WO2013034780A2 - Procédé de préparation de l'estétrol et de composés analogues - Google Patents

Procédé de préparation de l'estétrol et de composés analogues Download PDF

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WO2013034780A2
WO2013034780A2 PCT/EP2012/076358 EP2012076358W WO2013034780A2 WO 2013034780 A2 WO2013034780 A2 WO 2013034780A2 EP 2012076358 W EP2012076358 W EP 2012076358W WO 2013034780 A2 WO2013034780 A2 WO 2013034780A2
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Prior art keywords
alkyl
aryl
compound
formula
ether
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PCT/EP2012/076358
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English (en)
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WO2013034780A3 (fr
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Juan José FERREIRO GIL
Jesús Miguel IGLESIAS RETUERTO
Francisco Javier GALLO NIETO
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Crystal Pharma, S.A.U.
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Priority to PCT/EP2012/076358 priority Critical patent/WO2013034780A2/fr
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Publication of WO2013034780A3 publication Critical patent/WO2013034780A3/fr

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    • 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
    • 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
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • 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 invention relates to a process for obtaining Estetrol and 3-OH protected derivatives thereof, as well as to said 3-OH protected derivatives and intermediate products useful in the process.
  • Estrogenic substances are commonly used in methods of Hormone Replacement
  • HRT HTR Therapy
  • methods of female contraception These estrogenic substances can be divided in natural estrogens and synthetic estrogens.
  • natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens.
  • synthetic estrogens which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol.
  • Estetrol [estra-1 ,3,5(10)-trien-3,15a,16a,173-tetraol; CAS Nr. 15183-37-6] is a biogenic estrogen that is endogeneously produced by the fetal liver during human pregnancy.
  • the lUPAC-recommended ring lettering and atom numbering for steroids and steroid derivatives as depicted below, are applied.
  • Estetrol has been found effective as an estrogenic substance for use in HRT (EP 1 390 040 B1 , EP 1 446 128 B1 ), contraception (EP 1 390 041 B1 , EP 1 390 042 B1 ), therapy of auto-immune diseases (EP 1 51 1 496 B1 ), prevention and therapy of breast and colon tumors (EP 1 526 856 B1 ), enhancement of libido (EP 1 390 039 B1 ), treatment of infertility (EP 2 1 14 412 B1 ), treatment of acute vascular disorder (EP 1 971 344 B1 ), skin care and wound healing (EP 1 51 1 498 A1 ).
  • 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 C17 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).
  • Estetrol can be performed with a yield of approximately 8%, starting from estrone.
  • estrone (7) into 3-A-oxy-estra-1 ,3,5(10),15-tetraen-17-one (6), wherein A is a protecting group, this step involving in turn five sub-steps;
  • protecting group A is selected from an Ci-C 5 alkyl group or a C 7 Ci2 benzylic group and the protecting group C is selected from monofunctional aliphatic hydroxyl protecting groups.
  • Estetrol is obtained in an overall yield of 10.8%, starting from estrone. Specifically, the yield of the cis-dihydroxylation step as described in the example 9 is 43% after three crystallizations in order to purify the product from the 15 ⁇ ,1 ⁇ -diol isomer.
  • the process disclosed in WO 2004/041839 is suitable for an industrial scale preparation of Estetrol, the high number of synthetic steps and the isolation and purification of each intermediate product results in a loss of yield, thereby reducing the overall yield of Estetrol.
  • the conversion of 7 into 6 involves a halogenation and a dehalogenation step, typically a bromination and a debromination step. In particular during said halogenation and dehalogenation reactions, various side products are produced.
  • A is a protecting group selected from the group consisting of a Ci-C 5 alkyl group, a C7-C12 benzylic group and a-Si(R 1 ) 3 group, wherein R 1 is independently selected from the group consisting of a C C 6 alkyl group and a C 6 -Ci 2 aryl group;
  • R 2 is independently selected from the group consisting of a Ci-C 6 alkyl group and a C 6 -Ci 2 aryl group;
  • C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups.
  • step 5 oxidation of the carbon-carbon double bond from the intermediate product VI to form protected Estetrol VII, is 43% after purifications, with a purity of 98.7%. If a Palladium catalyst is used, the cost of the process increases to a large extent.
  • the invention faces the problem of providing an efficient process for the preparation of Estetrol.
  • the inventors have surprisingly found a process for obtaining Estetrol in which the oxidation of the double bond of ring D proceeds over a starting material having the ⁇ -hydroxyl group at C17 free, avoiding therefore the need of using the corresponding protecting groups.
  • the free hydroxyl group at C17 is not oxidized during the process but also the oxidation of the carbon-carbon double bond of ring D shows a high stereoselectivity to afford the desired 15a,16a-diol.
  • the present invention refers to a process for the preparation of a compound of formula (I)
  • R represents H or an hydroxyl protecting group (HPG);
  • the compound of formula (I) is Estetrol. If R is not H, the process preferably further comprises the deprotection of the hydroxyl group to give Estetrol.
  • the compound of formula (II) or a salt or solvate thereof is prepared by a process comprising the reduction of the keto group at C17 of a compound of formula (III)
  • R represents an hydroxyl protecting group selected from:
  • R can be selected from from alkyl, cycloalkyi, aryl and arylalkyi, with the proviso that R is not butanamide-4-oxy, butanoic acid 4-oxy, ethyl butanoate-4-oxy and ⁇ -D-Glucopyranosiduronic acid;
  • alkoxy and aryloxy alkyl ethers such as alkoxy and aryloxy methyl ether [-CH 2 - OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -ORw], where R w can be selected from alkyl, cycloalkyi, aryl and arylalkyi;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyi, with the proviso that CORw is not acetyl, 4-(aminosulfonyl)benzoyl or 3- (aminosulfonyl)benzoyl;
  • R w and R v can be independently selected from alkyl, cycloalkyi, aryl and arylalkyi;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyi.
  • R represents an hydroxyl protecting group selected from:
  • R can be selected from alkyl, cycloalkyi, aryl and arylalkyi, with the proviso that R is not C1 -C5 alkyl; - alkoxy and aryloxy alkyl ethers such as alkoxy and aryloxy methyl ether [-CH 2 - OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH2-OR w ], where R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl, with the proviso that COR w is not acetyl or C7-C12 benzoyl;
  • R w and R v can be independently selected from alkyl, cycloalkyl, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl.
  • alkyl refers to a linear or branched alkane derivative containing from 1 to 6 (“CrC 6 alkyl”), preferably from 1 to 3 (“CrC 3 alkyl”), carbon atoms and which is bound to the rest of the molecule through a single bond.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, etc.
  • alkoxy refers to a radical of the formula -OR where R is an alkyl radical as defined above having one or more (e.g., 1 , 2, 3 or 4) oxygen linkages and from 1 to 6 carbon atoms or preferably 1 to 3 carbon atoms, e. g., methoxy, ethoxy, propoxy, etc.
  • aryloxy refers to a radical of formula -OR wherein R is an aryl radical as defined below, e.g., -O-phenyl, -O-p-tolyl, -O-m-tolyl, -O-o-tolyl or -O- naphtyl.
  • aryl refers to an aromatic group having between 6 and 18 (“C 6 -Ci 8 aryl”), preferably between 6 and 10 (“C 6 -Ci 0 aryl”), more preferably 6 or 10 carbon atoms, comprising 1 , 2 or 3 aromatic nuclei bound through a carbon-carbon bond or fused to one another.
  • aryl groups include phenyl, naphthyl, biphenyl, indenyl, phenanthryl, etc.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above, such as (C6-Ci8)aryl(Ci-C 6 )alkyl, (C6-Cio)aryl(Ci-C 6 )alkyl and (C 6 -Cio)aryl(Ci-C 3 )alkyl.
  • aryl group as defined above, such as (C6-Ci8)aryl(Ci-C 6 )alkyl, (C6-Cio)aryl(Ci-C 6 )alkyl and (C 6 -Cio)aryl(Ci-C 3 )alkyl.
  • examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc.
  • cycloalkyl refers to a radical derived from cycloalkane containing from 3 to 7 (“C3-C7 cycloalkyl”), preferably from 3 to 6 (“C3-C6 cycloalkyl”) carbon atoms.
  • Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • halogen refers to bromine, chlorine, iodine or fluorine.
  • Heterocyclyl refers to a stable cyclic radical of 3 to 10 members, preferably a cycle of 5 or 6 members consisting of carbon atoms and from 1 to 5, preferably from 1 to 3, heteroatoms selected from nitrogen, oxygen and sulfur, and which may be completely or partially saturated or be aromatic (“heteroaryl").
  • the heterocyclyl can be a mono-, bi- or tricyclic system which may include fused ring systems.
  • heterocyclyl groups include, for example, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, benzimidazole, benzothiazole, furan, pyrrole, pyridine, pyrimidine, thiazole, thiophene, imidazole, indole, etc.
  • substituents include, for example and in non-limiting sense, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, N0 2 , CF 3 , -N(R a )(R b ), -OR c , -SR d , -C(0)R e , -C(0)OR f , -C(0)N(R g )(R h ), - OC(0)Ri; wherein R a , R b , R c , Rd, R e , R f , R g , R h and R, are independently selected from hydrogen, alkyl, aryl, heterocyclyl, heteroaryl and
  • hydroxyl protecting group refers to a group blocking the OH function for subsequent reactions that can be removed under controlled conditions. Hydroxyl protecting groups are well known in the art. Illustrative examples of hydroxyl protecting groups have been described by Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471 -16019-9). Virtually any hydroxyl protecting group can be used to put the invention into practice. Illustrative, non-limiting examples of HPGs include:
  • R x , R y and R z can be independently selected from alkyl, cycloalkyl, aryl, alkoxy and halogen.
  • silyl ethers include trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert- butyldiphenylsilyl ether, tri-isopropylsilyl ether, diethylisopropylsilyl ether, thexyldimethylsilyl ether, triphenylsilyl ether, di-tert-butylmethylsilyl ether, dimethylphenyl ether;
  • R can be selected from alkyl, cycloalkyl, aryl and arylalkyl.
  • ethers include methyl ether, tert-butyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, allyl ether;
  • alkoxy and aryloxy alkyl ethers such as alkoxy and aryloxy methyl ether [-CH 2 - OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -ORw].
  • R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl. Examples of alkoxy and aryloxy alkyl ethers include methoxymethyl ether, 2-methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, 2-
  • R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl.
  • esters include acetyl, benzoyl, pivaloyl, methoxyacetyl, chloroacetyl, levulinyl ester;
  • R w and R v can be independently selected from alkyl, cycloalkyl, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyl, aryl and arylalkyl.
  • Examples of carbonates include benzyl carbonate, p-nitrobenzyl carbonate, tert-butyl carbonate, 2,2,2-trichloroethyl carbonate, 2- (trimethylsilyl)ethyl carbonate, allyl carbonate.
  • the invention also provides "salts" of the compounds described in the present description.
  • said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the persons skilled in the art.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two.
  • Nonaqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred.
  • said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate
  • base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, ⁇ /,/V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, ⁇ /,/V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts.
  • the compounds described in the present description can be obtained both as free compounds or as solvates (e.g., hydrates, alcoholates, etc.), both forms being included within the scope of the present invention.
  • solvates e.g., hydrates, alcoholates, etc.
  • the solvation methods are generally known in the state of the art.
  • pharmaceutically acceptable relates to molecular entities and compositions being physiologically tolerable and normally not causing an allergic reaction or similar adverse reaction, such as gastric discomfort, dizziness and the like, when they are administered to a human being.
  • pharmaceutically acceptable means approved by a governmental regulatory agency or listed in the US pharmacopoeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the compounds of the invention also include compounds which differ in the presence of one or more isotopically enriched atoms.
  • compounds having the structures defined herein, with the exception of the substitution of at least one hydrogen by a deuterium or tritium, or the substitution of at least one carbon by a carbon enriched in 13 C or 14 C, or at least one nitrogen by a nitrogen enriched in 15 N are within the scope of this invention.
  • the term "about” means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term “about” can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention. Further, to provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about”.
  • the invention refers to a process for the preparation of a compound of formula (I)
  • R represents H or an hydroxyl protecting group (HPG);
  • the process of the invention has been found to provide high stereoselectivities in favour of the desired ⁇ , ⁇ -isomer as well, typically ⁇ 90%.
  • the oxidation of the carbon-carbon double bond in ring D of the compound of formula (II) is carried out with an oxidizing agent providing selective cis-hydroxylation of the carbon-carbon double bond to render a compound of formula (I).
  • the oxidation reagent is Os0 4 or a source of osmium tetroxide such as potassium osmate(VI) dihydrate (K 2 0s0 4 -2H 2 0) or osmium(lll) chloride hydrate (OsCI 3 -xH 2 0) which easily oxidise to osmium(VIII).
  • Os0 4 (or a source of Os0 4 ) supported/immobilized such as osmium tetroxide supported on poly(4-vinyl-pyridine) (Os0 4 -PVP) (cf. G. Cainelli et al., Synthesis 1989, 45 - 47), AD-mix (alpha and beta) or Os EncatTM.
  • Os0 4 -PVP poly(4-vinyl-pyridine)
  • AD-mix alpha and beta
  • Os EncatTM Os EncatTM.
  • the amount of Os0 4 supported on PVP is about 5%.
  • AD mix-a is a commercially available mixture containing (DHQ) 2 PHAL (hydroquinine 1 ,4-phthalazinediyl diether) 0.0016 mole, potassium carbonate, powder 0.4988 mole, potassium ferricyanide 0.4988 mole, and potassium osmate dihydrate 0.0007 mole.
  • AD mix- ⁇ is a commercially available mixture containing (DHQD) 2 PHAL (hydroquinidine 1 ,4-phthalazinediyl diether) 0.0016 mole, potassium carbonate, powder 0.4988 mole, potassium ferricyanide 0.4988 mole, and potassium osmate dihydrate 0.0007 mole.
  • Os EncatTM is Os0 4 immobilized in a polyurea matrix; in particular Os EnCatTM 40 has the following properties: Os metal content 4.8 - 5.7 % w/w and Os0 4 loading 40 - 300 mmol/g (average 165 mmol/g).
  • an oxidation co-reagent or co-oxidant is added additionally, such as trimethylamine-N-oxide, triethylamine-N-oxide, dimethylbencilamine-N-oxide, N-methyl morpholine-N-oxide, TEMPO or hydrogen peroxide and derivatives, more preferably trimethylamine-N-oxide.
  • This reaction of cis-dihydroxylation is typically carried out in a suitable organic solvent, such as an ether, for example, an acyclic ether (e.g., diisopropylether, etc.) or a cyclic ether (e.g., tetrahydrofuran (THF), a dioxane, etc.), a halogenated solvent such as, for example, dichloromethane, etc., or in an aromatic solvent such as, for example, toluene, etc.
  • the solvent is THF. More preferably, Os0 -PVP (poly(4-vinyl- pyridine) and trimethylamine-N-oxide are used with THF as the solvent.
  • the amount of the organic solvent may be a proportion between 3 and 20 mL per gram of the compound of formula (II), more preferably between 8 and 15 mL per gram of the compound of formula (II).
  • the quantity of oxidation co-reagent may vary between 0.95 and 4 equivalents, more preferably between 1 .0 and 2.5 equivalents and the amount of the oxidation reagent may be used between 10% and 50% per gram of the compound of formula (II), more preferable between 15% and 25% per gram of the compound of formula (II).
  • the mixture is preferably heated such as at a temperature comprised between room temperature and 100°C.
  • the reaction rate depends on the particular conditions including the temperature, where at a temperature comprised between 55°C and 60°C the reaction usually takes place in a time period of between 20-24 hours.
  • Estetrol can be prepared from a compound of formula (I) wherein R is a hydroxyl protecting group by conventional methods of deprotection known by persons skilled in the art (Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471 -16019-9). The progress of the reaction of deprotection can be easily monitored by TLC.
  • the compound of formula (II) or a salt or solvate thereof is prepared by a process comprising reacting a compound of formula (III)
  • This step can be carried out by means of any reduction reaction which allows the transformation of the keto group at C17 of a compound of formula (III) into a hydroxyl group to render a compound of formula (II).
  • the reduction reaction can be carried out under conventional conditions known in the art.
  • the reaction is performed using a reducing agent selected from a metallic hydride such as sodium borohydride, sodium cyanoborohydride, potassium borohydride, potassium cyanobohydride and lithium aluminum hydride.
  • the reducing agent is sodium borohydride, preferably in the presence of cerium trichloride (NaBH 4 /CeCI 3 ). More preferably, the reducing agent for use herein is NaBH 4 in combination with CeCI 3 hydrate, preferably cerium trichloride heptahydrate (CeCI 3 ⁇ 7H 2 0).
  • the reduction reaction is carried out using between 1 and 10, preferably between 1 and 5, more preferably between 1 and 3 equivalents of the reducing agent per equivalent of compound of formula (III), or a salt or solvate thereof.
  • the reaction of the compound of formula (III) with the reducing agent is carried out in a mixture of a protic solvent, such as MeOH and THF.
  • a protic solvent such as MeOH and THF.
  • a preferred volume ratio of MeOH to THF is 2: 1 to 5: 1 .
  • the 3-OH group of the estrone is protected for instance by acylation, silylation, formation of an ether, etc.
  • the 3-OH group is preferably acylated using a reagent selected from benzoyl, benzyl or acetyl chloride in dichloromethane and triethylamine as base.
  • intermediate product (VII) may be protected by treatment with ethylene glycol, triethylortoformiate and p-toluene sulfonic acid to render compound (VI) in practically quantitative yield.
  • an alpha-bromination may be carried out with pyridinium bromide in THF in presence of ethylene glycol to obtain the compound (V).
  • the amount of ethylene glycol may be from 5 to 25% with respect to the amount of THF.
  • the carbon-carbon double bond of ring D may be achieved with treatment of the compound (V) with i-BuOK in DMSO; under said conditions, if an ester is used as hydroxyl protecting group at C3 is unstable.
  • the dehydrobromination reaction is carried out using between 1 and 10, more preferably between 2 and 6 equivalents of i-BuOK per equivalent of compound of formula (V) and the amount of DMSO may be between 5 and 20 mL per gram of the compound of formula (V), more preferably between 7 and 1 1 mL per gram of the compound of formula (V).
  • the dehydrobromination reaction is carried out using between 2 and 6 equivalents of i-BuOK equivalent of compound of formula (V) and an amount of DMSO between 7 and 1 1 mL per gram of the compound of formula (V),
  • the compound of formula (IV) may be prepared from the compound of formula (VI) in a one-pot process, without isolating the intermediate compound (V). However, in a preferred variant of the invention, the compound of formula (V) is isolated.
  • the compound of formula (IV) obtained in the dehydrobromination reaction does not need further purifications (such as crystallizations or chromatographies) nor requires to be dried.
  • the preparation of the unsaturated estrone (III) is not limited to the specific process shown in Scheme 6, but as the skilled person will appreciate, protection and deprotection of the hydroxyl group at position 3 and the keto group at position 17 can be performed at any stage of the synthesis. The most suitable stage for said protection and/or deprotection can be readily determined by those skilled in the art. In a particular embodiment, the hydroxyl group at position 3 is not protected during the process. A particular embodiment of the invention, wherein the 3-OH group is free during the w
  • the preferences described above for the processes are combined.
  • the present invention is also directed to such combinations of preferred conditions of the processes.
  • the present invention refers to a compound of formula (I) per se
  • R represents an hydroxyl protecting group selected from:
  • silyl ethers [-Si(R x )(R y )(R z )], where R x , R y and R z can be independently selected from alkyl, cycloalkyl, aryl, alkoxy and halogen; - ethers [-R], where R can be selected from from alkyl, cycloalkyi, aryl and arylalkyl, with the proviso that R is not butanamide-4-oxy, butanoic acid 4-oxy, ethyl butanoate-4-oxy and ⁇ -D-Glucopyranosiduronic acid;
  • alkoxy and aryloxy alkyl ethers such as alkoxy and aryloxy methyl ether [-CH 2 - OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -ORw], where R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl, with the proviso that CORw is not acetyl, 4-(aminosulfonyl)benzoyl or 3- (aminosulfonyl)benzoyl;
  • R w and R v can be independently selected from alkyl, cycloalkyi, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl.
  • R is a silyl ether [- Si(R x )(Ry)(R z )] selected from trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, tri-isopropylsilyl ether, diethylisopropylsilyl ether, thexyldimethylsilyl ether, triphenylsilyl ether, di-tert-butylmethylsilyl ether, dimethylphenyl ether.
  • R is an ether [-R] selected from alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl; cycloalkyi such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; aryl such as phenyl, naphthyl, biphenyl, indenyl, phenanthryl; and arylalkyl such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl.
  • alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl
  • cycloalkyi such as cyclopropyl
  • R is a alkoxy or aryloxy alkyl ether such as alkoxy and aryloxy methyl ether [-CH 2 -OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -OR w ] selected from methoxymethyl ether, 2-methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, 1 -methoxyethyl ether, 1 -ethoxyethyl ether, 1 -n- propoxyethyl ether, 1 -isopropoxyethyl ether, 1 -n-butoxyethyl ether, 1 -isobutoxyethyl ether, 1 -sec-butoxyethyl ether, 1 -tert-butoxyethyl ether, 1 -tert-butoxyethyl
  • R is an ester [-COR w ] selected from acetyl, benzoyl, pivaloyl, methoxyacetyl, chloroacetyl, levulinyl.
  • R is an amide [-CONR w R v ] such as dimethylamide.
  • R is a carbonate [-COOR w ] selected from benzyl carbonate, p-nitrobenzyl carbonate, tert-butyl carbonate, 2,2,2- trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, allyl carbonate.
  • the present invention refers to a compound of formula (II) per se
  • R represents an hydroxyl protecting group selected from:
  • R can be selected from alkyl, cycloalkyi, aryl and arylalkyl, with the proviso that R is not C1 -C5 alkyl;
  • alkoxy and aryloxy alkyl ethers such as alkoxy and aryloxy methyl ether [-CH 2 - OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -ORw], where R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl, with the proviso that COR w is not acetyl or C7-C12 benzoyl;
  • R w and R v can be independently selected from alkyl, cycloalkyi, aryl and arylalkyl;
  • R w can be selected from alkyl, cycloalkyi, aryl and arylalkyl.
  • R is an ether [-R] selected from C6-alkyl; cycloalkyi such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; aryl such as phenyl, naphthyl, biphenyl, indenyl, phenanthryl; and arylalkyl such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl.
  • R is a alkoxy or aryloxy alkyl ether such as alkoxy and aryloxy methyl ether [-CH 2 -OR w ] and alkoxy and aryloxy ethyl ether [-CH 2 -CH 2 -OR w ] selected from methoxymethyl ether, 2- methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, 1 -methoxyethyl ether, 1 -ethoxyethyl ether, 1 -n- propoxyethyl ether, 1 -isopropoxyethyl ether, 1 -n-butoxyethyl ether, 1 -isobutoxyethyl ether, 1 -sec-butoxyethyl ether, 1 -tert-butoxyethyl ether, 1 -tert-butoxyethyl
  • R is an ester [-COR w ] selected from benzoyl, pivaloyl, methoxyacetyl, chloroacetyl, levulinyl ester.
  • R is an amide [-CONR w R v ] such as dimethylamide.
  • R is a carbonate [-COOR w ] selected from benzyl carbonate, p-nitrobenzyl carbonate, tert-butyl carbonate, 2,2,2- trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, allyl carbonate.
  • a 5% suspension of PVP-Os0 4 (0.27 g/g) was prepared in 10 mL/g of THF. Then trimethylamine-N-oxide and a solution of 4.5 g of 3-benzyl-17-acetoxy-A-15-estradiol in 45 mL of THF were added at room temperature. It was heated at 50-55 °C until positive control. Cis-dihydroxylation products were measured in the HPLC control with a ratio of 80/20 (15 ⁇ ,16 ⁇ / 15 ⁇ ,16 ⁇ ).
  • the reaction mixture was cooled to room temperature and the solid was filtered off, washed with THF (10 mL) and the organic layer was concentrated.
  • the solid residue was dissolved in AcOEt (25 mL) and water (25 mL). 1 N aqueous HCI (1 .0 mL) was added to the aqueous layer. The two layers were separated and the aqueous layer was extracted with AcOEt (15 mL). Then, the organic layers were mixed and dried (Na 2 S0 4 ).
  • the organic phase was concentrated in vacuo until a residue was formed and then triturated with heptane/AcOEt (1 :1 ,10 mL) and stirred at room temperature.
  • the solid obtained was filtered off to afford a solid (4.0 g, 88%).
  • the product was purified by recrystallization from heptane/AcOEt/EtOH (2: 1 : 1 ) three times to afford a white solid (2.0 g, 44%).
  • the final organic phase was concentrated under vacuum until a final volume of 90 mL.
  • the solvent was changed with methanol by subsequent steps of addition and evaporation with three portions of 90 mL of methanol, concentrating in each case until a final volume of 90 mL.
  • the final suspension was stirred at 0/5 °C for 30 minutes and then, the solid was filtered off.
  • the solid was washed with 30 mL of methanol at 0/5 °C and it was dried at 50 °C, to afford a final dry cake: 42.5 g of 3-benzoyl-Estrone. Yield: 100% Molar.
  • the wet cake of the previous step A-15-17,17-ethylenedioxy-Estrone_ was suspended again in 250 mL of acetone and 1 .5 g of p-toluenesulfonic acid were added (if pH is not below 3, more p-TSA is added).
  • the reaction was complete after 1 hour at 20 ⁇ 5 °C, and then 1 mL of pyridine was charged. The mixture was concentrated until 100 mL and 100 mL of water were added. It was filtered and washed with 50 mL of water.
  • the maximum amount of osmium tetroxide supported on PVP which can be obtained is 5% by weight.
  • ⁇ -15-Estradiol (10 g) was dissolved in a mixture of 40 ml of dichloromethane and 40 ml of Methanol under inert atmosphere, at room temperature. K 2 C0 3 1 .5 g were added and then 13.0 ml of Benzyl bromide were added thereto and the mixture was refluxed until completion of the reaction was observed by TLC. The mixture was cooled and the solid was filtered off and washed with Methanol (10 mL) Then, the organic phase was evaporated under reduced pressure.
  • the suspended solid was filtered and washed with heptane and recrystallized in a mixture of dichloromethane/Methanol 1 :1 , filtered off and dried in an oven at 50°C to yield 12.01 g, 90% molar.
  • NMR-C 13 156.1 ; 137.4; 135.9; 132.4; 129.9; 128.4; 127.6; 127.5; 125.9; 1 14.5; 1 12.24; 83.9; 68.9; 56.2; 50.88; 43.9; 40.1 ; 35.9; 34.5; 29.1 ; 27.1 ; 25.7; 12.5.
  • NMR-C 13 156.1 ; 137.6; 137.4; 132.3; 128.4; 127.6; 127.5; 126.3; 1 14.5; 1 12.24; 83.4; 75.0; 69.2; 69.0; 55.5; 43.7; 40.1 ; 39.1 ; 38.9; 29.5; 27.2; 25.7; 13.9.
  • ⁇ -15-estradiol (10 g) was dissolved in 100 ml of dichloromethane and 1 1 ml of triethylamine under inert atmosphere, at a temperature of about 10-15°C and 5.15 ml of Benzoyl chloride were added thereto at a temperature lower than 30°C.
  • the reaction mixture was stirred at room temperature for about one hour until completion of the reaction was observed by HPLC.
  • NMR-C 13 164.7; 148.3; 137.8; 137.7; 136.0; 133.9; 129.9; 129.7; 129.0; 128.9; 126.1 ; 121 .5; 1 18.8; 83.36; 56.2; 50.9; 44.0; 35.7; 34.5; 28.8; 26.8; 25.6; 12.5.
  • Example 12 Preparation of 3-Benzoyl-Estetrol
  • 3-Benzoyl-A-15-Estradiol (10.1 g) was dissolved in 1 12 ml of THF under inert atmosphere.
  • PVP-Os0 4 2.0 g
  • trimethylamine N-oxide 2 H 2 0 5.1 g
  • the mixture was heated until 55-60°C for 20-24 h.
  • the mixture was filtered and the solid was extracted with THF.
  • a first portion of the resulting organic phase was evaporated under vacuum, water (40 ml) was added to the liquid phase and the organic phase was evaporated under vacuum.
  • the ratio between the 15a,16a-diol and 15 ⁇ ,16 ⁇ - ⁇ is 90/10.
  • NMR-C 13 164.7; 148.3; 137.8; 137.7; 129.9; 129.7; 128.9; 128.4; 126.1 ; 121 .5; 1 18.8;
  • ⁇ -15-estradiol (3.0 g) was dissolved in 15 ml of THF under inert atmosphere at room temperature. Imidazol (2.0 g) and TBDMS chloride (3.18 g) were added. The reaction mixture was stirred at room temperature until completion of the reaction was observed by HPLC.
  • NMR-C 13 152.7; 137.4; 136.0; 132.9; 129.9; 125.9; 1 19.5; 1 16.9; 83.9; 56.2; 50.9; 43.92; 36.9; 34.5; 28.8; 27.0; 25.8; 25.7; 25.6; 17.9; 12.5; -4.5.
  • 3-tert-butyl-dimethyl-sylil-A-15-Estradiol (1.0 g) was dissolved in 1 1 ml of THF under inert atmosphere.
  • PVP-Os0 4 (0.2 g) and trimethylamine N-oxide (0.51 g) were added at room temperature, the mixture was heated until 55-60°C for 20-24 h. Then, the mixture was filtered and the solid was extracted with THF. A first portion of the resulting organic phase was evaporated under vacuum, water (4 ml) was added to the liquid phase and the organic phase was evaporated under vacuum.
  • the ratio between the 15a,16a-diol and 15 ⁇ ,16 ⁇ - ⁇ is 90/10.
  • NMR-C 13 152.7; 137.4; 133.9; 125.9; 1 19.5; 1 16.9; 83.9; 76.8; 68.5; 56.2; 50.9; 41 .92; 36.9; 34.5; 28.8; 27.0; 25.8; 25.7; 25.6; 17.9; 12.5; -4.5.
  • ⁇ -15-Estradiol 2.0 g was dissolved in 10 ml of THF and 1 .59 ml of n-butylvinyl ether under inert atmosphere at room temperature. Molecular sieves (0.2 g) and p- toluenesulphonic acid (0.2 g) were added. The reaction mixture was stirred at room temperature until completion of the reaction was observed by HPLC.
  • 3-(1 -butoxyethyl) ether-A-15-estradiol (2.0 g) was dissolved in 22 ml of THF under inert atmosphere.
  • PVP-Os0 4 0.4 g
  • trimethylamine N-oxide 1.0 g
  • the mixture was heated until 55-60°C for 20-24 h.
  • the mixture was filtered and the solid was extracted with THF.
  • a first portion of the resulting organic phase was evaporated under vacuum, water (7.5 ml) was added to the liquid phase and the organic phase was evaporated under vacuum.
  • the ratio between the 15a,16a-diol and 15 ⁇ ,16 ⁇ - ⁇ is 90/10.

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  • Organic Chemistry (AREA)
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  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé d'obtention de l'estétrol et de dérivés de celui-ci de formule (I) ou d'un sel ou d'un solvate de celui-ci, dans laquelle R représente H ou un groupe protecteur d'hydroxyle, le procédé comprenant l'étape consistant à faire réagir un composé de formule (II) ou un sel ou solvate de celui-ci, dans laquelle R est tel que défini précédemment, avec un agent oxydant ; l'invention concerne également lesdits dérivés comprenant un groupe hydroxyle protégé en position 3 de formule (I) et des produits intermédiaires utiles dans le procédé.
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WO2021044302A1 (fr) 2019-09-03 2021-03-11 Richter Gedeon Nyrt. Procédé industriel pour la préparation d'estétrol de pureté élevée
IT201900017414A1 (it) * 2019-09-27 2021-03-27 Ind Chimica Srl Processo per la preparazione di (15α,16α,17β)-estra-1,3,5(10)-triene-3,15,16,17-tetrolo (Estetrolo) ed intermedi di detto processo
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

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Cited By (13)

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Publication number Priority date Publication date Assignee Title
WO2015040051A1 (fr) * 2013-09-18 2015-03-26 Crystal Pharma, S.A.U. Procédé pour la préparation d'estétrol
JP2016531159A (ja) * 2013-09-18 2016-10-06 クリスタル ファルマ、エセ、ア、ウＣｒｙｓｔａｌ Ｐｈａｒｍａ，Ｓ．Ａ．Ｕ． エステトロールの製造プロセス
US9988417B2 (en) 2013-09-18 2018-06-05 Crystal Pharma, S.A.U. Process for the preparation of estetrol
JP2022546016A (ja) * 2019-09-03 2022-11-02 リヒター ゲデオン ニュイルヴァーノシャン ミューコェデー レースヴェーニュタールシャシャーグ 高純度エステトロールを調製するための産業的方法
CN114302889A (zh) * 2019-09-03 2022-04-08 吉瑞工厂 用于制备高纯度的雌四醇的工业方法
WO2021044302A1 (fr) 2019-09-03 2021-03-11 Richter Gedeon Nyrt. Procédé industriel pour la préparation d'estétrol de pureté élevée
US11633406B2 (en) 2019-09-03 2023-04-25 Richter Gedeon Nyrt. Industrial process for the preparation of high purity estetrol
JP7265087B2 (ja) 2019-09-03 2023-04-25 リヒター ゲデオン ニュイルヴァーノシャン ミューコェデー レースヴェーニュタールシャシャーグ 高純度エステトロールを調製するための産業的方法
CN114302889B (zh) * 2019-09-03 2023-08-29 吉瑞工厂 用于制备高纯度的雌四醇的工业方法
IT201900017414A1 (it) * 2019-09-27 2021-03-27 Ind Chimica Srl Processo per la preparazione di (15α,16α,17β)-estra-1,3,5(10)-triene-3,15,16,17-tetrolo (Estetrolo) ed intermedi di detto processo
IT202100019631A1 (it) 2021-07-23 2023-01-23 Newchem S P A Metodo per produrre estetrolo e i suoi intermedi
WO2023001866A1 (fr) 2021-07-23 2023-01-26 Newchem S.P.A. Procédés pour préparer de l'estétrol et ses intermédiaires
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

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