[go: up one dir, main page]

US20140235882A1 - Process for the preparation of estetrol - Google Patents

Process for the preparation of estetrol Download PDF

Info

Publication number
US20140235882A1
US20140235882A1 US14/233,362 US201214233362A US2014235882A1 US 20140235882 A1 US20140235882 A1 US 20140235882A1 US 201214233362 A US201214233362 A US 201214233362A US 2014235882 A1 US2014235882 A1 US 2014235882A1
Authority
US
United States
Prior art keywords
group
oxy
estra
process according
iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/233,362
Other languages
English (en)
Inventor
Johannes Jan Platteeuw
Herman Jan Tijmen Coelingh Bennink
Franciscus Wilhelmus Petrus Damen
Michiel Christine Alexander Van Vliet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pantarhei Biocience BV
Estetra SRL
Original Assignee
Pantarhei Biocience BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44582248&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20140235882(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Pantarhei Biocience BV filed Critical Pantarhei Biocience BV
Priority to US14/233,362 priority Critical patent/US20140235882A1/en
Assigned to PANTARHEI BIOSCIENCE B.V. reassignment PANTARHEI BIOSCIENCE B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COELINGH BENNINK, HERMAN JAN TIJMEN, DAMEN, FRANCISCUS WILHELMUS PETRUS, PLATTEEUW, JOHANNES JAN, VAN VLIET, MICHIEL CHRISTIAN ALEXANDER
Publication of US20140235882A1 publication Critical patent/US20140235882A1/en
Assigned to DONESTA BIOSCIENCE B.V. reassignment DONESTA BIOSCIENCE B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PANTARHEI BIOSCIENCE B.V.
Assigned to ESTETRA SPRL reassignment ESTETRA SPRL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DONESTA BIOSCIENCE B.V.
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol (estetrol), starting from estrone.
  • the invention further relates to a process for the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, starting from estrone, via the corresponding silyl enol ether 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene, wherein A is a protecting group and B is —Si(R 2 ) 3 .
  • Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and in methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability, include ethinyl estradiol and mestranol.
  • Estetrol has been found effective as an estrogenic substance for use in HRT, as is disclosed in WO 02/094276.
  • Estetrol is a biogenic estrogen that is endogeneously produced by the fetal liver during human pregnancy.
  • Other important applications of estetrol are in the fields of contraception, therapy of auto-immune diseases, prevention and therapy of breast and colon tumors, enhancement of libido, skin care, and wound healing as described in WO 02/094276, WO 02/094279, WO 02/094278, WO 02/094275, WO 03/041718 and WO 03/018026.
  • estetrol [estra-1,3,5(10)-trien-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol] I is shown below. In this description the IUPAC-recommended ring lettering and atom numbering for steroids and steroid derivatives, as depicted below, are applied.
  • estetrol is synthesised from estrone derivative III as shown in Scheme 1 (numbering according to Fishman et al.).
  • This compound IVa was subsequently acetylated which produced 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IVb).
  • the dioxolane group of compound IVb was hydrolysed by using p-toluene sulfonic acid to compound Vb, followed subsequently by reduction of the carbonyl group at C 17 (compound Vc) and oxidation of the double bond of ring D thereby forming estra-1,3,5(10)-triene-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol-3,17-diacetate (compound VIb).
  • Suzuki et al., Steroids 1995, 60, 277-284 also discloses the synthesis of estetrol by using compound Vb of Nambara et al. as starting material.
  • the carbonyl group at C 17 of this compound was first reduced followed by acetylation yielding estra-1,3,5(10),15-tetraene-3,17-diol-3,17-diacetate (compound 2b).
  • the latter was subjected to oxidation with OsO 4 which provided estra-1,3,5(10)-triene-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol-3,17-diacetate (compound 3b) in 46% yield.
  • estetrol can be performed with a yield of approximately 8%, starting from estrone.
  • estrone derivative VI starting from estrone is disclosed by Cantrall et al., J. Org. Chem. 1964, 29, 214-217 and 64-68, and by Johnson et al., J. Am. Chem. Soc. 1957, 79, 2005-2009, and is shown in Scheme 3 (numbering according to Johnson et al.).
  • estrone derivative VI of Scheme 3 Another method to prepare estrone derivative VI of Scheme 3, wherein the hydroxyl group on the 3-position of estrone is protected as a methyl ether, is disclosed in Li et al., Steroids 2010, 75, 859-869, and is shown in Scheme 4 (numbering according to Li et al.). After protection of the 3-OH group of estrone 39 as the methyl ether to form 40, the keto function on C 17 is converted into trimethylsilyl enol ether 41.
  • a method for the preparation of enones using hypervalent iodine(V) species is disclosed by Nicolaou et al., Angew. Chem. 2002, 114, 1038-1042.
  • Various ketones are converted into ⁇ , ⁇ -unsaturated enones via oxidation of the corresponding trimethylsilyl enol ethers, induced by o-iodoxybenzoic acid (IBX) or IBX complexed to an N-oxide ligand such as 4-methoxypyridine-N-oxide (IBX.MPO).
  • IBS 2-iodoxybenzenesulphonic acid
  • Yamada et al. discloses the use of IBS, in a catalytic amount, for the conversion of several cyclic alcohols with a relatively simple structure such as cyclopentanol and (optionally substituted) cyclohexanol into ⁇ , ⁇ -unsaturated enones.
  • IBS IBS for the conversion of complex molecules such as steroids into ⁇ , ⁇ -unsaturated enone derivatives is not disclosed in Yamada et al. or in EP 2085373.
  • Step (1) of this process the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6) starting from estrone (7), is shown in Scheme 7 and comprises the following steps:
  • estetrol is obtained in an overall yield of 10.8%, starting from estrone.
  • the process disclosed in WO 2004/041839 is suitable for an industrial scale preparation of estetrol 1, and although estetrol is obtained with a reasonable overall yield, the process still suffers from several disadvantages.
  • the conversion of 7 into 6 is performed in a total of 5 steps. Isolation and purification of each intermediate product inevitably results in a loss of yield, thereby reducing the overall yield of estetrol.
  • the conversion of 7 into 6 involves a halogenation (step 1c) and a dehalogenation step (step 1d), typically a bromination and a debromination step.
  • steps 1d typically a bromination and a debromination step.
  • various side products are produced. Since these side products need to be removed from the intermediate products, an extensive amount of purification of the intermediate products is required, resulting in a substantial loss of yield of the intermediate products, and therefore, ultimately, in a substantial loss in the overall yield of estetrol.
  • the present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol I which comprises the steps of:
  • the invention further relates to a process for the synthesis of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group, which comprises the steps of:
  • indefinite article “a” or “an” does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there is one and only one of the elements.
  • the indefinite article “a” or “an” thus usually means “at least one”.
  • alkyl includes linear, branched and cyclic alkyl groups such as for example methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, s-pentyl, t-pentyl, cyclopentyl, methylcyclobutyl and cyclohexyl.
  • a benzyl group is defined as a —CH 2 (C 6 H 5 ) group.
  • a C 7 -C 12 benzylic group is defined as a benzyl group, i.e. a —CH 2 (C 6 H 5 ) group as defined above, or a benzyl group that is substituted with one or more substituents at the ortho, meta and/or para position of the aromatic nucleus, wherein the substituents are aliphatic groups, optionally substituted by one or more heteroatoms and/or halogen atoms that do not adversely interfere with the synthetic process.
  • Examples of a substituted benzyl group include —CH 2 (C 6 H 4 Me) or —CH 2 (C 6 H 3 Me 2 ), wherein Me is defined as a methyl group (—CH 3 ).
  • a C 6 -C 12 aryl group is defined as a monocyclic, bicyclic or polycyclic structure comprising 6 to 12 carbon atoms.
  • the aryl groups may be substituted by one or more substituents at the ortho, meta and/or para position of the aromatic nucleus, wherein the substituents are aliphatic groups, optionally substituted by one or more heteroatoms and/or halogen atoms that do not adversely interfere with the synthetic process.
  • substituents are aliphatic groups, optionally substituted by one or more heteroatoms and/or halogen atoms that do not adversely interfere with the synthetic process.
  • Examples of an aryl group include phenyl, p-tolyl, mesityl and naphthyl.
  • the alkyl and benzylic groups and the —Si(R 1 ) 3 groups are intended as a protecting group and these groups must therefore be relatively easy to add and relatively easy to remove under conditions that have substantially no adverse effect on the molecular structure of the estrone derived steroid molecules.
  • the present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3,15 ⁇ ,16 ⁇ ,17 ⁇ -tetraol I (estetrol) which comprises the steps of:
  • B is —Si(R 2 ) 3 , wherein R 2 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 13 aryl group; and C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups, i.e. a monofunctional protecting group that is suitable for the protection of an aliphatic hydroxyl group.
  • R 2 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 13 aryl group
  • C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups, i.e. a monofunctional protecting group that is suitable for the protection of an aliphatic hydroxyl group.
  • Step (1) Conversion of estrone II into 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III, Wherein A is a Protecting Group and B is —Si(R 2 ) 3
  • Step 1 of the process comprises the steps of (1a) the protection of the hydroxyl group on the 3-position of estrone II with a protecting group A, and (1b) the conversion of the keto functionality on the 17-position into the corresponding silyl enol ether.
  • step (1a) is executed first, followed by step (1b), in other words, the 3-hydroxyl group of estrone II is first protected with a protecting group A, followed by the conversion of the thus obtained 3-protected estrone into the corresponding 3-protected silyl enol ether III, as is shown in Scheme 9.
  • step (1a) and (1b) may be executed simultaneously, or in a “two-reactions-one-pot” procedure.
  • Step (1a) relates to the protection of the 3-hydroxyl group of estrone II with a protecting group A.
  • Protecting group A is selected from the group consisting of a C 1 -C 5 alkyl group, a C 7 -C 12 benzylic group and a —Si(R 1 ) 3 group, wherein R 1 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group.
  • A When protecting group A is a C 1 -C 5 alkyl group, A may for example be methyl, ethyl, propyl, iso-propyl (i-propyl), butyl, iso-butyl (i-butyl) or tertiair butyl (t-butyl). Preferably, if A is a C 1 -C 5 alkyl group, A is methyl.
  • A is a C 7 -C 12 benzylic group
  • A is a benzyl group, —CH 2 (C 6 H 5 ).
  • the C 7 -C 12 benzylic group may also be a substituted benzyl group, such as for example —CH 2 (C 6 H 3 Me 2 ).
  • A is a benzyl group.
  • each R 1 group is independently selected, in other words, each of the three R 1 groups within one —Si(R 1 ) 3 group may be different from the others.
  • R 1 is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, phenyl, p-tolyl and mesityl.
  • Suitable —Si(R 1 ) 3 groups include trimethylsilyl (TMS), triethylsilyl (TES), diethylisopropylsilyl (DEIPS), isopropyldimethylsilyl (IPDMS), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS) and t-butyldiphenylsilyl (TBDPS).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • DEIPS diethylisopropylsilyl
  • IPDMS isopropyldimethylsilyl
  • TIPS triisopropylsilyl
  • TIPS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • the —Si(R 1 ) 3 group is a sterically hindered (“bulky”) —Si(R 1 ) 3 group such as for example a DEIPS, IPDMS, TIPS, TBDMS or TBDPS group.
  • a sterically hindered (“bulky”) —Si(R 1 ) 3 group such as for example a DEIPS, IPDMS, TIPS, TBDMS or TBDPS group.
  • the protection of the hydroxyl group on C 3 by alkylation is typically carried out by reacting estrone with a component selected from an alkylating reagent, preferably a C 1 -C 5 alkyl halogenide, preferably a methyl halogenide, or a C 7 -C 12 benzylic halogenide, preferably benzyl halogenide.
  • an alkylating reagent preferably a C 1 -C 5 alkyl halogenide, preferably a methyl halogenide, or a C 7 -C 12 benzylic halogenide, preferably benzyl halogenide.
  • the halogen atom of the alkylating agent is bromide, chloride or iodide, most preferably bromide or iodide.
  • the most preferred alkylating agent is benzyl bromide or methyl iodide, wherein benzyl bromide is more preferred than methyl iodide.
  • a dialkyl sulphate instead of a C 1 -C 5 alkyl halogenide, wherein the alkyl groups contain 1-5 carbon atoms and wherein the alkyl groups are preferably methyl (i.e. the preferred dialkyl sulphate is then dimethyl sulphate).
  • the protection of the 3-OH group by silylation is typically carried out by reacting estrone with a silylation reagent, such as for example a silyl chloride, a silyl iodide or a silyl triflate, in the presence of a base, for example an amine base.
  • a silylation reagent such as for example a silyl chloride, a silyl iodide or a silyl triflate
  • Suitable bases are known to a person skilled in the art, and include for example potassium bases such as potassium carbonate (K 2 CO 3 ), potassium t-butoxide (KOtBu), potassium hexamethyldisilazide (KHMDS) or potassium hydride (KH), sodium bases such as sodium methoxide (NaOMe), sodium t-butoxide (NaOtBu), sodium hexamethyldisilazide (NaHMDS) or sodium hydride (NaH), lithium bases such as lithium diisopropylamide (LDA), lithium tetramethylpiperidide (LiTMP) or lithium hexamethyldisilazide (LiHMDS), amine bases such as triethyl amine (Et 3 N), tetramethylethylene diamine (TMEDA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diaza
  • potassium bases such as potassium carbonate (K 2 CO 3 ), potassium
  • the type of base that is preferred in a specific reaction depends strongly on the type of alkylating or silylation reagent used in said reaction.
  • the 3-OH group is protected via an alkylation reaction, e.g. with benzyl bromide as alkylating reagent, then the use of an amine base in that reaction is less preferred.
  • the 3-OH group is protected via a silylation reaction, then the use of a small alkoxide, such as for example NaOMe, as a base is less preferred.
  • Suitable solvents for the protection reaction include for example dimethylformamide (DMF), dichloromethane (DCM), ethyl acetate (EtOAc), toluene, acetonitrile (MeCN), dimethyl sulfoxide (DMSO), dimethylacetamide, dimethyl carbonate (DMC), tetrahydrofuran (THF) and other ethers such as for example 1,4-dioxane, 2-methyltetrahydrofuran (2-MeTHF), methyl t-butyl ether (MTBE),1,2-dimethoxyethane (DME) and cyclopentyl methylether, mixtures of two or more of these solvents, and mixtures of these solvents with different solvents such as for example methanol (MeOH).
  • DMF dimethylformamide
  • DCM dichloromethane
  • EtOAc ethyl acetate
  • MeCN dimethyl sulfoxide
  • DMC dimethylacetamide
  • the reaction may be executed at ambient temperature, at an elevated temperature (e.g. reflux), or at low temperature.
  • elevated temperature e.g. reflux
  • the preferred reaction conditions such as solvent and reaction temperature strongly depend on the nature of the specific reaction, in particular on the alkylating or silylation reagent and/or the type of base used in said reaction.
  • K 2 CO 3 may be used as a base and the reaction may be executed in a mixture of DCM and MeOH (e.g. a 1:1 mixture) at elevated temperature (reflux).
  • NaOMe may be used as a base and the reaction may be performed in a mixture of 2-methyltetrahydrofuran and methanol at an elevated temperature of around 60° C.
  • K 2 CO 3 may be used as a base and the reaction may be performed in DMF while keeping the temperature around 20° C.
  • step (1a) and (1b) may be executed simultaneously or in a “two-reactions-one-pot” procedure, e.g. by reaction of estrone II with at least two equivalents of a base followed by reaction with at least two equivalents of silylation reagent (such as for example trimethylsilyl chloride or triethylsilyl chloride) in order to introduce A and B, or, alternatively, by reaction of estrone II with at least two equivalents of a base (such as for example LDA), followed by reaction with one equivalent of a silylation agent (such as for example trimethylsilyl chloride) in order to introduce B, followed by reaction with one equivalent of alkylating agent (such as for example benzyl bromide) in order to introduce A.
  • silylation reagent such as for example trimethylsilyl chloride or triethylsilyl chloride
  • Step (1b) relates to the conversion of the keto functionality on C 17 into the corresponding silyl enol ether to form the 3-protected 17-silyl enol ether 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III
  • B is a —Si(R 2 ) 3 group, wherein each R 2 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group.
  • each R 2 group in —Si(R 2 ) 3 is independently selected, in other words each of the three R 2 groups within one —Si(R 2 ) 3 group may be different from the others.
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, phenyl, p-tolyl and mesityl.
  • B is a trimethylsilyl (TMS) or a triethylsilyl (TES) group.
  • B is a TMS group.
  • silyl enol ether III is typically carried out by reacting the 3-protected estrone with a silylation reagent, such as for example a silyl chloride or a silyl triflate, in the presence of a base.
  • a silylation reagent such as for example a silyl chloride or a silyl triflate
  • the silylation reagent is trimethylsilylchloride (TMSC1), trimethylsilyliodide (TMSI) or trimethylsilyltriflate (TMSOTf).
  • Suitable bases are known to a person skilled in the art, and include for example potassium bases such as K 2 CO 3 or KH, sodium bases such as NaH or NaOMe, lithium bases such as LiAlH 4 , LDA, LiTMP or LiHMDS, amine bases such as Et 3 N, imidazole and 2,6-lutidine, TMEDA, DBU and the like.
  • the base is LDA or Et 3 N.
  • Suitable solvents for the silyl enol ether conversion are known to the person skilled in the art, and include for example dimethylformamide (DMF), dichloromethane (DCM), toluene, tetrahydrofuran (THF) and other ethers such as for example 1,4-dioxane, 2-methyltetrahydrofuran (2-MeTHF), methyl t-butyl ether (MTBE), 1,2-dimethoxyethane (DME) and cyclopentyl methylether, or mixtures thereof.
  • DMF dimethylformamide
  • DCM dichloromethane
  • THF tetrahydrofuran
  • other ethers such as for example 1,4-dioxane, 2-methyltetrahydrofuran (2-MeTHF), methyl t-butyl ether (MTBE), 1,2-dimethoxyethane (DME) and cyclopentyl methylether, or mixtures thereof.
  • reaction conditions such as solvent and reaction temperature strongly depend on the nature of the specific reaction, in particular on the silylation reagent and/or the type of base used in said reaction.
  • the reaction may be executed at ambient temperature with TMSOTf as silylation reagent, Et 3 N as a base and in toluene or DCM as a solvent.
  • step (2) Extensive purification of silyl enol ether III before subjecting it to the next step of the process is not necessary.
  • crude III i.e. III that has not undergone extensive purification, is used as the starting material for step (2).
  • Step (2) Conversion of 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, Wherein A is a Protecting Group
  • Step (2) relates to the conversion of silyl enol ether III into ⁇ , ⁇ -unsaturated enone IV. There are several methods to execute this oxidation.
  • step (2) of the process i.e. the conversion of III into IV, is performed in the presence of an iodine(V) species.
  • said iodine(V) species is present in an amount of about 0.001 mol % or more, for example in an amount of about 0.1 mol % or more, or in an amount of about 0.5 mol % or more, with respect to compound III
  • the iodine(V) species is present in an amount of about 100 to about 500 mol % (about 1 to 5 equivalents), preferably in an amount of about 100 to about 300 mol % (about 1 to 3 equivalents), more preferably in an amount of about 100 to about 150 mol % (about 1 to 1.5 equivalents), even more preferably in an amount of about 100 to about 130 mol % (about 1 to 1.3 equivalents), and most preferably in an amount of about 100 mol % (about 1 equivalent), with respect to compound III.
  • the iodine(V) species is present in an amount of about 100 mol % or less, preferably in an amount of about 75 mol % or less, more preferably in an amount of about 50 mol % or less, even more preferably in an amount of about 30 mol % or less, and even more preferably in an amount of about 20 mol % or less, all with respect to the amount of III
  • the iodine(V) species is present in an amount of about 15 mol % or less, preferably about 10 mol % or less, more preferably about 5 mol % or less, with respect to the amount of III
  • the iodine(V) species comprises 2-iodoxybenzoic acid (IBX), 2-iodoxybenzenesulphonic acid (IBS), and/or a derivative thereof.
  • the iodine(V) species may be generated in situ.
  • IBX may for example be generated in situ from 2-iodobenzoic acid and Oxone (2 KHSO 5 .KHSO 4 .K 2 SO 4 )
  • IBS may for example be generated in situ from 2-iodobenzenesulphonic acid and Oxone.
  • IBX stabilized IBX
  • IBX stabilized IBX
  • IBX isophthalic acid and benzoic acid disclosed by Ozanne et al., Org. Lett. 2003, 5, 2903-2906, incorporated by reference.
  • the iodine(V) species comprises stabilised IBX.
  • IBX derivatives are, amongst others, 2,3,4,5-tetrafluoro-6-iodoxybenzoic acid (FIBX), disclosed by Richardson et al., Angew. Chem. Int. Ed. 2007, 46, 6529-6532, incorporated by reference, and 5-methoxy-3-methyl-2-iodoxybenzoic acid, disclosed by Moorthy et al., Tetrahedron Lett. 2008, 49, 80-84, incorporated by reference.
  • An example of an IBS derivative is 5-methyl-2-iodoxybenzenesulphonic acid (5-Me-IBS), disclosed by Yamada, Spec. Chem. Mag. 2011, 31, 18-20, incorporated by reference.
  • 5-Me-IBS may for example be generated in situ from 5-methyl-2-iodobenzenesulphonic acid potassium salt and Oxone.
  • the iodine(V) species comprises a derivative formed by complexation of IBX, IBS and/or a derivative thereof with a ligand, in particular with dimethyl sulfoxide (DMSO) or with an N-oxide.
  • a ligand in particular with dimethyl sulfoxide (DMSO) or with an N-oxide.
  • suitable N-oxides are N-methylmorpholine-N-oxide (NMO), 4-methoxypyridine-N-oxide (MPO), trimethylamine-N-oxide, 2-picoline-N-oxide and 4-phenylpyridine-N-oxide.
  • the ligand is selected from DMSO, NMO, MPO, or a combination of two or more of these ligands.
  • Said derivatives may be formed for example by stirring a solution of said IBX, IBS and/or derivative thereof with said ligand, optionally at an elevated temperature.
  • the iodine(V) species comprises a species formed by activation of I 2 O 5 and/or HIO 3 in DMSO. In another alternative embodiment, the iodine(V) species comprises a species formed by complexation of I 2 O 5 and/or HIO 3 with a ligand, in particular with an N-oxide as described above.
  • the iodine(V) species comprises 2-iodoxybenzenesulphonic acid (IBS) and/or a derivative thereof, as described above.
  • the IBS and/or derivative thereof is then preferably present in an amount of less than 100 mol % (1 equivalent), for example in an amount of about 0.001 to about 50 mol %, preferably about 0.01 to about 40 mol %, more preferably about 0.1 to about 30 mol % even more preferably about 0.5 to about 20 mol % and most preferably about 1 to about 10 mol %, all with respect to compound III.
  • Suitable solvents for the conversion of III into IV in the presence of an iodine(V) species are known to the person skilled in the art, and include for example dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate, acetone, or a mixture thereof.
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • NMP N-methylpyrrolidone
  • acetonitrile ethyl acetate
  • acetone acetone
  • a mixture of said solvents with other organic solvents such as for example dichloromethane (DCM), chloroform or fluorobenzene may be used.
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, a combination thereof, and a combination of DMSO, DMF, DMA and/or NMP with one or more organic solvents, such as for example DCM, chloroform or fluorobenzene.
  • the reaction is executed in DMSO, or in a mixture of DMSO with one or more organic solvents, such as for example DCM, chloroform or fluorobenzene.
  • the reaction is executed in DMF, or in a mixture of DMF with one or more organic solvents, such as for example DCM, chloroform or fluorobenzene.
  • the reaction may be executed at ambient temperature or at elevated temperature.
  • reaction conditions such as solvent and reaction temperature strongly depend on the nature of the specific reaction, in particular on the type of iodine(V) species that is employed in the reaction.
  • step (2) of the process i.e. the conversion of III into IV
  • step (2) of the process is performed in the presence of a transition metal compound.
  • said transition metal compound is present in an amount of about 0.001 mol % or more, for example in an amount of about 0.01 mol % or more, or in an amount of about 0.1 mol % or more, with respect to compound III
  • the transition metal compound comprises a palladium (Pd) compound, and more preferably, the transition metal is a palladium compound.
  • palladium compounds are palladium black, Pd(OH) 2 on carbon (Pd(OH) 2 /C, also known as Pearlman's catalyst), Pd(dba) 2 or Pd(OAc) 2 .
  • the palladium compound may also be a ligand-stabilised palladium compound, wherein the palladium is stabilised with for example a bidentate nitrogen or carbene ligand, such as for example palladium stabilised with 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline (neocuproine), 2,2′-bipyridine, etc.
  • the palladium compound may be a palladium(0) or a palladium(II) compound.
  • the palladium compound comprises a palladium(II) compound, such as for example palladium(II)acetate, Pd(OAc) 2 .
  • the transition metal compound is palladium(II)acetate.
  • the transition metal compound may be present in an amount of about 100 mol % (1 equivalent) with respect to compound III, or more. However, it is preferred that the transition metal compound is present in a substoichiometric amount, in other words in an amount of less than about 100 mol % with respect to III.
  • the transition metal compound may for example be present in an amount of 0.01 to about 50 mol %, or in an amount of about 0.1 to about 30 mol %, about 0.5 to about 20 mol %, about 1 to about 15 mol %, or about 3 to about 10 mol %, relative to compound III. Most preferably, the transition metal compound is present in an amount of about 1 to about 5 mol % relative to III.
  • the reaction may also be performed in the presence of an oxidizing agent (an oxidant) in order to facilitate the reoxidation of the transition metal.
  • an oxidizing agent an oxidant
  • the presence of an oxidant is particularly preferred when the transition metal compound is a palladium(0) compound, or when a palladium(II) compound is present in a substoichiometric amount, i.e. in an amount of less than 1 equivalent, with respect to the compound III
  • the oxidant is preferably present in an amount of about 1 equivalent (about 100 mol %) or more, relative to compound III
  • the amount of oxidant present may range for example from about 1 to about 3 equivalents, preferably from about 1 to about 2 equivalents and more preferably from about 1 to about 1.5 equivalents, relative to the amount of III
  • Suitable oxidants are known to a person skilled in the art, and include for example molecular oxygen (O 2 ), copper(II)acetate (Cu(OAc) 2 ), allyl methyl carbonate, t-butylhydroperoxide (TBHP), N-methylmorpholine N-oxide (NMO) and similar N-oxides, benzoquinone, and the like.
  • the oxidant is copper(II)acetate.
  • the oxidant is allyl methyl carbonate.
  • the oxidant is O 2 .
  • the reaction may be performed in an O 2 -atmosphere. It is then preferred that the reaction is executed at atmospheric pressure (about 1 bar). However, execution of the reaction in an O 2 -atmosphere at elevated pressure is also possible.
  • the reaction may be performed by using the O 2 in air as an oxidant.
  • the reaction is then executed in an air atmosphere, either at atmospheric pressure or at an elevated pressure.
  • the reaction may be performed in “diluted air”, such as for example 8% O 2 in nitrogen (N 2 ) at elevated pressure, for example at a pressure of about 10 bar or more.
  • the reaction is executed in an O 2 -atmosphere or an air atmosphere, optionally at an elevated pressure.
  • the reaction is executed in an atmosphere of “diluted air” (e.g. ca. 8% O 2 in N 2 ) at an elevated pressure (e.g. about 10 bar or more).
  • Suitable solvents for the conversion of III into IV in the presence of a transition metal compound, in particular a palladium compound are known to the person skilled in the art, and include for example dimethyl sulfoxide (DMSO), sulfolane, etc. Additionally, a mixture of said solvents with for example DCM or chloroform may also be used. In a preferred embodiment, the reaction is executed in DMSO, or in a mixture of DMSO with one or more organic solvents, such as for example DCM or chloroform.
  • DMSO dimethyl sulfoxide
  • sulfolane sulfolane
  • a mixture of said solvents with for example DCM or chloroform may also be used.
  • the reaction is executed in DMSO, or in a mixture of DMSO with one or more organic solvents, such as for example DCM or chloroform.
  • the reaction may be executed at ambient temperature or at elevated temperature.
  • Step (3) Reduction of the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17 ⁇ -ol V, Wherein A is a Protecting Group
  • Step (3) relates to the reduction of the 17-keto functionality to form V, and said reduction of the 17-keto group may be performed as disclosed in WO 2004/041839.
  • Said reduction is preferably performed by reacting 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV with a reducing agent selected from the group of metal hydride compounds, said group of metal hydride compounds preferably comprising LiAlH 4 , AlH 3 , NaBH 4 , NaBH(OAc) 3 , ZnBH 4 , and NaBH 4 /CeCl 3 .
  • the metal hydride compound is NaBH 4 /CeCl 3 .
  • More preferred reducing agents for use herein are those that will provide a chemo- and stereo-selective reduction of the 17-keto group in favour of the position. For that reason, the most preferred chemo- and stereo-selective reducing agent for use herein is NaBH 4 in combination with CeCl 3 hydrate, preferably the heptahydrate.
  • reaction mixture preferably 2 N HCl
  • an acid preferably 2 N HCl
  • the temperature is then raised to about 70° C. to induce phase separation.
  • the organic phase is then separated, washed with an aqueous solution of Na 2 CO 3 and water.
  • the final organic phase is dried by azeotropic distillation, cooled to about 50° C. and used for the next step.
  • Step (4) Protection of the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17 ⁇ -ol V to form 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene VI, Wherein A and C are Protecting Groups
  • Step (4) of the process relates to the protection of the hydroxyl group on the 17-position of V with a protecting group C, wherein C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups, i.e. monofunctional protecting groups that are suitable for the protection of an aliphatic hydroxyl group.
  • C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups, i.e. monofunctional protecting groups that are suitable for the protection of an aliphatic hydroxyl group.
  • These protecting groups are known to a person skilled in the art, and described in for example P. J. Kocienski, “Protecting Groups”, 3 rd ed., Georg Thieme Verlag, New York 2005, and T. W. Greene et al., “ Protective Groups in Organic Synthesis”, 3 rd ed., John Wiley & Sons, New York, 1991.
  • Step (4) may for example be executed as disclosed in WO 2004/041839.
  • C is an acetyl protecting group.
  • the 17-OH group is preferably protected by acetylation using a reagent selected from acetic anhydride or acetyl chloride.
  • a reagent selected from acetic anhydride or acetyl chloride.
  • acetic anhydride is used.
  • a solution of the compound in pyridine with acetic anhydride and 4-dimethylaminopyridine.
  • the mixture is stirred for a period of time. Preferably after 2 hours at room temperature the volatiles are removed.
  • the residue is dissolved in ethyl acetate (EtOAc) and the resulting solution is washed with water and brine.
  • the solution is dried using sodium sulphate and concentrated to give the crude product. Recrystallization from a mixture of organic solvents, preferably ethyl acetate, heptane and ethanol gives the product as a white solid.
  • the reaction may be performed with a trialkylamine, preferably triethylamine, and an acetyl halide (about two equivalents), preferably acetyl chloride (about 1.5 equivalent) in toluene at about 25° C. to about 60° C., preferably about 40° C. to about 50° C.
  • the work up is then performed by washing with water, aqueous acid and aqueous base.
  • Purification of the product is then achieved by crystallisation, i.e. by removing the toluene by distillation, dissolving the crude product in ethyl acetate and heating this solution to about 70° C. to about 80°.
  • small portions of ethanol are added to induce crystallisation (preferred ratio of ethyl acetate to ethanol is about 1 to about 8).
  • Step (5) Oxidation of the Carbon-Carbon Double Bond of Ring D of 3-A-Oxy-17-C-oxy-estra-1,3,5(10),15-tetraene VI to form protected estetrol VII, wherein A and C are protecting groups
  • Step (5) relates to the oxidation of the carbon-carbon double bond of ring D to form protected estetrol VII, and is preferably executed as is disclosed in WO 2004/041839.
  • the oxidation of the carbon-carbon double bond in ring D is carried out with an oxidising agent providing selective cis-hydroxylation of the carbon-carbon double bond.
  • the oxidising agent is osmium tetroxide (OsO 4 ) and more preferably the oxidising agent is osmium tetroxide immobilized on PVP (OsO 4 -PVP) that is used in a catalytic amount (cf. G. Cainelli et al., Synthesis 1989, 45-47) in combination with a co-oxidant selected from trimethylamine-N-oxide, N-methyl morpholine-N-oxide or hydrogen peroxide, preferably trimethylamine-N-oxide. More preferably, OsO 4 -PVP and trimethylamine-N-oxide are used with THF as the solvent.
  • OsO 4 -PVP it is preferred to add OsO 4 -PVP to a heated solution of the compound prepared in the previous step in THF.
  • the addition is performed at 50° C. followed by the addition of trimethylamine-N-oxide.
  • the addition of trimethylamine-N-oxide is performed portion wise during 1 hour.
  • the mixture is stirred at this temperature for a period of time.
  • the mixture is cooled to room temperature and filtered.
  • the volatiles are removed and the residue is dissolved in ethyl acetate and water is added.
  • the aqueous layer is acidified and the layers are separated.
  • the aqueous layer is extracted with ethyl acetate.
  • the combined extracts are dried with sodium sulphate and concentrated.
  • the resulting residue is triturated with heptanes and ethyl acetate to give the product as a white precipitate that is filtered off
  • the product is purified by recrystallization from a mixture of organic solvents, preferably ethyl acetate, heptane and ethanol to give the product as a white solid.
  • Step (6) of the process relates to the removal of the protecting groups A and C to form estetrol I, and is preferably performed as disclosed in WO 2004/041839.
  • WO 2004/041839 discloses that not all protective groups can be removed without adverse effects on the obtained product.
  • A is a C 1 -C 5 alkyl group
  • removal of the protecting group is preferably performed using BBr 3 .
  • A is a C 7 -C 12 benzylic group
  • removal of the protecting group is preferably performed using catalytic hydrogenation conditions, for example Pd/H 2 , as is well known to the person skilled in the art.
  • the protected estetrol VII in a protic solvent, preferably methanol.
  • the conversion is then executed at ambient temperature in the presence of a catalytic amount of Pd/C (e.g. 10%) on carbon (e.g. as a preformed suspension in methanol) in a hydrogen atmosphere, preferably of 1 atmosphere.
  • Removal of protecting group C is effective using a protic solvent such as methanol and a base, preferably K 2 CO 3 , to yield estetrol.
  • a protic solvent such as methanol and a base, preferably K 2 CO 3
  • the order of the two deprotection steps above can be reversed.
  • the complete deprotection can be accomplished by first removing protecting group C, followed by catalytic hydrogenation to remove protecting group A where A is a protective C 7 -C 12 benzylic group.
  • the procedures are identical to the ones described above. However, it is preferred to first remove protecting group A and subsequently protective group C.
  • step (6) protecting group A is removed first to form 17-OC protected estetrol VIII, and subsequently protecting group C is removed to form estetrol I, as is depicted in Scheme 10.
  • step (6) the deprotection reactions, i.e. the removal of A and C, are performed in a single step if A is a protective C 7 -C 12 benzylic group.
  • A is a protective C 7 -C 12 benzylic group.
  • compound VII is dissolved in a C 1 -C 3 alkyl alcohol, preferably methanol, and subjected to hydrogenation at room temperature. Thereafter, the solution of compound VIII is preferably used in the subsequent step, i.e. the removal of C as described above.
  • the invention relates to a process for the synthesis of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group, which comprises the steps of:
  • the iodine(V) species comprises 2-iodoxybenzoic acid (IBX), stabilised 2-iodoxybenzoic acid (SIBX) 2-iodoxybenzenesulphonic acid (IBS), and/or a derivative thereof.
  • IBX 2-iodoxybenzoic acid
  • SIBX stabilised 2-iodoxybenzoic acid
  • IBS 2-iodoxybenzenesulphonic acid
  • Reversed phase HPLC was performed using UV detection at 230 nm, using three different isocratic methods, all at a flow of 1 ml/min and at ambient temperature.
  • Method A used a 250 ⁇ 4.6 mm Supelcosil LC-ABZ column (medium polarity) and methanol/20 mM aqueous phosphate buffer pH 3.8 in a 80/20 ratio.
  • Method B used a 250 ⁇ 4 mm Nucleosil C-18 column and H 2 O/MeOH/acetonitrile in a 15/50/35 ratio, containing 50 mM ammonium acetate.
  • Method C used a 250 ⁇ 4 mm Nucleosil C-18 column and methanol/20 mM aqueous phosphate buffer pH 3.8 in a 80/20 ratio.
  • estrone (II; 100 g, 0.370 mol) and K 2 CO 3 (160 g, 1.16 mol) in DCM/MeOH (800 ml, 1:1 v/v ratio) at room temperature (RT) was added benzyl bromide (132 ml, 1.10 mol) in one portion.
  • the resulting mixture was refluxed for 16 h (50% conversion after 4 h according to TLC).
  • the reaction mixture was cooled to RT and solids were filtered off.
  • the filter-cake was washed with MeOH.
  • the solution was concentrated (to a total volume of ca. 300 ml). The precipitate that had formed was collected by filtration and washed with heptanes to give a white solid.
  • the filtrate was concentrated further (to a total volume of 100 ml) and triturated with heptane.
  • the resulting precipitate was filtered off and combined with the first batch of product.
  • the product (153 g, max 0.370 mol) still contained traces off benzyl bromide but was used without further purification.
  • the product can be purified by recrystallization from DCM/MeOH (1/2).
  • Unstabilised IBX 1.0 g; 3.6 mmol
  • a catalytic amount of trimethylamine-N-oxide 40 mg, 10 mol %)
  • 3 ⁇ molecular sieves 100 mg
  • Stabilised 2-iodoxybenzoic acid (SIBX, 0.5 g; 0.8 mmol oxidant) was dissolved in 4 ml anhydrous DMSO containing 0.8 mmol of amine-N-oxide cocatalyst. These mixtures were pre-incubated for 30 minutes at ambient temperature. To this solution was added a solution of benzylestrone-trimethylsilyl enol ether III (0.215 g; 0.5 mmol) in 1 ml anhydrous fluorobenzene. The solidified mixtures were heated slightly to 30-35° C. to enable mixing. After 20-30 minutes the reaction mixtures became homogeneous. HPLC analysis by showed a clean conversion of the enol ether to the enone, with in some cases some ketone present due to hydrolysis. Results are summarized in Table 1.
  • Stabilised 2-iodoxybenzoic acid (SIBX, 0.5 g; 0.8 mmol oxidant) was dissolved in 4 ml anhydrous dimethylformamide (DMF) containing 0.8 mmol of N-methylmorpholine-N-oxide cocatalyst. These mixtures were pre-incubated for 30 minutes at ambient temperature. To this solution was added solid benzylestrone-trimethylsilyl enol ether III (0.215 g; 0.5 mmol). The reaction mixture was agitated for 1 hour at ambient temperature and then further heated to 40° C. The total reaction time was 2 hours. Results are summarized in Table 2.
  • Benzylestrone-trimethylsilyl enol ether III (0.20/0.215 g; 0.5 mmol) and allyl methyl carbonate (0.115 ml; 1.0 mmol) were mixed with 4.5 ml anhydrous acetonitrile.
  • Palladium acetate stock solution (0.25 ml; 5 mol; 1 mol %) in acetonitrile was added and the mixture was stirred in an argon atmosphere at 75° C.
  • HPLC analysis after 67 hours showed a complete conversion of the enol ether with a 51% selectivity for the enone IV.
  • estetrol as a white solid (12.2 g, 40.1 mmol, 92.5%) after drying at 40° C. in an air-ventilated oven.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US14/233,362 2011-07-19 2012-07-18 Process for the preparation of estetrol Abandoned US20140235882A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/233,362 US20140235882A1 (en) 2011-07-19 2012-07-18 Process for the preparation of estetrol

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161509168P 2011-07-19 2011-07-19
EP11174509A EP2383279A1 (fr) 2011-07-19 2011-07-19 Procédé de préparation d'estetrol
EP11174509.7 2011-07-19
PCT/NL2012/050514 WO2013012328A1 (fr) 2011-07-19 2012-07-18 Procédé pour la préparation d'estétrol
US14/233,362 US20140235882A1 (en) 2011-07-19 2012-07-18 Process for the preparation of estetrol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2012/050514 A-371-Of-International WO2013012328A1 (fr) 2011-07-19 2012-07-18 Procédé pour la préparation d'estétrol

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/426,209 Continuation US10844088B2 (en) 2011-07-19 2017-02-07 Process for the preparation of estetrol

Publications (1)

Publication Number Publication Date
US20140235882A1 true US20140235882A1 (en) 2014-08-21

Family

ID=44582248

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/233,362 Abandoned US20140235882A1 (en) 2011-07-19 2012-07-18 Process for the preparation of estetrol
US15/426,209 Active 2033-08-03 US10844088B2 (en) 2011-07-19 2017-02-07 Process for the preparation of estetrol

Family Applications After (1)

Application Number Title Priority Date Filing Date
US15/426,209 Active 2033-08-03 US10844088B2 (en) 2011-07-19 2017-02-07 Process for the preparation of estetrol

Country Status (16)

Country Link
US (2) US20140235882A1 (fr)
EP (2) EP2383279A1 (fr)
CN (1) CN103781795B (fr)
CA (1) CA2842035C (fr)
CY (1) CY1118288T1 (fr)
DK (1) DK2734536T3 (fr)
ES (1) ES2602227T3 (fr)
HR (1) HRP20161467T1 (fr)
HU (1) HUE029783T2 (fr)
LT (1) LT2734536T (fr)
PL (1) PL2734536T3 (fr)
PT (1) PT2734536T (fr)
RS (1) RS55384B1 (fr)
SI (1) SI2734536T1 (fr)
SM (2) SMT201600464T1 (fr)
WO (1) WO2013012328A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US20220406595A1 (en) * 2021-06-22 2022-12-22 Applied Materials, Inc. Novel oxidants and strained-ring precursors
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component
US12458649B2 (en) 2020-04-16 2025-11-04 Estetra Srl Contraceptive compositions with reduced adverse effects

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2764008T3 (pl) * 2011-10-07 2017-04-28 Estetra S.P.R.L. Sposób wytwarzania estetrolu
WO2013034780A2 (fr) 2012-12-20 2013-03-14 Crystal Pharma, S.A.U. Procédé de préparation de l'estétrol et de composés analogues
US9988417B2 (en) 2013-09-18 2018-06-05 Crystal Pharma, S.A.U. Process for the preparation of estetrol
HU231240B1 (hu) * 2019-09-03 2022-04-28 Richter Gedeon Nyrt. Ipari eljárás nagytisztaságú ösztetrol hatóanyag előállítására
ES2915058B2 (es) * 2019-09-27 2024-06-21 Ind Chimica Srl Proceso para preparar (15alfa,16alfa,17beta)-estra-1,3,5(10)-trieno-3,15,16,17-tetrol (Estetrol) e intermedios de dicho proceso
IT202100019631A1 (it) 2021-07-23 2023-01-23 Newchem S P A Metodo per produrre estetrolo e i suoi intermedi
WO2023021026A1 (fr) 2021-08-17 2023-02-23 Aspen Oss B.V. Voie synthétique pour estra-1,3,5(10)-triène-3,15a,16a,17b-tétrol
HUP2400151A1 (hu) 2024-02-28 2025-09-28 Richter Gedeon Nyrt Ösztetrol-monohidrát kristályosítási eljárás

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041839A2 (fr) * 2002-11-08 2004-05-21 Pantarhei Bioscience B.V. Synthese d'esterol par l'intermediaire de steroides derives d'estrone

Family Cites Families (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE144266C (fr)
US3138588A (en) 1962-08-24 1964-06-23 American Home Prod 17-ketals of estrone and derivatives thereof
US3177206A (en) 1963-03-07 1965-04-06 American Home Prod Selective bromination of a-ring aromatic 17-ketalized steroids
US3433785A (en) 1966-07-11 1969-03-18 Sterling Drug Inc 15,16-disubstituted aromatic steroids,intermediates and processes
US3673180A (en) 1970-06-18 1972-06-27 Merck & Co Inc 19-nor-6,6-ethylene-20-spiroxenes
US4792620A (en) * 1983-10-14 1988-12-20 Bp Chemicals Limited Carbonylation catalysts
US4739078A (en) 1984-02-17 1988-04-19 The Upjohn Company Use of borohydride-salt lanthanide salt reagents for stereo selective reduction of C-15-keto prostaglandin precursors
IE60780B1 (en) 1987-01-23 1994-08-10 Akzo Nv New 11-aryl steroid derivatives
DE3710728A1 (de) 1987-03-31 1988-10-13 Schering Ag Verfahren zur herstellung von 17(alpha)-ethinyl-17ss-hydroxy-18-methyl-4,15-estradien-3-on und die neuen zwischenprodukte fuer dieses verfahren
US5073374A (en) 1988-11-30 1991-12-17 Schering Corporation Fast dissolving buccal tablet
US5340586A (en) 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in treating oophorectomized women
JPH07101977A (ja) 1993-10-05 1995-04-18 Kureha Chem Ind Co Ltd ホルモン作用を軽減した新規なエストラジオール誘導体及びその増殖因子阻害剤
DE4344405C2 (de) 1993-12-24 1995-12-07 Marika Dr Med Ehrlich Ovulationshemmendes Mittel und Verfahren zur hormonalen Kontrazeption
WO1997004752A1 (fr) 1995-07-26 1997-02-13 Duramed Pharmaceuticals, Inc. Compositions pharmaceutiques d'oestrogenes conjugues et leurs modes d'emploi
US6117446A (en) 1999-01-26 2000-09-12 Place; Virgil A. Drug dosage unit for buccal administration of steroidal active agents
TW548277B (en) 1999-07-16 2003-08-21 Akzo Nobel Nv Orally active androgens
PL202999B1 (pl) 1999-12-02 2009-08-31 Organon Nv Androgeny zawierające pierścień cyklopropanowy w pozycjach 14, 15 i zastosowanie takich androgenów
US20020132801A1 (en) 2001-01-11 2002-09-19 Schering Aktiengesellschaft Drospirenone for hormone replacement therapy
EP1216713A1 (fr) 2000-12-20 2002-06-26 Schering Aktiengesellschaft Compositions de complexes de estrogen-cyclodextrine
DE60217324T2 (de) 2001-05-18 2007-04-26 Pantarhei Bioscience B.V. Pharmazeutische zusammensetzung für die hormonersatztherapie
EP1260225A1 (fr) 2001-05-18 2002-11-27 Pantarhei Bioscience B.V. Compositions pharmaceutiques pour le traitement hormonal substitutif
ES2337129T3 (es) 2001-05-23 2010-04-21 Pantarhei Bioscience B.V. Sistema de administracion de medicamento comprendiendo un estrogeno tetrahidroxilado para el uso en la anticoncepcion hormonal.
EP1390042B1 (fr) 2001-05-23 2007-11-28 Pantarhei Bioscience B.V. Systeme d'administration de medicament comprenant un oestrogene tetrahydroxyle destine a une contraception hormonale
WO2003018026A1 (fr) 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Utilisation de composes oestrogeniques combines avec des composes progestogeniques dans une hormonotherapie substitutive
US8026228B2 (en) 2001-11-15 2011-09-27 Pantarhei Bioscience B.V. Estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy
US6723348B2 (en) 2001-11-16 2004-04-20 Ethypharm Orodispersible tablets containing fexofenadine
HU227198B1 (en) 2001-11-27 2010-10-28 Richter Gedeon Nyrt Pharmaceutical composition for emergency contraception containing levonorgestrel
RS50909B (sr) 2002-02-21 2010-08-31 Bayer Schering Pharma Aktiengesellschaft Farmaceutske kompozicije koje se sastoje od jednog ili više steroida, jedne ili više tetrahidrofolatne komponente i vitamina b12
US20050147670A1 (en) 2002-05-29 2005-07-07 Impax Laboratories Inc. Oral disintegrating dosage forms
US7923440B2 (en) 2002-06-11 2011-04-12 Pantarhei Bioscience B.V. Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein
US7943604B2 (en) 2002-06-11 2011-05-17 Pantarhei Bioscience B.V. Method of treating human skin and a skin care composition for use in such a method
ATE382356T1 (de) 2002-07-12 2008-01-15 Pantarhei Bioscience Bv Pharmazeutische zusammensetzung enthaltend estetrolderivate und anwendung in der krebsbehandlung
JP2005538150A (ja) 2002-08-28 2005-12-15 キャスパー，ロバート エストロゲン補充療法
CN100528167C (zh) 2002-10-23 2009-08-19 潘塔希生物科学股份有限公司 用于治疗癌症的包含雌四醇衍生物的药物组合物
DE60330888D1 (de) 2002-11-05 2010-02-25 Bayer Schering Pharma Ag Verwendung von drospirenon zur behandlung von hypertension
CA2526338C (fr) 2003-05-22 2012-09-25 Pantarhei Bioscience B.V. Utilisation de compositions comprenant un composant oestrogene pour le traitement et la prevention de la douleur musculo-squelettique
AU2004275470B2 (en) 2003-09-29 2010-12-02 Novo Nordisk Health Care Ag Improved stability of progestogen formulations
JP2007506796A (ja) 2003-09-29 2007-03-22 ノボ・ノルディスク・フェムケア・アーゲー Ｈｒｔ製剤
EP1535618A1 (fr) 2003-11-26 2005-06-01 Schering Aktiengesellschaft Préparation pharmaceutique pour le traitement hormonal continuel sur plus de 21-28 jours comprenant deux compositions d'estrogène et/ou de progestine
MY151322A (en) 2004-04-30 2014-05-15 Bayer Ip Gmbh Management of breakthrough bleeding in extended hormonal contraceptive regimens
DE102004026670A1 (de) 2004-05-28 2005-12-15 Grünenthal GmbH Hormonales Kontrazeptivum enthaltend eine Kombination aus Ethinylestradiol und Chlormadinonacetat
DK1755562T3 (da) 2004-05-28 2013-12-16 Richter Gedeon Nyrt Kontraceptivum, som indeholder folsyre
UA89964C2 (ru) 2004-09-08 2010-03-25 Н.В. Органон 15β-ЗАМЕЩЕННЫЕ СТЕРОИДЫ, КОТОРЫЕ ИМЕЮТ СЕЛЕКТИВНУЮ ЭСТРОГЕННУЮ АКТИВНОСТЬ
UY29527A1 (es) 2005-05-13 2006-12-29 Schering Ag Composicinn farmaccutica que contienen gestrgenos y/o estrngenos y 5-metil - (6s) - tetrhidrofolato.
AU2006251154B2 (en) 2005-05-26 2012-06-28 Solvay Pharmaceuticals Gmbh 17beta-HSD1 and STS inhibitors
ATE478946T1 (de) 2005-07-25 2010-09-15 Riboxx Gmbh Verfahren und kit zur amplifikation von heteropolymerer oder poly(c)- rna
US20070048369A1 (en) 2005-08-26 2007-03-01 National Starch And Chemical Investment Holding Corporation Mucosal delivery tablet
US20090221540A1 (en) 2006-01-09 2009-09-03 Pantarhei Bioscience B.V. Method of Treating An Acute Vascular Disorder
WO2007106264A2 (fr) 2006-03-02 2007-09-20 Warner Chilcott Company, Inc. Procede de contraception orale multiphase a cycles prolonges
US20070286819A1 (en) 2006-06-08 2007-12-13 Warner Chilcott Company, Inc. Methods to administer ethinyl estradiol and prodrugs thereof with improved bioavailability
SG174785A1 (en) 2006-06-08 2011-10-28 Warner Chilcott Co Llc Methods to administer solid dosage forms of ethinyl estradiol and prodrugs thereof with improved bioavailabilty
US20080113953A1 (en) 2006-06-08 2008-05-15 Warner Chilcott Company, Inc. Methods to administer solid dosage forms of ethinyl estradiol and prodrugs thereof with improved bioavailability
CN101489563A (zh) 2006-07-06 2009-07-22 拜耳先灵医药股份有限公司 用于避孕和预防先天性畸形风险的药物制剂
MX2009000256A (es) 2006-07-06 2009-02-18 Bayer Schering Pharma Ag Preparaciones farmaceuticas para la anticoncepcion y para prevenir el riesgo de malformaciones congenitas.
GB0621926D0 (en) 2006-11-03 2006-12-13 Medlock Medical Ltd Multi directional stretch tubular bandages
AU2007325207A1 (en) 2006-11-29 2008-06-05 Wyeth Estrogen/ serm and estrogen/ progestin bi-layer tablets
JP5649305B2 (ja) 2006-12-20 2015-01-07 テバ ウィメンズ ヘルス インコーポレイテッド プロゲスチンを含む口腔内崩壊性固体剤形ならびにその製造方法および使用方法
DE602008001783D1 (de) 2007-01-08 2010-08-26 Pantarhei Bioscience Bv Verfahren zur behandlung oder prävention von unfruchtbarkeit bei weiblichen säugern und pharmazeutisches kit zur anwendung dieses verfahrens
WO2008089087A2 (fr) 2007-01-12 2008-07-24 Wyeth Composition de type comprimé-dans-comprimé
ATE537833T1 (de) 2007-06-21 2012-01-15 Pantarhei Bioscience Bv Behandlung des mekoniumaspirationssyndroms mit östrogenen
US8518923B2 (en) 2007-07-19 2013-08-27 Pantarhei Bioscience B.V. Treatment or prevention of hypertensive disorders of pregnancy or fetal growth retardation
ES2403203T3 (es) 2007-08-31 2013-05-16 National University Corporation Nagoya University Método para producir compuesto carbonilo y prooxidante usado para la producción de compuesto carbonilo
EP2077272A1 (fr) 2007-12-21 2009-07-08 Affibody AB Librairies de polypeptides avec une structure d'échafaudage prédéterminée
EP2077273B1 (fr) 2007-12-31 2011-09-14 Animal Technology Institute Taiwan Procédés pour séparer la caséine de protéines solubles dans une composition
US8530636B2 (en) 2008-05-07 2013-09-10 The Board Of Trustees Of The Leland Stanford Junior University Method for regulating protein function in cells in vivo using synthetic small molecules
WO2010033832A2 (fr) 2008-09-19 2010-03-25 Evestra, Inc. Formulations à base d’oestriol
DE102009007771B4 (de) 2009-02-05 2012-02-16 Bayer Schering Pharma Aktiengesellschaft Bukkales Applikationssystem, 17α-Estradiol enthaltend
ES2625950T3 (es) 2009-06-23 2017-07-21 Bayer Intellectual Property Gmbh Composición farmacéutica para la anticoncepción de emergencia
CN102058604A (zh) 2009-11-17 2011-05-18 北京万全阳光医学技术有限公司 一种含有地诺孕素和戊酸雌二醇的药物组合物及其制备方法
BR112012026115B1 (pt) 2010-04-15 2019-12-24 Bayer Ip Gmbh forma de dosagem oral sólida, seu uso, e unidade de acondicionamento
AR081670A1 (es) 2010-06-29 2012-10-10 Leon Farma Sa Lab Composicion farmaceutica que comprende drospirenona y kit anticonceptivo
US9603860B2 (en) 2010-07-28 2017-03-28 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
WO2012055840A1 (fr) 2010-10-28 2012-05-03 Bayer Pharma Aktiengesellschaft Composition et préparation pour le traitement de la dysménorrhée et de la douleur menstruelle et utilisation d'un agent hormonal et d'un sel de zinc pour le traitement de troubles menstruels
MX341561B (es) 2011-06-01 2016-08-25 Estetra Sprl Proceso para la produccion de intermediarios de estetrol.
PL2714712T3 (pl) 2011-06-01 2017-05-31 Estetra S.P.R.L. Metoda wytwarzania półproduktów estetrolu
EP2383279A1 (fr) 2011-07-19 2011-11-02 Pantarhei Bioscience B.V. Procédé de préparation d'estetrol
EP2734193B1 (fr) 2011-07-19 2015-05-20 Pantarhei Bioscience B.V. Comprimé contenant de la déhydroépiandrostérone (dhea)
HUE033590T2 (hu) 2011-08-11 2017-12-28 Estetra Sprl Esztetrol alkalmazása sürgõsségi fogamzásgátlóként
CN103781467B (zh) 2011-09-16 2016-08-31 辉凌公司 一种快速溶解药物组合物
PL2764008T3 (pl) 2011-10-07 2017-04-28 Estetra S.P.R.L. Sposób wytwarzania estetrolu
WO2013090117A1 (fr) 2011-12-13 2013-06-20 Arstat, Inc. Schéma de contraception multiphase pour préparation orale associant un progestatif et un œstrogène
EP2653163A1 (fr) 2012-04-19 2013-10-23 Université de Liège Constituants estrogènes pour l'utilisation dans le traitement de troubles neurologiques
WO2014159377A1 (fr) 2013-03-14 2014-10-02 Teva Women's Health, Inc. Composition contenant du tanaproget et des œstrogènes naturels
JP2016520590A (ja) 2013-05-21 2016-07-14 プレディクティヴ セラピューティクス, リミテッド ライアビリティー カンパニーPredictive Therapeutics, LLC 治療薬および使用法
US9988417B2 (en) 2013-09-18 2018-06-05 Crystal Pharma, S.A.U. Process for the preparation of estetrol
LT3079671T (lt) 2013-12-12 2018-02-12 Donesta Bioscience B.V. Burnoje dezintegruojantis farmacinis dozės vienetas, turintis estetrolio komponentą
WO2016053946A1 (fr) 2014-09-29 2016-04-07 The Regents Of The University Of California Compositions et méthodes pour améliorer la fonction cognitive
JP2018515552A (ja) 2015-05-18 2018-06-14 アジル・セラピューティクス・インコーポレイテッドＡｇｉｌｅ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． 避妊用組成物ならびに有効性改善および副作用調節方法
MA44206B1 (fr) 2015-06-18 2021-04-30 Estetra Sprl Comprimé orodispersible comprenant estetrol
JP6863547B2 (ja) 2015-06-18 2021-04-21 エステトラ ソシエテ プリーヴ ア レスポンサビリテ リミテ エステトロール成分を含有する口腔内崩壊性投与単位
LT3310345T (lt) 2015-06-18 2021-06-25 Estetra Sprl Burnoje disperguojama tabletė, turinti estetrolio
JP6866560B2 (ja) 2015-06-18 2021-04-28 エステトラ ソシエテ プリーヴ ア レスポンサビリテ リミテ エステトロール成分を含有する口腔内崩壊性投与単位
CN108025014B (zh) 2015-06-23 2021-10-22 莱昂实验室制药股份有限公司 用于过重女性患者的基于屈螺酮的避孕药
US10863492B2 (en) 2015-07-16 2020-12-08 Qualcomm Incorporated Low latency device-to-device communication
CA3178291A1 (fr) 2016-08-05 2018-04-12 Estetra Srl Methode de prise en charge de la dysmenorrhee et des douleurs menstruelles
JP2018533542A (ja) 2016-10-28 2018-11-15 エステトラ ソシエテ プリーヴ ア レスポンサビリテ リミテ 月経困難症および月経痛の管理のための方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041839A2 (fr) * 2002-11-08 2004-05-21 Pantarhei Bioscience B.V. Synthese d'esterol par l'intermediaire de steroides derives d'estrone

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Larock et al, Tetrahedron Letters, A Simple, Effective, New, Palladium-Catalyzed Conversion of Enol Silanes to Enones and Enals, 1995, 36(14), pp. 2423-2426. *
Li et al, Steroids, Stereoselective Synthesis of Some Methyl-substituted Steroid Hormones and Their In Vitro Cytotoxic Activity Against Human Gastric Cancer Cell Line MGC-803, 2010, 75, pp.859-869. *
Nicolaou et al (Angewandte Chemie International Edition, Oxidation of Silyl Enol Ethers by Using IBX and IBX N-oxide Complexes: A Mild and Selectiove Reaction for the Synthesis of Enones, 2002, 41(6), pp. 996-1000. *
Nicolaou et al, Angewandte Chemie International Edition, Oxidation of Silyl Enol Ethers by Using IBX and IBX N-oxide Complexes: A Mild and Selectiove Reaction for the Synthesis of Enones, 2002, 41(6), pp. 996-1000. *
Ozanne et al, Organic Letters, A Stabilized Formulation of IBX (SIBX) for Safe Oxidation Reactions Including a New Oxidative Demethylation of Phenolic Methyl Aryl Ethers, 2003, 5(16), pp. 2903-2906. *
Zaragoza Dorwald , Side Reactions in Organic Synthesis, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Preface. Pg. IX. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11964055B2 (en) 2015-06-18 2024-04-23 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US12427114B2 (en) 2015-06-18 2025-09-30 Estetra Srl Orodispersible dosage unit containing an estetrol component
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US11793760B2 (en) 2015-06-18 2023-10-24 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11666585B2 (en) 2018-04-19 2023-06-06 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US12390478B2 (en) 2018-04-19 2025-08-19 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US12458651B2 (en) 2018-04-19 2025-11-04 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms
US12458649B2 (en) 2020-04-16 2025-11-04 Estetra Srl Contraceptive compositions with reduced adverse effects
US20220406595A1 (en) * 2021-06-22 2022-12-22 Applied Materials, Inc. Novel oxidants and strained-ring precursors

Also Published As

Publication number Publication date
HRP20161467T1 (hr) 2017-01-27
SMT201600464T1 (it) 2017-03-08
CN103781795A (zh) 2014-05-07
CN103781795B (zh) 2016-08-17
LT2734536T (lt) 2016-12-27
EP2734536A1 (fr) 2014-05-28
SI2734536T1 (sl) 2017-01-31
US20170369521A1 (en) 2017-12-28
PT2734536T (pt) 2017-01-02
SMT201600464B (it) 2017-03-08
RS55384B1 (sr) 2017-03-31
WO2013012328A1 (fr) 2013-01-24
CY1118288T1 (el) 2017-06-28
EP2734536B1 (fr) 2016-09-28
EP2383279A1 (fr) 2011-11-02
CA2842035C (fr) 2020-06-23
CA2842035A1 (fr) 2013-01-24
ES2602227T3 (es) 2017-02-20
US10844088B2 (en) 2020-11-24
PL2734536T3 (pl) 2017-03-31
DK2734536T3 (en) 2016-12-12
HUE029783T2 (en) 2017-04-28

Similar Documents

Publication Publication Date Title
US10844088B2 (en) Process for the preparation of estetrol
US10000524B2 (en) Synthesis of estetrol via estrone derived steroids
AU2012320423C1 (en) Process for the production of estetrol
CA2924255C (fr) Procede pour la preparation d'estetrol
EP2714710B1 (fr) Procédé pour la production d'intermédiaires d'estétrol
US20190077827A1 (en) 6.Alpha.-Alkyl-6,7-Dione Steroids as Intermediates for the Production of Steroidal FXR Modulators
KR20020092890A (ko) 경구 활성 안드로겐
WO2013034780A2 (fr) Procédé de préparation de l'estétrol et de composés analogues
TWI275593B (en) Novel androgens
RS90504A (sr) C-17 spirolaktonizacija i 6,7-oksidacija steroida
US6790843B1 (en) C-19-halogen-substituted steroids of the androst-9(11)-ene-series, methods for the production and use thereof
HK1199882B (en) Process for the production of estetrol

Legal Events

Date Code Title Description
AS Assignment

Owner name: PANTARHEI BIOSCIENCE B.V., NETHERLANDS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PLATTEEUW, JOHANNES JAN;COELINGH BENNINK, HERMAN JAN TIJMEN;DAMEN, FRANCISCUS WILHELMUS PETRUS;AND OTHERS;REEL/FRAME:032599/0315

Effective date: 20140205

AS Assignment

Owner name: DONESTA BIOSCIENCE B.V., NETHERLANDS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PANTARHEI BIOSCIENCE B.V.;REEL/FRAME:035632/0119

Effective date: 20150429

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: ESTETRA SPRL, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DONESTA BIOSCIENCE B.V.;REEL/FRAME:051777/0010

Effective date: 20200207