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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compound
formula
process according
butyl
trimethylphenyl
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PCT/FI2013/000039
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French (fr)
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Jan Tois
Ainoliisa PIHKO
Arne Grumann
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Fermion Oy
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Priority to JP2015537313A priority Critical patent/JP6174156B2/en
Priority to EP13789369.9A priority patent/EP2909164A1/en
Priority to US14/436,706 priority patent/US9321712B2/en
Publication of WO2014060639A1 publication Critical patent/WO2014060639A1/en

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    • 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)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention is related to the process for the preparation ospemifene or (Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) and to intermediate compounds used in the process.

Description

A PROCESS FOR THE PREPARATION OF OSPEMIFENE
Field of the invention
The invention is related to a process for the preparation ospemifene and to intermediate compounds used in the process.
Background of the invention
Ospemifene or (Z)-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol is represented by formula (I):
Figure imgf000003_0001
Ospemifene is an estrogen receptor agonist/antagonist currently investigated e.g. for the treatment of vulvar and vaginal atrophy due to menopause.
Preparation of ospemifene starting from Z-4-(4-hydroxy-l,2-diphenyl-but-l- enyl)phenol has been described in WO 96/07402. Use of McMurry coupling reaction for the manufacture of ospemifene has been described in WO 2008/099059 and WO 2011/089385. These methods suffer from the drawback that large amounts of expensive reagents or solvents, such as titanium tetrachloride, LiAlH4, and 2-Me- THF, are needed.'
Thus, it is desirable to provide an improved method for producing
ospemifene in high yield and purity the method also being economically feasible and suitable; for use in a large scale.
Summary of the invention
The present invention provides a process for the preparation of a compound of formula (I)
Figure imgf000004_0001
(I) which process comprises
(a) reacting a compound of formula (III)
Figure imgf000004_0002
wherein R is a protecting group tolerant to Grignard or other organometallic reagents, with phenylmagnesium halide to produce a compound of formula (IV)
a (IV) with hydrochloric acid to produce a co
Figure imgf000004_0003
(c) cleaving the ester bond of a compound of formula (V) wherein R is as defined above, to give a compound of formula (I).
In another aspect, 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 (ΙΠ) and (IV) wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.
Detailed description of the invention
... ^The^tenn "lower alcohol" means Pi^.alcpholj.preierably.Pi^.alcQbol. Representative examples include methanol, ethanol, isopropanol and butanol.
Particularly preferred is methanol and ^thanol. .
In accordance with the present invention the compound of formula (III)
Figure imgf000005_0001
wherein R is as defined above.
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 (ΓΠ). 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 NH4Cl-solution. Phenylmagnesium halide reagent is at typically used in molar excess, e.g. in 1.5 - 2 molar equivalents per compound of formula (ΠΓ). The resulting compound of formula (IV) can be isolated, if desired, by evaporation of the solvents and subsequent crystallization or the crude compound can be forwarded directly to the next step.
In the next step the compound of formula (IV) is subjected to dehydration and ring-opening reaction by treating it' with hydrochloric acid to produce the ester compound of formula (V). ! · > »: : ■ ■ < J -
dissolved in a suitable solvent such as
Figure imgf000006_0001
lution is added slowly to 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. Thus, after completion of the ring opening reaction the reaction mixture can be poured on saturated NaHC03 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.
; , . Compounds of formula (III) can be prepared using the methods known in the art. . ; , -A
For example, compound of formula (ΓΠ) can be suitably prepared by reacting a compound of formula (II)
Figure imgf000007_0001
with a compound of formula X1-CH2-CH2-X2, wherein Xi and X2 is a leaving group and R is a protecting group tolerant to Grignard or other organometallic - , . reagents. Suitable leaving groups
Figure imgf000007_0002
and X2 include, but are not limited to, halogens, para-toluenesulfonate (CH3C6H4SO O-), methanesulfonate (CH3S020-) and trifluoromethanesulfonate (CF3S02O-) groups. According to one embodiment of the invention X | and X2 are halogens, in particular X] is Br and X2 is CI. The reaction between the compound of formula (II) and the compound of formula Xi-CH2-CH2- X2 is suitably carried out in the presence of a phase transfer catalyst (PTC), such as quaternary ammonium or phosphonium salts. Examples of phase transfer catalyst include tetrabutylammonium hydrogensulfate (TBAHS), benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide. Thus, compound of formula (Π) is dissolved in suitable solvent such as toluene under nitrogen atmosphere at room temperature followed by the addition of phase transfer catalyst such as TB AHS and aqueous NaOH solution (e.g. 50 % NaOH solution) to the reaction mixture. The resulting two-phase system is stirred vigorously and the compound of formula Xi- CH2-CH2-X2 is added dropwise: The reaction is typically completed within 12 hours. The organic phase is isolated, washed, filtered, dried and evaporated to obtain the compound of formula (III).
Alternatively, the reaction between the compound of formula (II) and the compound of formula Xi-CH2-CH2-X2 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.
Compounds of formula (Π) can be prepared using the methods known in the art. -.. . . ..
For example; compound of formula (II) can be suitably prepared by reacting a compound of formula (VI)
Figure imgf000008_0001
wherein R is Gis alkyl or an optionally substituted phenyl, with 2-phenyl- acetic acid. Typically, the reaction is catalyzed by a Br0nsted acid, such as polyphosphoric acid (PPA). Thus, to warmed PPA is added compound of formula (VI) and 2-phenylacetic acid. After stirring for about 3 h, water is added and the mixture, is stirred further at room temperature for about 2 h. The precipitated compound of formula (Π) is filtered, washed and dried, and, if desired, recrystallised from suitable solvent such as hexane/isopropanol (1 : 1).
According to One embodiment of the invention, 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)
Figure imgf000009_0001
such that the hydroxyl group of ospemifene is formed.
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. When the hydrolysis is carried out at room temperature, the reaction is completed typically within 12 hours or less. Thereafter, water and suitable organic solvent such as EtOAc is added and the organic phase is washed, dried, filtered and concentrated.
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. The reaction is suitably carried out at room temperature and under nitrogen atmosphere. The reaction may be suitably quenched by addition of saturated NH4Cl-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.
Examples EXAMPLE 1. Preparation of 2-phenoxyethyl pivalate
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. After additions 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 NaHC03-solution (2 x 150. ml), water (1 x 100 ml) and brine (1 x 100 ml). After drying (Na2S04) and filtration the solvent was evaporated yielding the tile compound (76.78 g, 0.345 mol, 95 %) as a yellow oil. Ή-NMR (400 MHz, DMSO- l6) S (ppm): 7.3 1 -7.27 (2H, m, ArH), 6.96-6.93 (3Η, m, ArH), 4.34 (2Η, m, CH2CH2OPiv), 4. 19 (2Η, m, ArOCH2CH2), 1. 13 (9H, s, 3 x Me). C-NMR (100 MHz, DMSO-c¾ δ (ppm): 177.7, 158.7, 130.1, 121 . 1 , 1 14.9, 66. 1 , 62.9, 38.5, 27.6.
, . EXAMPLE 2. Preparation of 2-(4-(2^Phenylacetyl)phenoxy)ethyl pivalate
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). After 3 hours 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 /. i-PrOH 1 : 1 yielding the title compound as slightly yellow solid (51.49 g, 0.151 mol, 67 %). 1H-NMR (400 MHz, DMSC δ (ppm): 8,02 (2H, d, J=9.2Hz, ArH), 7.32-7.22 (5Η, m, ArH), 7.07 (2Η, d, (2Η, m, CH2CH2OPiv), 4.31 (2Η, s, ArCH.CO), 4.3 (2Η, m,
Figure imgf000010_0001
ArOCH2CH2), 1.12 (9H, s, 3 x Me). 13C-NMR (100 MHz, DMSO-d6) δ (ppm):
196.4, 177.7, 162.6, 135.8, 131.2, 129.9, 129.8, 128.7, 126.8, 1 14.8, 66.5, 62.7, 44.8, 38.6, 27.2.
EXAMPLE 3. Preparation of 2-(4-(l-Phenylcyclopropanecarbonyl)phenoxy)- ethyl pivalate
2-(4-(2-Phenylacetyl)phenoxy)ethyl pivalate (15 g, 44.1 mmol) was dissolved in nitrogen bubbled toluene (150 ml) and stirred under nitrogen atmosphere for 10 min at room temperature. Tetrabutylammonium hydrogensulfate (1.496 g, 4.41 mmol) catalyst was added to the stirred solution followed by 50 % NaOH-solution ; (60 ml, 1137 mmol). The two-phase system was stirred vigorously for 10 min. 1 - Bromo.-2-chloroefhane (9.17 niL, 110 mmol) was dissolved in toluene (35 ml) and added dropwise to the. stirred reaction mixture. After 12 hours the starting material was consumed and water (100 ml), was added. The phases were separated and the aqueous layer was extracted with toluene (50 ml). The combined toluene phases were washed with water (100 ml) and brine (100 ml). After drying (Na2S04) and filtration toluene was removed in vacuo. Crude title compound (15.39 g, 42 mmol, 95 %) was obtained as sticky brown oil contamined with 15 % of O-alkylated byproduct. 'H-NMR (400 MHz, CDC13) δ (ppm): 7.80 (2H, d, 7=9.2Hz, ArH), 7.26- ΊΛ6 (5Η, m, ArH), 6.77 (2Η, d, 7=8.8Hz, ArH), 4.37 (2Η, t, 7=4.8Hz,
CH2CH2OPiv), 4.15 (2Η, t, 7=5.0Hz, ArOCH2CH2), 1.60 (2H, AB-system, J=4.4Hz, CH2CH2), 1.32 (2H, AB-system, 7=4.4Hz, CH2CH2), 1. 17 (911, s, 3 x Me). 13C-NMR ( 100 MHz, CDC13) f)" (ppm): 198.6, 178.9, 162. 1 , 141.7, 132.3, 130.2, 129. 1 , 127.9, 126.8, 1 14.2, 67.0, 62.8, 39.2, 35.0, 27.5, 16.1.
EXAMPLE 4. Preparation of (Z)-2-(4-(4-Chloro-l,2-diphenylbut-l -en- 1-yl)- phenoxy)ethyl pivalate ■ . ·. . , .
Crude 2-(4-(l-Phenylcyclopropanecarbonyl)phenoxy)ethyl pivalate (15.3 g, 41.8 mmol) was dissolved in tetrahydrofuran (THF) (200 ml) under nitrogen with stirring. 1 M THF-solution of phenylmagnesium chloride (35:5 ml, 71 mmol) was added dropwise to the solution at room temperature. After addition the reaction was warmed to 60 °C and kept at this temperature for two hours. The reaction was quenched by addition of saturated NH4Cl-solutioh (300 ml). The pH was adjusted to 4 with 5 % HCl-solution and THF-phase was separated. 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 (Na2S04) 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 NaHC03-solution (350 ml). The phases were separated and DCM-phase was washed with water ( 100 ml) and brine (100 ml). After drying (Na2S04) and filtration the solvent was evaporated. The residue was dissolved in boiling methanol, cooled to 40 °C and seeded. After stirring at room temperature (12 h) ,the precipitated title compound was filtered and washed with cold MeOH. The title compound was obtained as a white solid (5.4 g, 1 1.7 mmol, 28 % over two steps), 1H-NMR (400 MHz, CDC13) δ (ppm): 7.39-7.13 (6H, m, ArH), 6.79 (2Η, d, 7=8.8Hz, ArH), 6.56 (2Η, d, 7=8.8Hz, ArH), 4.31 (2Η, t, J=4.4Hz, CH2CH2OPiv), 4.04 (2Η, t,
Figure imgf000012_0001
ArOCH2CH2), 3.41 (2H, t, 7=7.6Hz, C1CH2CH2), 2.92 (2H, t, 7=7.6Hz, C1CH2CH2), 1.17 (9Η, s, 3 x Me). 13C-NMR (100 MHz, CDC13) δ (ppm): 178.5, 156.8, 142.8, 141.6, 140.9, 135.3, 135.2, 131.7, 129.5, 129.4, 128.4, 128.2, 127.0, 126.6, 1 13.6, 65.7, 62.7, 42.8, 38.7, 38.6, 27.1.
' EXAMPLE 5. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospemifene) by base hydrolysis of pivaloyl-groiip
; . (Z)-2-(4-(4-Chloro- l ,2-diphenylbut-l-en- l-yl)phenqxy)ethyl pivalate ( 1 g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH (1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added in orie portion and the reaction was stirred at room temperature for 12 h. After completion of the reaction the mixture was partitioned between water (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20 ml) and brine (20 ml); dried (Na2S04), filtered, and concentrated: The residue was crystallized from -PrOH yielding ospernifene (0:29 g, 35 %) as a white solid. 1H-NMR (400 MHz, CDC13) δ (ppm): 7.37 (2H, t, 7=8Hz, ArH), 7.29 (3Η, t, J=7.2Hz, ArH), 7.20 (2Η, t,7=7.6Hz, ArH), 7.16-7.13 (3Η, m, ArH), 6.80 (2Η, d, J=8.8Hz, ArH), 6.57 (2Η, d, 7=8.8Hz, ArH), 3.94 (2Η, t, y=4.4Hz, ArOCH2CH2OH), 3.87 (2H, m, ArOCH2CH OH), 3.42 (2H, t, J=7.2Hz, C1CH2CH2), 2.92 (2H, t, 7=7.2Hz, C1CH2CH2), 1.95 (1Η, t, 7=6.4Hz, OH). 13C- NMR (100 MHz, CDC13) δ (ppm): 157.2, 143.2, 142.1 , 141.3, 2 x 135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.
EXAMPLE 6. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospernifene) by reductive cleavage of pivaloyl-grou
(Z)-2-(4-(4-Chloro- 1 ,2-diphenylbut- 1 -en- 1 -yl)phenoxy)ethyl pivalate (3.5 g, 7.56 mmol) was dissolved in toluene (35 ml) and stirred under nitrogen for 5 min at room temperature. Lithium aluminium hydride solution (1 M in THE) (7.56 ml, 7.56 n mbi) was added dropwise to the reaction and the mixture was stirred at room temperature for 30 min. After HPLC indicated completion, the reaction was quenched by addition of saturated NH4Cl-sblution (75 ml). Additional amount of toluene (30 ml) was added and the phases were separated. The organic phase was washed with water (50 ml), brine (50 ml), dried (Na2S04), filtered and concentrated in vacuo. The residue was crystallized from 90 % MeOH yielding ospernifene (1 ,75 g, 61 9c) as a white solid.

Claims

1. A process for the preparation of a compound of formula (I)
Figure imgf000014_0001
(I) which process comprises (a) reacting a compound of formula (III)
rant to Grignard or other organometallic reage produce a compound of formula (IV)
la (IV) with hydrochloric acid to produce a co
Figure imgf000014_0002
Figure imgf000015_0001
(V) wherein R is as defined above, and
(c) cleaving the ester bond of a compound of formula (V) wherein R is as defined above, to give a compound of formula (I).
2. A process according to claim 1, wherein the phenylmagnesium halide is phenylmagnesium chloride.
3. A process according to any of claims 1 or 2, wherein the compound of formula (V) is isolated by crystallization.
4. A process according to claim 3, wherein the compound of formula (V) is crystallized from lower alcohol.
5. A process according to claim 4, wherein the compound of formula (V) is crystallized from a solvent consisting of methanol or ethanol.
6. A process according to any of claims 1 - 5, wherein the cleavage of the ester bond of the compound of formula (V) in step (c) is carried out by using a base catalysed hydrolysis or a reductive cleavage.
,
7. A process according to claim 6, wherein the reductive cleavage is carried out in the presence of lithium aluminium hydride.
... ! .
8. A process according to any of claims 1 - 7, wherein the produced compound of formula (I) is isolated by crystallization.
9. A process according to claim 8, wherein the compound of formula (I) is crystallized from Ci.$ alcohol or from a mixture of C1-5 alcohol and water.
■ .
10. A process according to any of claims 1-9, wherein R is t-butyl, adamantyl or 2;4,6-trimethylphenyl,
11. A process according to claim 10, wherein R is t-butyL
12. A process according to any of claims 1-11, wherein the compound of formula (ΠΓ) is prepared by reacting a compound of formula (II)
Figure imgf000016_0001
with a compound of formula Xi-CH2-CH2-X2, wherein X and X2 is a leaving group and R is a protecting group tolerant to Grignard or other organometallic reagents.
13. A process according to claim 12, wherein X! is halogen and X2 is , halogen. .
14. A process according to claim 13, wherein Xi is Br and X2 is CI.
15. A process according to any of claims 12-14, wherein R is t-butyl, adamantyl' pr 2,4,6-trimethylphenyl.
16. A process according to claim 15, wherein R is t-butyl.
17. A process according to any of claims 12-16, wherein the reaction is carried out in the presence of a phase transfer catalyst.
18. A process according ito claim 15, wherein the phase transfer catalyst is tetrabutylammoniurn hydrbgensulfate (TBAHS).
19. A process according to any of claims 1-18, wherein the compound of formula (II) is prepared by reacting a compound of formula (VI)
Figure imgf000016_0002
(VI) wherein R is a protecting group tolerant to Grignard or other organometallic reagents, with 2-phenylacetic acid.
20. A process according to claim 19, wherein R is t-butyl, adamantyl or 2,4,6- trimethylphenyl,
21. A process according to: claim 20, wherein R is t-butyl.
22. A process for the preparation of a compound of formula (I)
Figure imgf000017_0001
(I) comprising the steps of treating the compound of formula (IV)
Figure imgf000017_0002
wherein R is a protecting group tolerant to Grignard or other organometallic reagents, with hydrochloric acid to produce a compound of formula (V)
ng the ester bond of a compound of formula
Figure imgf000017_0003
(V) wherein R is as defined above, to give a compound of formula (I).
23. A process according to claim 2, wherein R is t-butyl, adamantyl or 2,4,6- trimefhylphenyl.
24. A process according to claim 23, wherein R is t-butyl.
5. A compound of formula (III)
,4,6-trimethylphenyl. 25, wherein R is t-butyl.
Figure imgf000018_0001
wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl. 28. A compound according to claim 21, wherein R is t-butyl.
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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 (en) 2016-03-15 2017-09-21 塩野義製薬株式会社 Method for producing phenoxyethanol derivative

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007402A1 (en) 1994-09-07 1996-03-14 Orion-Yhtymä Oy Triphenylethylenes for the prevention and treatment of osteoporosis
WO2008099059A1 (en) 2007-02-14 2008-08-21 Hormos Medical Ltd Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2011089385A1 (en) 2010-01-19 2011-07-28 Cambrex Karlskoga Ab New processes for producing benzophenone derivatives

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2182786A (en) 1938-09-14 1939-12-12 Dow Chemical Co Hydroxy-alkyl ethers of benzophenone
US2831768A (en) 1956-01-19 1958-04-22 Eastman Kodak Co Polymeric light-sensitive photographic elements
US4117121A (en) 1977-04-22 1978-09-26 Hoffmann-La Roche Inc. Method of increasing bile flow and decreasing lipid levels
CS196471B1 (en) 1977-11-28 1980-03-31 Ivan Lukac New p-acylated phenoxyethanoles
US4656187A (en) 1981-08-03 1987-04-07 Eli Lilly And Company Treatment of mammary cancer
EP0072475B1 (en) 1981-08-17 1986-08-20 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Carbamic esters, preparation thereof, pesticidal compositions on the basis of these compounds and their use in combating pests
FI77839C (en) 1982-05-27 1989-05-10 Farmos Oy FOERFARANDE FOER FRAMSTAELLNING AV NYA THERAPEUTIC EFFECTIVE TRIPHENYLALKAN- OCH ALKENDERIVAT.
GB2126576B (en) 1982-06-25 1985-06-19 Farmos Group Limited Alkane and alkene derivatives
US5491173A (en) 1982-06-25 1996-02-13 Orion-Yhtyma Oy Tri-phenyl alkene derivatives and their preparation and use
US4625048A (en) 1982-08-13 1986-11-25 Hoffmann-La Roche Inc. Carbamic acid esters
US4729999A (en) 1984-10-12 1988-03-08 Bcm Technologies Antiestrogen therapy for symptoms of estrogen deficiency
US4935243A (en) 1988-12-19 1990-06-19 Pharmacaps, Inc. Chewable, edible soft gelatin capsule
DE3936592A1 (en) 1989-11-03 1991-05-08 Basf Ag METHOD FOR PRODUCING AND PURIFYING 2-HYDROXY-4- (2'-HYDROXY-ETHOXY) PHENYLARYL KETONES
US5189212A (en) 1990-09-07 1993-02-23 University Of Georgia Research Foundation, Inc. Triarylethylene carboxylic acids with estrogenic activity
US5219548A (en) 1990-10-01 1993-06-15 Board Of Regents, The University Of Texas System High affinity halogenated-tamoxifen derivatives and uses thereof
US6096874A (en) 1990-10-01 2000-08-01 Board Of Regents, The University Of Texas System High affinity tamoxifen derivatives
CA2092996A1 (en) 1990-10-01 1992-04-02 David Yang High affinity tamoxifen derivatives and uses thereof
US5118667A (en) 1991-05-03 1992-06-02 Celtrix Pharmaceuticals, Inc. Bone growth factors and inhibitors of bone resorption for promoting bone formation
US5196435A (en) 1991-11-21 1993-03-23 Eli Lilly And Company Melatonin derivatives and combinations with antiestrogen compounds for treating mammalian breast carcinoma
GB9207437D0 (en) 1992-04-03 1992-05-20 Orion Yhtymae Oy Topical administration of toremifene and its metabolites
US5352699A (en) 1992-04-30 1994-10-04 University Of Massachusetts Medical Center Use of retinioc acid to treat vaginal atrophy
US5446203A (en) 1992-08-25 1995-08-29 New York University Synthesis of haloenones and aryl or alkyl substituted enones or alkenes
DE4335876A1 (en) 1993-10-17 1995-04-20 Schering Ag Combination of progesterone antagonists and partial agonist antiestrogens for hormone replacement therapy for peri- and postmenopausal women
US5461064A (en) 1993-12-21 1995-10-24 Eli Lilly And Company Methods of inhibiting atrophy of the skin and vagina
US5650425A (en) 1994-04-04 1997-07-22 Pharmos Corporation Permanently ionic derivatives of steroid hormones and their antagonists
US5681835A (en) 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US5604248A (en) 1994-05-05 1997-02-18 Eli Lilly And Company Method for minimizing the uterotrophic effect of tamoxifen and tamoxifen analogs
US5470883A (en) 1994-05-23 1995-11-28 Stromberg; Brent V. Method of treating peripheral vasoconstriction with tamoxifen citrate
FI100692B (en) 1994-05-24 1998-02-13 Leiras Oy A process for the preparation of pharmaceutical compositions, wherein the compositions are based on microemulsion gels and new gels directed to microemulsions.
US5441986A (en) 1994-07-19 1995-08-15 Pfizer Inc. Estrogen agonists as remedies for prostate and cardiovascular diseases
US5658931A (en) 1994-09-20 1997-08-19 Eli Lilly And Company Method for inhibiting mammalian breast carcinoma with tamoxifen, and analogs thereof, and certain naphthyl compounds
US6562862B1 (en) 1994-10-20 2003-05-13 Eli Lilly And Company Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y
EP0794771A1 (en) 1994-11-29 1997-09-17 Hoechst Marion Roussel, Inc. Method of using triaryl-ethylene derivatives in the treatment and prevention of osteoporosis
US5821254A (en) 1995-02-17 1998-10-13 The United States Of America As Represented By The Department Of Health And Human Services Uses of 9-cis-retinoic acids and derivatives thereof alone or in combination with antineoplastic agents in the prevention or treatment of cancer
GB9509572D0 (en) 1995-05-11 1995-07-05 Cancer Res Campaign Tech Cancer therapy
DE19526146A1 (en) 1995-07-07 1997-01-09 Schering Ag Triphenylethylenes, processes for their preparation, pharmaceutical preparations containing these triphenylethylenes and their use for the preparation of medicaments
US5747059A (en) 1996-01-11 1998-05-05 Novo Nordisk A/S Atrophy of skin/mucous membrane
GB9604577D0 (en) 1996-03-04 1996-05-01 Orion Yhtymae Oy Serum cholesterol lowering agent
DE19653736C2 (en) 1996-12-12 2002-11-21 Lancaster Group Gmbh Cosmetic preparation with added peptide
GB9803521D0 (en) 1998-02-19 1998-04-15 Orion Yhtymo Oy New compounds and pharmaceutical compositions thereof
US6632447B1 (en) 1998-05-07 2003-10-14 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer
US6465445B1 (en) 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6525084B2 (en) 1998-07-23 2003-02-25 Novo Nordisk A/S Stable pharmaceutical formulation
US6245352B1 (en) 1999-04-27 2001-06-12 Eli Lilly And Company Pharmaceutical formulation
TW593256B (en) 1999-11-16 2004-06-21 Hormos Medical Oy Ltd Triphenylalkene derivatives and their use as selective estrogen receptor modulators
CO5271697A1 (en) 2000-01-12 2003-04-30 Pfizer Prod Inc COMPOSITIONS AND PROCEDURES FOR THE TREATMENT OF AFFECTIONS THAT RESPOND TO AN INCREASE OF TESTOSTERONE
KR20020073566A (en) 2000-01-28 2002-09-27 앙도르쉐르슈 인코포레이티드 Selective estrogen receptor modulators in combination with estrogens
DE60104614T2 (en) 2000-02-17 2005-01-05 Appleton Papers Inc., Appleton PROCESS FOR THE PREPARATION OF ALKOXY OR ARYLMETHOXY AROXYETHANES
US20010034340A1 (en) 2000-03-20 2001-10-25 American Home Products Corporation Hormone replacement therapy
US6245819B1 (en) 2000-07-21 2001-06-12 Hormos Medical Oy, Ltd. Method for the treatment of vaginal dryness and sexual dysfunction in women during or after the menopause
FI111710B (en) 2001-05-04 2003-09-15 Hormos Medical Oy Ltd Process for the preparation of a therapeutically active substance
US20050215528A1 (en) 2001-08-10 2005-09-29 Shuichi Furuya Gnrh agonist combination drugs
US20070197664A1 (en) 2001-11-29 2007-08-23 Steiner Mitchell S Prevention and treatment of androgen-deprivation induced osteoporosis
EP1460969B1 (en) 2001-11-29 2008-05-07 GTX, Inc. Prevention and treatment of androgen-deprivation induced osteoporosis
EP1509215B1 (en) 2002-06-06 2006-11-02 Hormos Medical Ltd. Treatment or prevention of urogenital atrophy and its symptoms in women
US20040248989A1 (en) 2003-06-05 2004-12-09 Risto Santti Method for the treatment or prevention of lower urinary tract symptoms
US8236861B2 (en) 2004-02-13 2012-08-07 Hormos Medical Corporation Method for enhancing the bioavailablity of ospemifene
US20050187302A1 (en) 2004-02-23 2005-08-25 Hormos Medical Corporation Method for treatment or prevention of osteoporosis in individuals with high bone turnover
US8642079B2 (en) 2004-02-23 2014-02-04 Hormos Medical Corporation Solid formulations of ospemifene
US7405303B2 (en) 2004-02-25 2008-07-29 Smithkline Beecham Corporation Substituted quinoline compounds for use as selective estrogen receptor modulator
US8758821B2 (en) 2004-05-04 2014-06-24 Hormos Medical Ltd. Oral formulations of ospemifene
US7504530B2 (en) 2007-02-14 2009-03-17 Hormos Medical Ltd. Methods for the preparation of fispemifene from ospemifene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007402A1 (en) 1994-09-07 1996-03-14 Orion-Yhtymä Oy Triphenylethylenes for the prevention and treatment of osteoporosis
WO2008099059A1 (en) 2007-02-14 2008-08-21 Hormos Medical Ltd Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2011089385A1 (en) 2010-01-19 2011-07-28 Cambrex Karlskoga Ab New processes for producing benzophenone derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ZHANG, DAN ET AL: "Two-step synthesis technology of ospemifene", XP002719430, retrieved from STN Database accession no. 2013:1491112 *
ZHANG, DAN ET AL: "Two-step synthesis technology of ospemifene", XIANDAI YAOWU YU LINCHUANG , 27(4), 351-352 CODEN: XYYLAW; ISSN: 1674-5515, vol. 27, no. 4, 29 March 2012 (2012-03-29), pages 351 - 352, XP002719433, Retrieved from the Internet <URL:http://www.tiprpress.com/xdywlc/ch/reader/create_pdf.aspx?file_no=201204004&flag=1&journal_id=xdywlc&year_id=2012> [retrieved on 20140129] *

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* Cited by examiner, † Cited by third party
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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 (en) 2016-03-15 2017-09-21 塩野義製薬株式会社 Method for producing phenoxyethanol derivative
CN108137457A (en) * 2016-03-15 2018-06-08 盐野义制药株式会社 The manufacturing method of Phenoxyethanol derivative
KR20180122330A (en) 2016-03-15 2018-11-12 시오노기 앤드 컴파니, 리미티드 Process for producing phenoxyethanol derivative
US10472312B2 (en) 2016-03-15 2019-11-12 Shionogi & Co., Ltd. Method for producing phenoxyethanol derivative
EP3835285A1 (en) 2016-03-15 2021-06-16 Shionogi & Co., Ltd Method for producing phenoxyethanol derivative
CN108137457B (en) * 2016-03-15 2022-09-06 盐野义制药株式会社 Method for producing phenoxyethanol derivative

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