI)
  • R is Gis alkyl or an optionally substituted phenyl, with 2-phenyl- acetic acid.
  • the reaction is catalyzed by a Br0nsted acid, such as polyphosphoric acid (PPA).
  • PPA polyphosphoric acid
  • particularly suitable compounds of formula (II), (III), (IV), (V) and (VI) are those wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.
  • Particularly preferred compounds of formula (II), (III), (IV), (V) and (VI) are those wherein R is t-butyl.
  • the compound of formula (I) (ospemifene) is obtained by subjecting the compound of formula (V) to cleavage ofthe ester bond (dashed bond below) of the compound of formula (V)
  • the cleavage of the ester bond of the compound of formula (V) can be carried out by using well known methods such hydrolysis or a reductive cleavage.
  • Hydrolysis of the ester bond of the compound of formula (V) can be catalysed by a base or acid.
  • a base catalysed hydrolysis is particularly preferred.
  • the base catalysed hydrolysis can be carried in a suitable solvent such as aqueous THF or aqueous THF/MeOH mixture in the presence of a suitable base, such as NaOH or Li OH at room temperature for a time sufficient to complete the hydrolysis.
  • a suitable base such as NaOH or Li OH
  • Ospemifene can be conveniently Isolated from the residue by crystallization from a suitable crystallization solvent.
  • Preferred solvents for crystallization are C]_ 5 alcohols, particularly methanol, ethanol or isopropanol, or aqueous C 1-5 alcohols such as aqueous methanol (e.g. 80 % or 90 % methanol). .* ⁇ - . ⁇
  • Reductive cleavage of the ester bond of the compound of formula (V) to ; : obtain ospemifene can be carried out in the presence of a reducing agent such as lithium aluminium hydride i a suitable organic solvent such' as toluene, THF,' ⁇ > hexane or xylene or mixture thereof.
  • a reducing agent such as lithium aluminium hydride i
  • suitable organic solvent such' as toluene, THF,' ⁇ > hexane or xylene or mixture thereof.
  • the reaction is suitably carried out at room temperature and under nitrogen atmosphere.
  • the reaction may be suitably quenched by addition of saturated NH 4 Cl-solution.
  • Organic phase is washed, dried, filtered and concentrated.
  • Ospemifene can be conveniently isolated from the residue by crystallization from a suitable crystallization solvent as described above.
  • the invention is further illustrated, by the following non-limiting examples.
  • 2-Phenoxyethanol 50 g, 0.362 mol was dissolved in dichloromethane (500 ml) and the solution was cooled to 0-5 °C.
  • Triethylamine 101 ml, 0.724 mol was added to the cooled solution followed by pivaloyl chloride (53.5 ml, 0.434 mol) maintaining the temperature below 5 °C.
  • the mixture was stirred at 5 °C for 30 min and at room temperature for 12 h.
  • the reaction was quenched by addition of lM HCl-solution (300 ml) and stirred vigorously. The phases were separated and organic phase was washed with saturated NaHC0 3 -solution (2 x 150.
  • Polyphosphoric acid (PPA) 250 g was charged to a reaction vessel and warmed to 50 °C (bath temperature) with mechanical stirring.
  • 2-Phenylacetic acid 30.6 g, 0.225 mol was added to PPA followed by 2-phenoxyethyl pivalate (50 g, 0.225 mol).
  • TLC and HPLC indicated full conversion and water (1000 ml) was add£d.
  • the mixture was' stirred at room temperature for 2 h.
  • the precipitated product was filtered and washed with water (300 ml). After drying in vacuo the crude product (65 g) was re-crystallized With hexane /.
  • the aqueous phase was extracted with dichloromethane (2 x 75 ml),combined with THF-phase, and washed with water (100 ml) and brine (100 ml). After drying (Na 2 S0 4 ) and filtration the solvents were evaporated and crude cyclopropylcarbinol intermediate (21 g) was directly submitted to the ring-opening step.
  • the crude cyclopropylcarbinol intermediate was dissolved in dichloromethane (DCM) (150 ml) and treated with 30 % HCl-solution (120 ml). After 60 min the dehydration and ring-opening was complete and reaction mixture was poured on saturated NaHC0 3 -solution (350 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/FI2013/000039 2012-10-19 2013-10-17 A process for the preparation of ospemifene Ceased WO2014060639A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2015537313A JP6174156B2 (ja) 2012-10-19 2013-10-17 オスペミフェンの製造方法
US14/436,706 US9321712B2 (en) 2012-10-19 2013-10-17 Process for the preparation of ospemifene
EP13789369.9A EP2909164A1 (en) 2012-10-19 2013-10-17 A process for the preparation of ospemifene

Applications Claiming Priority (2)

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US201261716171P 2012-10-19 2012-10-19
US61/716,171 2012-10-19

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US (1) US9321712B2 (enExample)
EP (1) EP2909164A1 (enExample)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016108172A1 (en) 2014-12-29 2016-07-07 Olon S.P.A. Process for the preparation of ospemifene and fispemifene
WO2016110805A1 (en) * 2015-01-09 2016-07-14 Glenmark Pharmaceuticals Limited Process for preparation of ospemifene
WO2017159669A1 (ja) 2016-03-15 2017-09-21 塩野義製薬株式会社 フェノキシエタノール誘導体の製造方法

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CN108137457A (zh) * 2016-03-15 2018-06-08 盐野义制药株式会社 苯氧乙醇衍生物的制造方法
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CN108137457B (zh) * 2016-03-15 2022-09-06 盐野义制药株式会社 苯氧乙醇衍生物的制造方法

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