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    • 专利摘要:
    The present invention relates to a new process for the synthesis of 3a-hydroxy-5a-pregnan-20-one, commonly known as brexanolone, wherein the corresponding cyclic 20-ketal or cyclic 20-thioketal compound of formula (IV) is deprotected with the use or iodine in an organic solvent: (I).
    公开号:ES2837136A2
    申请号:ES202190022
    申请日:2019-10-21
    公开日:2021-06-29
    发明作者:Claudio Delfrate；Davide Rigamonti；Tea Borelli；Roberto Lenna
    申请人:Industriale Chimica SRL；
    IPC主号:
    专利说明:

    [0002] Process for the preparation of 3a-hydroxy-5a-pregnan-20-one (Brexanolone)
    [0004] FIELD OF THE INVENTION
    [0006] The present invention relates to the field of processes for the synthesis of active principles for pharmaceutical use and, in particular, to a process for the preparation on an industrial scale of 3a-hydroxy-5a-pregnan-20-one, a useful active principle for the treatment of postpartum depression. The compound is also known by the name allopregnanolone or by the American name brexanolone (USAN), which will be used in the rest of the text, and has the following formula:
    [0011] STATE OF THE ART
    [0013] Brexanolone was first described in GB 442,319 in 1934, assigned to Schering-Kahlbaum Aktiengesellschaft. The patent indicates a brief experimental description of the preparation of the compound in question starting from 3-hydroxybisnorocolenic acid which, however, has only historical-academic value, but no practical use.
    [0014] A more recent synthesis process is described in the article “Synthesis of the allylic gonadal steroids, 3a-hydroxy-4-pregnen-20-one and 3a-hydroxy-4-androsten-17-one, and of 3a-hydroxy-5a -pregnan-20-one ", JP Wiebe et al., Steroids (1985) Vol. 45, No. 1, pp. 39 51. The synthesis is presented in the scheme of Figure 1 on page 43 of the article; In this synthetic route, by causing 150 mg of compound 9 to react with potassium tri-s-butylborohydride (K selectride), 55 mg of brexanolone (compound 10 in the figure) are obtained after chromatographic purification.
    [0015] The article “Synthesis, metabolism, and pharmacological activity of 3a-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes ”, RH Purdy et al., Journal of Medicinal Chemistry, 1990, Vol. 33 (6), 1572-1581, describes another brexanolone synthesis route, described referring to scheme 1 on page 1573. In this synthesis, a sample of brexanolone (intermediate 2a) is obtained from the corresponding isomer 3p (intermediate 1) with a final yield of 54 % after crystallization and chromatographic purification (point of melting = 174-176 ° C).
    [0016] Patent EP 2 688 902 B1 describes another synthesis of the compound. In this patent (example 5) a sample of brexanolone is obtained from the corresponding benzoate (intermediate 3, scheme 1 on page 8) with a final yield of 80% after chromatographic purification. However, the melting point, 161.7-162.8 ° C, is clearly lower than that described in the aforementioned article by RH Purdy et al. These data, associated with the fact that the EP text does not contain information about purity, cast doubt on the quality of the product obtained. After experimental checks carried out by the present inventors, aimed at evaluating the contents of the patent, it seems likely that the product obtained in this patent is brexanolone containing 16% epimer at position 17, which has a melting interval between 163.8 <T <165.6 ° C (DSC).
    [0017] In the course of their experimental activities, the inventors have constantly observed the epimerization of position 17 when brexanolone or one of its synthesis intermediates with a pregnane structure with the deprotected carbonyl function have acidic or basic pH, capable of generating an intermediate enolate or an enol in the course of the reaction.
    [0022] The formation of the double bond generates an intermediate with a planar structure between positions 17 and 20 that evolves in the reaction that regenerates the single bond with spatial configuration both p, predominant, and a, minority but quantitatively relevant for the objective of the necessary quality for a pharmaceutical product. Despite the research activity carried out by the present inventors, it has proven difficult, if not impossible, to identify the pH limits at which these unwanted reactions occur. since the reaction can take place in an organic solvent or in an aqueous organic solvent, at various concentrations and temperatures, and with different acids or bases.
    [0023] During their experimental activity, the inventors have also tried to protect carbonyl at position 20 as ketal with the use of ethylene glycol, but all subsequent hydrolysis tests resulted in epimerization of position 17. The conditions analyzed for ketal deprotection were: 1M HCl in methyl alcohol at 25 ° C; 10 mol% para-toluenesulfonic acid (PTSA) in acetone at 55 ° C; 5 mol% of PTSA in acetone at 25 ° C; 5 mol% PTSA in acetone at 0 ° C; 1 mol% PTSA in acetone at 25 ° C; 5 mol% pyridinium para-toluenesulfonate (PPTS) in acetone at 25 ° C; Anhydrous FeCh in an acetone / dichloromethane mixture at 25 ° C.
    [0024] Eliminating or at least limiting this unwanted chemical reaction (epimerization) is relevant to both the process performance and the quality of the brexanolone.
    [0025] In the article "Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity", AS Campos Neves et al., Tetrahedron, 55 (1999) pp. 3255-64 describes epimerization at position 17 in a brexanolone-like steroid (scheme 1 on p. 3257) in an acidic environment; This unwanted reaction involves the formation of a 12% by-product that is eliminated by crystallization, with a yield of 60% reaching an intermediate with a purity of 95-97%, which, however, is still far from a pharmaceutical quality.
    [0026] An object of the present invention is to provide a synthetic route for the preparation of brexanolone, which is applicable at an industrial level and which allows a product of pharmaceutical quality to be obtained, overcoming the drawbacks associated with the processes described in the prior art.
    [0028] SUMMARY OF THE INVENTION
    [0030] This object is achieved with the present invention, which refers to a method for the preparation of brexanolone that consists of the deprotection of a cyclic ketal or a cyclic thioketal of this with the general formula (IV) with the use of iodine in a solvent organic, according to the reaction scheme:
    [0032] where X = O (oxygen) in the case of ketal and X = S (sulfur) in the case of thioketal, and R is a radical selected from among ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2 -) and 2,2-dimethylpropylene (-CH 2 -C (CH 3 ) 2 -CH 2 -).
    [0033] Brexanolone obtained by means of this preparation method has an amount of epimer at position 17 of less than 0.15%, as determined by HPLC analysis.
    [0034] In a preferred embodiment, the invention relates to a process for the synthesis of brexanolone comprising the following steps:
    [0035] 1) Catalytic hydrogenation of the double bond at position 5,6 of pregnenolone to obtain the corresponding saturated steroid with formula (I), with the hydrogen atom at position 5 of the steroidal skeleton in a spatial arrangement at:
    [0040] 2)
    [0045] 3) protection of the carbonyl at position 20 of compound (II) as ketal or thioketal, obtaining the compound with the general formula (III), where X = O or X = S and R is a radical selected from among ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-) and 2 , 2-dimethylpropylene
    [0047] 4)
    [0052] 5) deprotection of position 20 of the compound with the general formula (IV) obtaining brexanolone:
    [0057] In a second aspect thereof, the invention relates to the following synthetic intermediates:
    [0058]
    [0060] BRIEF DESCRIPTION OF THE DRAWINGS
    [0062] Figure 1: NMR spectrum of the brexanolone-epimer mixture obtained in the preparation described in Example 6.
    [0063] Figure 2: NMR spectrum of the brexanolone-epimer mixture obtained in the preparation described in Example 7.
    [0064] Figure 3: NMR spectrum of brexanolone without epimer. Expansion from 2.3 to 3.2 ppm is indicated.
    [0065] Figure 4: DSC thermogram of pure brexanolone obtained after the Example process DETAILED DESCRIPTION OF THE INVENTION
    [0067] In the present description and in the claims, in the event of a discrepancy between the name of a compound and the structural formula indicated for it, the latter must be considered correct.
    [0068] The object of the present invention, in its first aspect, is a method for the preparation of brexanolone that consists of the deprotection of a cyclic ketal or a cyclic thioketal of this with the general formula (IV) with the use of iodine in a solvent organic, according to the reaction scheme:
    [0072] where X = O (oxygen) in the case of ketal and X = S (sulfur) in the case of thioketal, and R is a radical selected from among ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2 -) and 2,2-dimethylpropylene (-CH 2 -C (CH 3 ) 2 -CH 2 -).
    [0073] In the preferred embodiment of the invention, R is the ethylene radical, -CH2-CH2-.
    [0074] The reaction conditions are different depending on whether the compound of formula (IV) is a ketal or a thioketal.
    [0075] In the case of X = O, the ketal must be hydrolyzed in a neutral environment, avoiding the presence of acids or bases. Preferably, for the deprotection of the ketal, iodine is used in an amount of between 1 and 10% by weight with respect to the amount of compound (IV).
    [0076] As the reaction solvent, it is possible to use anhydrous acetone or a mixture of dichloromethane and acetone operating in the absence of water. The fact of operating with anhydrous acetone or with a mixture of dichloromethane and acetone in the absence of water is decisive for the result of the reaction.
    [0077] The reaction temperature is between -5 ° C and the reflux temperature of the reaction mixture.
    [0078] The reaction time is between 5 and 90 minutes. Preferably, it is operated in the interval between 10 and 45 minutes.
    [0079] In the case of X = S, the thioketal is reacted with iodine in organic solvent at a temperature between -30 and 20 ° C in the presence of a solid inorganic base such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, lithium bicarbonate and potassium bicarbonate; the preferred base is sodium bicarbonate. As the organic solvent, dichloromethane (DCM), methanol, or preferably a mixture of these can be used.
    [0080] The reaction time is between 2 and 36 hours, and is related to the amount of iodine used in the reaction and to the reaction temperature. Preferably, it is operated in the temperature range between -25 and -5 ° C for a time period of between 1 and 18 hours.
    [0081] The inventors have experimentally observed that through this synthesis process it is possible to obtain brexanolone that has an amount of epimer at position 17 of less than 0.15% (value determined by HPLC analysis), a value that corresponds to the maximum amount admitted according to the ICH guidelines issued by the European Medicines Agency (EMA) for the identified impurities present in active principles and intermediate products for the pharmaceutical industry (API) for which pharmacological studies have not been carried out that allow their presence in a greater amount. This result is possible by operating under the conditions of the invention without resorting to chromatographic purifications or special purification techniques applied to the brexanolone produced.
    [0082] Specifically, the brexanolone obtained according to the method of the invention, in the case of X = S, is substantially free of its epimer at position 17 and, therefore, no specific purification treatment is necessary to eliminate this impurity. In the case of X = O, in the crude product the presence of a minimum amount of epimer in position 17, less than 0.5%, is observed, which is easily reduced to values of less than 0.1% by crystallization.
    [0083] In a preferred embodiment, the invention relates to a complete process for the synthesis of brexanolone on an industrial scale comprising steps 1 to 5 indicated above.
    [0084] The reactions of steps 1) of pregnenolone to the compound of the formula (I), 2) of the compound of the formula (I) to the compound of the formula (II), and 4) of the compound of the general formula (III) to the compound with the general formula (IV), can be executed following the indications available in the literature, such as those disclosed in patent EP 2688 902 B1; therefore, these steps are briefly described below.
    [0085] In stage 1) intermediate (I) is produced starting from pregnenolone:
    [0088] The starting pregnenolone is a commercially available product. The methods of executing this step are known in the art.
    [0089] For the purposes of the present invention, the preferred conditions are the use of 5% supported palladium on carbon (Pd / C) as the hydrogenation catalyst. The amount used is approximately 5% of the weight of pregnenolone to be hydrogenated. The hydrogenation pressure is between 2 and 5 bar. The reaction solvent is tetrahydrofuran (THF). The hydrogenation temperature is between 35 and 45 ° C. The hydrogenation time is variable between 3 and 7 hours, the reaction ends when the consumption of hydrogen ceases.
    [0090] In step 2) it is caused by the reversal of the spatial orientation of the hydroxyl in the 3-position of intermediate (I) which, at the end of the reaction, is protected as a benzoic ester (intermediate
    [0092] Furthermore, this step can be carried out according to methods known in the field of study.
    [0093] In the case of the present invention, this step is preferably carried out by preparing the benzoic ester of the hydroxyl at position 3, causing the intermediate (I) to react with benzoic acid in tetrahydrofuran (THF) as solvent and allowing the system to react for 14-20 hours with triphenylphosphine and diisopropyl azodicarboxylate (DIAD) at 15-25 ° C
    [0094] The intermediate (II) thus obtained is then purified by refluxing it in an alcohol, preferably methanol, obtaining a suitable quality to continue the synthesis.
    [0095] In step 3), the carbonyl at position 20 of intermediate (II) is protected as a ketal or thioketal, obtaining the intermediate with the general formula (III), where X = O or X = S and R is a radical selected from between ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-) and 2,2-dimethylpropylene (-CH 2 -C (CH 3 ) 2 -CH 2 -):
    [0100] The ketal (X = O) can be obtained by refluxing a mixture of intermediate (II) with toluene, ethylene glycol, propylene glycol or 2,2-dimethylpropylene glycol, triethylorthoformate and ptoluenesulfonic acid. In this case, an amount of between 5 and 10% of the epimer 17a is formed, which is removed by crystallizing the crude intermediate (III) with an organic solvent, such as, for example, ethyl acetate, isopropyl acetate or 2 -propanol.
    [0101] Obtaining the thioketal is possible by causing the intermediate (II) to react with propanedithiol, 2,2-dimethylpropanedithiol or, preferably, ethanedithiol in a solvent selected from among acetic acid, dichloromethane (CH2Cl2), ethyl ether, acetonitrile, tetrahydrofuran (THF ) and 1,2-dichloroethane, in the presence of a catalyst selected from boron trifluoride etherate (BF3-Et2O), zinc iodide (Znh), titanium tetrachloride (TiCU), tin dichloride (SnCh), iodide of magnesium (Mgh), lithium perchlorate (LiClO4), aluminum trifluoromethanesulfonate (also known as aluminum triflate, Al (OTf) 3 ), lithium tetrafluoroborate (UBF4) and cobalt dichloride (CoCh), at a temperature in the range between 15 and 45 ° C and for a period of between 8 and 36 hours. Preferred reaction conditions contemplate the use of acetic acid as solvent, and of BF3 etherate (BF3-Et2O) as catalyst at a temperature of 30 ± 5 ° C for a period of 24-28 hours.
    [0102] In step 4) the hydrolysis of the benzoic ester of the intermediate with the general formula (III) is carried out, obtaining the intermediate with the general formula (IV):
    [0105] This step can be carried out following the indications available in the prior art.
    [0106] In the case of the present invention, this step is preferably carried out by refluxing intermediate (III) in methanol for a period of 20-28 h in the presence of a strong base, such as sodium hydroxide, and monitoring the progress of the reaction, for example, with TLC.
    [0107] Finally, step 5) of the process corresponds to the method of deprotection of ketals or thioketals according to the first aspect of the invention, described above in detail.
    [0108] The invention will be further illustrated by the following examples.
    [0109] INSTRUMENTS, METHODS AND EXPERIMENTAL CONDITIONS
    [0110] NMR:
    [0111] JEOL 400 YH NMR Spectrometer (400 MHz); JEOL Delta software v5.1.1;
    [0112] Spectra recorded in deuterated solvents: Chloroform-d, D 99.8%, containing 0.1% (v / v) of tetramethylsilane (TMS) as internal standard; Chloroform-d, "100%", D 99.96%, containing 0.03% (v / v) TMS; CD3OD; and DMSO-de.
    [0113] MS:
    [0114] Instrument: DSQ-trace Thermofisher;
    [0115] Sample introduction - direct exposure (dep) probe
    [0116] Chemical ionization (CI) with methane;
    [0117] Source temperature: 200 ° C.
    [0118] DSC
    [0119] Perkin Elmer instrument mod. Diamond;
    [0120] Perkin Elmer standard aluminum capsules and covers, code 02190041;
    [0121] Scanning speed: 10 ° C / min;
    [0122] Temperature range: 20 ° C to 220 ° C.
    [0123] HPLC
    [0124] For Pregnenolone, intermediate (I) and Brexanolone
    [0125] Agilent Model 1260 Infinity Chromatographic System; UV detector MODEL 1260 DAD VL; Advanced Column Chromatography Technologies ACE 3 C18-PFP 150X3 mm, 3 gm; mobile phase A: water, mobile phase B: acetonitrile, isocratic method 50/50, wavelength 200 nm, flow rate 0.5 ml / min, injection volume 5 gl, run time 25 min, temperature 25 ° C;
    [0126] For intermediates (II), (III) and (IV)
    [0127] Agilent Model 1260 Infinity Chromatographic System; MODEL 1260 DAD VL UV detector; Column: Supelco Ascentis C8 150X4.6mm, 5gm; mobile phase A: water, mobile phase B: methanol; 85/15 isocratic method, wavelength 216 nm, flow rate 1 ml / min, injection volume 5 gl, execution time 45 min, temperature 25 ° C.
    [0128] LC / Ms / Ms system
    [0129] Agilent Model 1100 Chromatographic System with UV DAD Detector connected to an Applied Biosystem API 2000 Mass Spectrometer.
    [0130] TLC MERCK: TLC Silica gel 60 F254 Aluminum sheets 20 x 20 cm, cod. 1.0554.0001.
    [0131] MERCK HPTLC : Silica gel 60 F254 HPTLC with concentration zone 10 x 2.5 cm, cod.
    [0132] 1,13727,0001.
    [0133] TLC detectors
    [0134] Cerium phosphomolybdate acid solution. Preparation: 25 g of phosphomolybdic acid hydrate (Aldrich), 10 g of cerium (IV) sulfate hydrate (Aldrich) and 600 ml of water are stirred until dissolved with 60 ml of 95-98% sulfuric acid (Aldrich 258105); it is brought to a final volume of 1000 ml with water; the sheet is impregnated with a solution, then heated until it acquires a blue tint.
    [0135] TLC and HPTLC eluent
    [0136] The conditions of the TLC checks are indicated in the experimental procedures.
    [0137] Specifications regarding the experimental descriptions of the examples:
    [0138] The water used in the experimental descriptions should be understood as pure water unless otherwise indicated.
    [0139] Organic solvents used in experimental descriptions are to be understood as "technical" quality unless otherwise stated.
    [0140] The reagents and catalysts used in the experimental descriptions are to be understood as commercial grade unless otherwise stated.
    [0141] EXAMPLE 1
    [0142] This example refers to stage 1) of the process of the invention.
    [0146] 10 g of pregnenolone was dissolved in 300 ml of THF at 20 ± 5 ° C and the solution was loaded into a hydrogenation reactor. 0.50 g of 5% Pd / C was added. Two vacuum / hydrogen cycles were carried out and finally hydrogen was charged up to a pressure of 4 bar.
    [0147] The reagent mixture was heated to 40 ± 5 ° C, keeping stirring until the end of hydrogen consumption was observed (approximately 5 hours). A 1 H-NMR check was carried out, observing the complete disappearance of the starting pregnenolone.
    [0148] The reagent mixture was cooled to 20 ± 5 ° C and filtered over celite, washing with 50 ml of THF. THF was removed with the rotary evaporator, heating to 40-45 ° C. Methyl ethyl ketone (MEK, 50 ml) was charged and the mixture was rotary evaporated, heating at 45 ° C twice. 30 ml of MEK was charged and the mixture was stirred under reflux for 10 minutes (no dissolution was observed). The mixture was cooled to 0 ° C and kept stirring for 1 h, after which it was filtered and washed with cold MEK. The solid was dried in an oven at 40 ° C for 4 h, obtaining 9.2 g of white solid (intermediate (I)).
    [0149] Pregnenolone Analysis:
    [0151] 1 H-NMR, CDCh: 5.36-5.35 (1H, m, H-6); 3.57-3.49 (1H, m, H-3); 2.54 (1H, t, J = 9Hz, H-17); 2.34-2.15 (2H, m); 2.13 (3H, s, H-21); 2.07-1.97 (2H, m); 1.89-1.82 (2H, m); 1.73-1.41 (10H, m); 1.29-1.06 (3H, m); 1.01 (3H, s, CH3); 0.63 (3H, s, CH3);
    [0152] Mass: 316 (M +).
    [0153] Intermediate analysis (I):
    [0155] 1 H-NMR, CDCh: 3.64-3.56 (1H, m, H-3); 2.52 (1H, t, J = 9Hz, H-17); 2.2-2.1 (1H, m); 2.11 (3H, s, H-21); 2.00 (1H, dt, J = 3-11.4 Hz); 1.84-1.53 (8H, m); 1.50-0.84 (11H, m); 0.80 (3H, s, CH3); 0.68 (1H, dt, J = 4-12 Hz); 0.60 (3H, s, CH3);
    [0156] Mass: 318 (M +).
    [0158] EXAMPLE 2
    [0159] This example refers to stage 2) of the process of the invention.
    [0161] 15.8 of the intermediate (I) obtained in the previous example were charged into a flask under a nitrogen atmosphere at 20-25 ° C. 390 ml of THF were added and the mixture was stirred until dissolved. 9.1 g of benzoic acid and 19.4 g of triphenylphosphine were added. Into the reaction mixture, 15.3 ml of 94% DIAD was dripped over 30 minutes, keeping the temperature below 30 ° C. The mixture was stirred at 20 ± 5 ° C for 16 hours, and a TLC check was carried out, observing the complete disappearance of the starting reagent. The TLC check was carried out under the following conditions:
    [0162] - start: in CH2Ch;
    [0163] - sample: reaction mixture in ethyl acetate. The organic phase settled; - eluent: toluene / isopropyl acetate 8/2; foil: HPTLC glass;
    [0164] - detector: UV / phosphomolybdic cerium.
    [0165] THF was distilled on a rotary evaporator under vacuum at 45 ± 5 ° C. The residue obtained was dissolved with 250 ml of ethyl acetate at 20 ± 5 ° C, and 200 ml of aqueous solution saturated with NaHCO3 were added. Stirring was maintained for 10 minutes at 20 ± 5 ° C, and then the phases were separated. The organic phase was washed with 200 ml of aqueous solution saturated with NaHCO3 and the phases were separated. The aqueous phases were pooled and re-extracted with ethyl acetate. The organic phases were rejoined and washed with 130 ml of aqueous solution saturated with NaCl. The phases were separated and the organic phase was washed with 100 ml of water. The phases were separated and the organic phase was distilled with a rotary evaporator under reduced pressure at 45 ± 5 ° C. 150 ml of heptane were added and the mixture was rotary evaporated under reduced pressure at 40 ± 5 ° C until all solvent was removed and then for another 30 minutes. 62.0 g of an almost white solid were obtained. The solid was suspended in 120 ml of MeOH at 20 ± 5 ° C, and the suspension was heated under reflux for 10 minutes; no total dissolution was observed. The system was allowed to cool spontaneously to 20 ± 5 ° C and then with an ice bath to 0 ± 5 ° C, keeping it stirred at this temperature for 1 hour. The mixture was filtered on a Büchner funnel washing with 40 ml of MeOH previously cooled to 0 ± 5 ° C. The solid was dried under vacuum in an oven at 45 ± 5 ° C for 16 hours, obtaining 19.7 g of white solid (intermediate (II)).
    [0166] Intermediate analysis (II):
    [0167] 1H-NMR, CDCls: 8.07 (2H, dd, J = 1.5-8.6 Hz, aromatic H); 7.59-7.53 (1H, m, H aromatic); 7.46 (2H, t, J = 7.8 Hz, aromatic H); 5.29 (1H, m, H-3); 2.54 (1H, t, J = 9Hz, H-17); 2.20-0.80 (22H, m); 2.12 (3H, s, H-21); 0.85 (3H, s, CH3); 0.62 (3H, s, CH3);
    [0168] Mass: 423 (M ++ 1).
    [0170] EXAMPLE 3
    [0171] This example refers to stage 3) of the process of the invention, in the case of X = S and R = ethylene,
    [0173] In a reaction flask with nitrogen, 17 g of the intermediate (II) obtained in the previous example and subsequently 85 ml of glacial acetic acid were charged: no complete dissolution was observed. 3.7 ml of 1,2-ethanithiol were added. On the reaction mixture, 3.7 ml of the boron trifluoride-ethyl ether complex (BF3Et2O) were dropped for approximately 10 minutes, without exceeding 25 ° C. The system was kept under stirring at 30 ± 5 ° C for a total of 26 h adding in portions another 3.8 ml of ethanithiol and checking the progress of the reaction by TLC (constant point of intermediate (II)). The TLC check was carried out under the following conditions:
    [0174] - start: in THF;
    [0175] - sample: NaOH 10% toluene;
    [0176] - eluent: heptane / isopropyl acetate 8: 2; sheet: silica gel;
    [0177] - detector: UV / phosphomolybdic cerium.
    [0178] Upon completion of the reaction, the mixture was cooled to 20 ° C. A 10% by weight NaOH solution cooled to 0 ° C was prepared separately by diluting 226 g of a 30% by weight NaOH solution with 452 g of water. The reaction mixture was poured onto the cold soda solution without exceeding 10 ° C (the formation of a precipitate was observed). The reaction flask was washed with water (150 ml), which was added to the basic mixture containing the product. The suspension thus obtained was stirred for 1 h at a temperature <20 ° C. The solid was filtered on a Büchner funnel and washed with water (500 ml) until a neutral pH was reached. The solid on the filter was dissolved with dichloromethane (400 ml), washed with 1.5% sodium hypochlorite solution and then with water. The solvent was removed by evaporation under reduced pressure at 45 ° C, obtaining 22.6 g of yellow solid (intermediate (III) crude)). 20 g of this intermediate was charged to a flask with nitrogen. 60 ml of MEK was added and the mixture was heated under reflux (complete dissolution was not observed). The system was allowed to cool spontaneously to 25 ° C and then cooled to 0 ° C for 1 hour. The mixture was filtered on a Büchner funnel and the solid was washed with cold MEK. The solid was dried at 45 ° C under reduced pressure for 2 hours, obtaining 10.3 g of white solid (intermediate (III)).
    [0179] Intermediate analysis (III):
    [0181] 1H-NMR CDCH: 8.07 (2H, dd, J = 1,4-8 Hz, aromatic H); 7.56 (1H, dt, J = 1.4-7.3, aromatic H); 7.46 (2H, t, J = 7.5 Hz, aromatic H); 5.30-5.28 (1H, m, H-3); 3.40-3.13 (4H, m, SCH2CH2S); 2.12-0.89 (23H, m); 1.87 (3H, s, H-21); 0.84 (3H, s, CH3); 0.81 (3H, s, CH3);
    [0183] 13 C-NMR, CDCh: 165.92 (C = O); 132.70 (aromatic CH); 131.14 (C aromatic); 129.53 (2 aromatic CHs); 128.32 (2 aromatic CHs); 71.41 (C, SCS); 70.70 (CH, C-3); 60.76 (CH); 56.41 (CH); 54.14 (CH); 44.27 (C); 41.41 (CH2); 40.39 (CH); 40.06 (CH2); 37.29 (CH2); 35.86 (C); 35.61 (CH3, C-21); 35.10 (CH); 33.17 (CH2); 32.97 (CH2); 31.74 (CH2); 28.32 (CH2); 26.98 (CH2); 26.29 (CH2); 23.94 (CH2); 20.73 (CH2); 13.36 (CH3); 11.41 (CH3);
    [0184] Mass: 498 (M +).
    [0186] EXAMPLE 4
    [0187] This example refers to step 4) of the process of the invention, in the case of X = S and R = ethylene, -CH2-CH2-.
    [0191] 10.1 g of the intermediate (III) obtained in the previous example was charged into a flask with a nitrogen flow. 250 ml of methanol were added; complete dissolution was not observed. 20.3 g of NaOH were added and the mixture was heated under reflux for 25 hours while keeping it under stirring. A TLC check was carried out, observing the completion of the reaction. The TLC check was carried out under the following conditions:
    [0192] - start: in dichloromethane;
    [0193] - reaction: in dichloromethane;
    [0194] - eluent: heptane / isopropyl acetate 8: 2; sheet: silica gel;
    [0195] - detector: UV / phosphomolybdic cerium.
    [0196] The reaction mixture was cooled to 25 ° C and 300 ml of water was added. Methanol was distilled off under reduced pressure with a rotary evaporator. The formation of a precipitate was observed, 350 ml of dichloromethane were added and the system was kept stirred for 10 minutes at 35 ° C, observing the complete dissolution of the solid. The phases were separated and the aqueous phase was re-extracted with 100 ml of dichloromethane at 35 ° C. The organic phases were pooled and washed with water (3 times x 300 ml) until a neutral pH was reached. The solvent was removed by evaporation under reduced pressure, obtaining 8.3 g of white solid (intermediate (IV)).
    [0197] Intermediate analysis (IV):
    [0199] 1 H-NMR, CDCh: 4.04 (1H, m, H-3); 3.4-3.1 (4H, m, SCH2CH2S); 2.11-0.86 (23H, m); 1.86 (3H, s, H-21); 0.80 (3H, s, CH3); 0.78 (3H, s, CH3);
    [0201] 13 C-NMR, CDCL: 71.43 (C, SCS); 66.58 (CH, C-3); 60.70 (CH); 56.43 (CH); 54.11 (CH); 44.25 (C); 41.39 (SCH2); 40.08 (CH2); 39.07 (CH); 37.29 (SCH2); 36.04 (C); 35.84 (CH2); 35.58 (CH3, C-21); 35.12 (CH); 32.12 (CH2); 31.81 (CH2); 28.98 (CH2); 28.48 (CH2); 26.97 (CH2); 23.93 (CH2); 20.66 (CH2); 13.35 (CH3); 11.18 (CH3);
    [0202] Mass: 394 (M +).
    [0204] EXAMPLE 5
    [0205] This example refers to step 5) of the process of the invention starting from a thioketal.
    [0209] 8 g of the intermediate (IV) obtained in the previous example were charged into a flask with nitrogen. Dichloromethane (56 ml) and methanol (88 ml) were added; complete dissolution was not observed. The system was cooled to -20 ° C and NaHCO 3 (15.3 g) was added. I2 (15.5 g) was added and the system was kept stirring at -20 ° C for 4 h, adding NaHCO 3 (4.95 g) and I2 (5.15 g) in portions, and checking the progress of reaction by TLC (complete reaction). The TLC check was carried out under the following conditions:
    [0210] - start: in THF;
    [0211] - reaction: in aqueous solution of Na2S2Ü 3, extracted with dichloromethane, the organic phase was seeded;
    [0212] - eluent: heptane / isopropyl acetate 1: 1; sheet: silica gel;
    [0213] - detector: UV / phosphomolybdic cerium.
    [0214] The reaction was neutralized by dripping a solution of Na 2 S 2 O 3 '5H 2 O (45.3 g) in water (90 ml) onto the reaction mixture keeping the temperature below -15 ° C (reaction was observed exothermic, but no water freezing problems were observed). The system was brought to 20 ° C and the suspension was filtered over a dicalite panel, washing the solid on the filter with dichloromethane preheated to 35 ° C. The phases were separated, the aqueous phase was extracted with dichloromethane; the organic phases were combined and washed with water.
    [0215] The solvent was removed by evaporation under reduced pressure with the rotary evaporator, obtaining 6.2 g of yellow powder (crude brexanolone), which was subsequently checked on HPLC; the crude brexanolone HPLC chromatogram thus obtained shows that the epimer content is not detectable.
    [0216] 4.5 g of crude brexanolone were purified with a chromatographic column (120 g of silica gel) eluting first with dichloromethane and then with acetone, obtaining 4.1 g of product that is crystallized with dichloromethane / methyl-t-butyl ether, obtaining 3.9 g of pure brexanolone. Figure 4 shows the thermogram obtained with the product with the DSC technique (sample of 1,158 mg; test conditions indicated above); For clarity of representation, only the portion of the thermogram above 120 ° C is displayed. The figure indicates that the sample melts at between 174 and 176 ° C, which is the melting range for the pure product indicated in the article by RH Purdy et al. previously mentioned.
    [0217] Brexanolone Analysis:
    [0219] 1H NMR, CDCl3: 4.05 (1H, m, H-3); 2.53 (1H, t, J = 9Hz, H-17); 2.20-2.10 (1H, m); 2.11 (3H, s, H-21); 2.00 (1H, dt, J = 3.2-11.9 Hz); 1.85-0.75 (20H, m); 0.78 (3H, s, CH3); 0.60 (3H, s, CH3);
    [0220] Mass: 318 (M +).
    [0222] EXAMPLE 6
    [0223] This example concerns the epimerization of brexanolone in a basic environment.
    [0227] 50 mg of brexanolone obtained after the preparation of Example 5 were dissolved in 1.25 ml of methanol and refluxed for 16 h with 38 mg of NaOH. The mixture of The reaction was cooled, the methanol was evaporated under reduced pressure, the solid was taken up with water and dichloromethane, the phases were separated and the organic phase was washed until a neutral pH was reached. The dichloromethane was evaporated, obtaining a crude product that was purified by column chromatography (heptane / isopropyl acetate 6: 4), obtaining 22 mg of product. By NMR analysis, the 17a epimer content was determined as a function of the signal ratio of the proton at position 17.
    [0228] Figure 1 shows the expansion from 0 to 4.3 ppm of the NMR spectrum; the signals from the proton at position 17, based on which the amount of brexanolone and epimer was calculated, are 2.53 and 2.79 ppm. The epimer content was 19%.
    [0229] Epimerization was analyzed under similar conditions also in intermediate (I), obtaining comparable results in terms of epimer formation.
    [0230] H-NMR.CDCl.g: 4.05 (1H, m, H-3); 4.03 (1H, m, isomer 17a of H-3); 2.79 (dd, J = 2.7 8.2 Hz, H-17 isomer 17a); 2.53 (1H, t, J = 9Hz, H-17); 2,120 (s, 17a isomer of H-21); 2.115 (3H, s, H-21); 0.904 (s, isomer 17a of CH3); 0.781 (3H, s, CH3); 0.764 (s, CH3 isomer 17a); 0.603 (3H, s, CH3).
    [0232] EXAMPLE 7
    [0233] This example concerns the epimerization of brexanolone in an acidic environment. 50 mg of brexanolone obtained after the preparation of Example 5 was dissolved in 1.2 ml of THF to which 0.5 ml of 2M HCl was added, heating the mixture under reflux for 16 h. The reaction mixture was cooled, THF was evaporated in vacuo, the solid was taken up with water and dichloromethane, the phases were separated and the organic phase was washed until a neutral pH was reached. Dichloromethane was evaporated under reduced pressure, obtaining 42 mg of white solid.
    [0234] Figure 2 shows the expansion from 2.5 to 4.3 ppm of the NMR spectrum; the signals relating to brexanolone and the epimer are the same as those indicated in Example 6 with reference to FIG. 1. The ratio of the signals shows that the product had an epimer 17a content of 18%.
    [0236] EXAMPLE 8
    [0237] This example refers to stage 3) of the process of the invention, in the case of X = O and R = ethylene, -CH2-CH2-.
    [0239] 10 g of intermediate (II), obtained as described in Example 2, were dissolved in 150 ml of toluene with nitrogen flow. Ethylene glycol (26.5 ml), triethylorthoformate (25.2 ml) and p-toluenesulfonic acid (0.36 g) were added. The mixture was brought to reflux temperature (105-110 ° C) and kept stirring for 2 hours. A TLC check was carried out, confirming the completion of the reaction (disappearance of the starting compound); the TLC check was carried out under the following conditions:
    [0240] - start: in CH2Ch;
    [0241] - sample: reaction mixture in NaHCO 3 + toluene;
    [0242] - eluent: toluene / isopropyl acetate 97/3; foil: HPTLC
    [0243] - detector: UV / phosphomolybdic cerium.
    [0244] The reaction mixture was cooled to 10 ° C and poured into a 4% NaHCO 3 aqueous solution, previously cooled to T <5 ° C. The system was kept under stirring for 10 minutes, the phases were separated and the aqueous phase was re-extracted with 20 ml of toluene. The organic phases were combined and washed with water. The solvent was removed in vacuo, obtaining 13.4 g of crude intermediate (III) (white solid).
    [0245] A 5.2 g portion of the crude intermediate (III) was suspended in 15.6 ml of ethyl acetate and heated under reflux for 5 minutes. The suspension was cooled by keeping it at 0 ° C for 1 hr, and then filtered on a Büchner funnel washing with ethyl acetate. The process was repeated two more times, obtaining, after drying with constant weight (T = 50 ° C and reduced P), 4.1 g of pure intermediate (III) (white solid).
    [0246] Intermediate analysis (III):
    [0248] 1H-NMR CDCH: 8.07 (2H, dd, J = 1.4 to 8.5 Hz, aromatic H); 7.56 (1H, t, J = 7.3 H aromatic); 7.46 (2H, t, J = 7.5 Hz, aromatic H); 5.29-5.27 (1H, m, H-3); 4.01-3.85 (4H, m, OCH2CH2O); 2.04 (1H, dt, J = 3-11.9, H-17); 1.88-0.76 (22H, m); 1.302 (3H, s, H-21); 0.847 (3H, s, CH3); 0.768 (3H, s, CH3);
    [0250] 13 C-NMR, CDCh: 165.92 (C = O); 132.69 (aromatic CH); 131.15 (C aromatic); 129.53 (2 aromatic CHs); 128.32 (2 aromatic CHs); 111.97 (C, OCO); 70.72 (CH, C-3); 65.25 (OCH2); 63.17 (OCH2); 58.37 (CH); 56.39 (CH); 54.33 (CH); 42.02 (C); 40.44 (CH); 39.63 (CH2); 35.90 (C); 34.95 (CH); 33.19 (CH2) 33.00 (CH); 31.83 (CH2); 28.37 (CH2); 26.30 (CH2); 24.59 (CH3, C-21); 23.69 (CH2); 22.88 (CH2); 20.62 (CH2); 13.05 (CH3); 11.43 (CH3); Mass: 466 (M +).
    [0251] Analysis of isomer 17a of intermediate (III):
    [0253] 1 H-NMR: the 17a isomer has the following characteristic signals: 1.323 (3H, s, H-21); 0.837 (3H, s, CH3); 0.813 (3H, s, CH3).
    [0255] EXAMPLE 9
    [0256] This example refers to step 4) of the process of the invention, in the case of X = O and R = ethylene, -CH2-CH2-.
    [0260] 3.2 g of ketal benzoate, obtained as described in Example 8, were suspended in 80 ml of methanol, and then 6.8 g of NaOH were added. The reaction mixture was refluxed (65 ° C) for 16 h without observing any dissolution. A TLC check was carried out, verifying the completion of the reaction (disappearance of the starting product). The TLC check was carried out under the following conditions:
    [0261] - start: in CH2Ch;
    [0262] - sample: reaction mixture in THF;
    [0263] - eluent: toluene / isopropyl acetate 6/4; foil: TLC;
    [0264] - detector: UV / phosphomolybdic cerium.
    [0265] The reaction mixture was cooled to 25 ° C and 100 ml of water was added. The solvent was removed in vacuo at 45 ° C. The reaction mixture was extracted with DCM, then the organic phase was washed with water until a neutral pH was reached. The organic fraction was concentrated under reduced pressure, obtaining 2.6 g of intermediate (IV) as a white solid, of suitable quality for the continuation of the synthesis.
    [0266] Intermediate analysis (IV):
    [0268] 1 H-NMR, CDCls: 4.04 (1H, m, H-3); 4.04-3.83 (4H, m, OCH2CH2O); 2.015 (1H, dt, J = 3.2-11.9, H-17); 1.82-0.72 (23H, m); 1.293 (3H, s, H-21); 0.780 (3H, s, CH3); 0.751 (3H, s, CH3);
    [0270] 13 C-NMR, CDCh: 112.00 (C, OCO); 66.59 (CH, C-3); 65.23 (OCH2); 63.19 (OCH2); 58.31 (CH); 56.41 (CH); 54.31 (CH); 42.01 (C); 39.66 (CH2); 39.14 (CH); 36.10 (C); 35.87 (CH2); 34.97 (CH); 32.16 (CH2); 31.91 (CH2); 29.00 (CH2); 28.55 (CH2); 24.58 (CH3, C-21); 23.70 (CH2); 22.88 (CH2); 20.56 (CH2); 13.07 (CH3); 11.20 (CH3);
    [0271] Mass: 362 (M +).
    [0272] Analysis of isomer 17a of intermediate (IV):
    [0273] The 17a isomer has the following characteristic signals: 1,300 (3H, s, H-21); 0.792 (3H, s, CH3); 0.772 (3H, s, CH3).
    [0275] EXAMPLE 10
    [0276] This example refers to step 5) of the process of the invention starting from a ketal.
    [0280] 1.5 g of intermediate (IV) obtained after the process of Example 9 were stirred with 22.5 ml of anhydrous acetone and 105 mg of iodine. The mixture was brought to reflux (T = 58 ° C) obtaining, after 10 minutes of stirring at reflux, a clear solution. Completion of the reaction was confirmed with a TLC check. The TLC check was carried out under the following conditions:
    [0281] - start: in CH2Ch;
    [0282] - sample: reaction mixture diluted in acetone;
    [0283] - eluent: toluene / isopropyl acetate 6/4; foil: TLC;
    [0284] - detector: UV / phosphomolybdic cerium.
    [0285] Acetone was removed by distilling at reduced P and the residue was taken up with DCM (50 ml). The organic phase was washed first with a 5% aqueous sodium thiosulfate solution and then with water. The organic phase was then dry-concentrated to reduced P, obtaining 1.25 g of crude brexanolone.
    [0286] HPLC analysis, carried out on the crude brexanolone thus obtained, without any further purification, showed that the product contains an amount of the 17a isomer equivalent to 0.29%.
    [0287] 1.0 g of the sample obtained above was completely dissolved under reflux with 7 ml of isopropyl acetate, cooled to 0 ° C for 1 h, and finally filtered. The solid was dried at 50 ° C obtaining 0.9 g of pure brexanolone which, analyzed by HPLC, contains an amount of the 17a isomer equivalent to 0.10%.
    [0288] EXAMPLE 11 (Comparative)
    [0289] This example relates to the deprotection of a ketal to form brexanolone under conditions other than those of the invention.
    [0290] 0.1 g of the intermediate (IV) obtained as described in Example 9 was charged into a flask with nitrogen. DCM (1.1 ml) and methanol (0.7 ml) were added; complete dissolution was not observed. NaHCO3 (0.096 g) was added. Then I2 (0.112 g) was added and the mixture was kept stirred at 25 ° C for 20 h, then the mixture was progressively brought to 40 ° C for 6 h checking the progress of the reaction by TLC. The mixture was cooled to 0 ° C, and the reaction was neutralized by dripping a solution of sodium thiosulfate (0.25 g) in water (5 ml) onto the reaction mixture while keeping the temperature below 10 ° C. The mixture was brought to 25 ° C and the suspension was filtered on a dicalite panel, washing the solid on the filter with DCM at 35 ° C. The phases were separated, the aqueous phase was extracted with DCM. The organic phases were combined and washed with water. The solvent was removed by evaporation under reduced pressure with a rotary evaporator, obtaining 0.09 g of brexanolone whose epimer content is equal to 0.7%.
    [0292] EXAMPLE 12
    [0293] 40 mg of intermediate (IV) obtained after the process of Example 9 were stirred with 0.8 ml of CH2Cl2 and 0.081 ml of acetone. 0.7 mg of iodine was added. The mixture was stirred at 25 ° C and after 10 minutes it was confirmed by a TLC check that the reaction was complete (disappearance of the starting compound). The mixture was kept under stirring for another 18 hours at 25 ° C to analyze the stability of the product. After TLC checking, the formation of degradation products was not observed. The organic phase was washed first with a 5% aqueous sodium thiosulfate solution and then with water. The organic phase was dry concentrated to reduced P, obtaining 36 mg of brexanolone.
    [0294] HPLC analysis, performed on the brexanolone thus obtained, without any further purification, showed that the product contains an amount of the epimer 17a equivalent to 0.04%.
    [0296] EXAMPLE 13
    [0297] 40 mg of intermediate (IV) obtained after the process of Example 9 were stirred with 0.8 ml of CH2Cl2 and 0.081 ml of acetone. 2.8 mg of iodine were added. The mixture was stirred at 0 ° C and, after 15 minutes, it was confirmed by a TLC check that the reaction was complete (disappearance of the starting compound). The organic phase was washed first with a 5% aqueous sodium thiosulfate solution and then with water. The organic phase was dry concentrated to reduced P, obtaining 35 mg of brexanolone.
    [0298] HPLC analysis, carried out on the brexanolone thus obtained, without any further purification, showed that the product contains an amount of the epimer 17a equivalent to 0.09%.
    权利要求:
    Claims (16)
    [1]
    1. Method for the preparation of 3a-hydroxy-5a-pregnan-20-one (brexanolone) that consists of the deprotection of a cyclic ketal or a cyclic thioketal of this with the general formula (IV) with the use of iodine in a organic solvent, according to the reaction scheme:

    [2]
    2. Method according to claim 1 where, when X = O, the ketal with formula (IV) is hydrolyzed in a neutral environment, using iodine in anhydrous acetone or in a mixture without water of dichloromethane and acetone, operating at a temperature of between -5 ° C and the reflux temperature of the reaction mixture.
    [3]
    3. Method according to claim 2, wherein iodine is used in an amount of between 1 and 10% by weight with respect to the amount of ketal (IV).
    [4]
    4. Method according to claim 1, wherein, when X = S, the thioketal with formula (IV) is hydrolyzed with iodine in an organic solvent at a temperature between -30 and 20 ° C in the presence of a solid inorganic base.
    [5]
    5. Method according to claim 4, wherein said organic solvent is selected from dichloromethane, methanol or a mixture of these, and the solid inorganic base is selected from sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, lithium bicarbonate, and potassium bicarbonate, and the reaction is carried out at -25 to -5 ° C for a time period of 1 to 18 hours.
    [6]
    6. Process for the preparation of 3a-hydroxy-5a-pregnan-20-one (brexanolone) comprising the following steps:
    1) Catalytic hydrogenation of the double bond at position 5,6 of pregnenolone to obtain the corresponding saturated steroid with formula (I), with the hydrogen atom at position 5 of the steroidal skeleton in a spatial arrangement at:

    [7]
    7. Process according to claim 6, wherein step 1) is carried out using palladium supported on carbon (Pd / C) at 5% as hydrogenation catalyst in an amount of 5% with respect to the weight of pregnenolone, with a hydrogen pressure of between 2 and 5 bar, in tetrahydrofuran (THF) as solvent, at a temperature of between 35 and 45 ° C and for a period of between 3 and 7 hours.
    [8]
    8. Process according to any of claims 6 and 7, wherein step 2) is carried out by reacting compound (I) with benzoic acid in tetrahydrofuran (THF) as solvent and allowing it to react for a period of between 14 and 20 hours with triphenylphosphine and diisopropyl azodicarboxylate (DIAD) at a temperature between 15 and 25 ° C.
    [9]
    9. Process according to any of claims 6 to 8, wherein in step 3) the carbonyl at position 20 of compound (II) is protected as a ketal, by reacting by refluxing a mixture of compound (II) with toluene, a glycol selected from ethylene glycol, propylene glycol and 2,2-dimethylpropylene glycol, triethyl orthoformate and p-toluenesulfonic acid.
    [10]
    10. Process according to any of claims 6 to 8, wherein in step 3) the carbonyl at position 20 of compound (II) is protected as thioketal, reacting the compound (II) with ethanedithiol or propanedithiol in a solvent selected from acetic acid, dichloromethane (CH2Cl2), ethyl ether, acetonitrile, tetrahydrofuran (THF) and 1,2-dichloroethane, in the presence of a catalyst selected from etherate of trifluoride of boron (BF 3 -Et 2 Ü), zinc iodide (Znh), titanium tetrachloride (TiCU), tin dichloride (SnCh), magnesium iodide (Mgh), lithium perchlorate (LiClÜ 4 ), aluminum trifluoromethanesulfonate ( aluminum triflate, Al (OTf) 3 ), lithium tetrafluoroborate (UBF4) and cobalt dichloride (CoCh), at a temperature in the range between 15 and 45 ° C and for a period of between 8 and 36 hours.
    [11]
    Process according to any one of claims 6 to 10, wherein step 4) is carried out by refluxing compound (III) in methanol for a period of between 20 and 28 hours in the presence of sodium hydroxide.
    [12]
    12. Compound with the general formula (III), where X = O or X = S and R is a radical selected from among ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-) and 2,2 -Dimethylpropylene (-CH2-C (CH3) 2-CH2-):

    [13]
    13. Compound according to claim 12, where R is ethylene and X is sulfur:

    [14]
    14. Compound according to claim 12, where R is ethylene and X is oxygen:

    [15]
    15. Compound with the general formula (IV), where X = O or X = S and R is a radical selected from among ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-) and 2,2 -dimethylpropylene (-CH2-C (CH3) 2-CH2-), provided that when X = O, R is other than ethylene:

    [16]
    16. Compound according to claim 15, where R is ethylene and X is sulfur:
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    同族专利:
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    GB2593352A|2021-09-22|
    DE112019005261T5|2021-07-01|
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    AR116790A1|2021-06-16|
    GB202106894D0|2021-06-30|
    IT201800009683A1|2020-04-22|
    AU2019369041A1|2021-06-10|
    WO2020083839A1|2020-04-30|
    CN112888701A|2021-06-01|
    FR3087439A1|2020-04-24|
    US20210388020A1|2021-12-16|
    BR112021007009A2|2021-07-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB442319A|1933-12-23|1936-02-06|Schering Kahlbaum Ag|Process for the production of pregnanolones|
    FR2720747B1|1994-06-02|1996-07-12|Roussel Uclaf|New process for the preparation of a 16-beta-methyl steroid and new intermediates.|
    US5795985A|1996-03-05|1998-08-18|Ciba Specialty Chemicals Corporation|Phenyl alkyl ketone substituted by cyclic amine and a process for the preparation thereof|
    FR2973031B1|2011-03-23|2013-11-29|Univ Strasbourg|DERIVATIVES OF ALLOPREGNANOLONE AND EPIALLOPREGNANOLONE AND USES THEREOF FOR TREATING A NEUROPATHOLOGICAL CONDITION|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT102018000009683A|IT201800009683A1|2018-10-22|2018-10-22|PROCESS FOR THE PREPARATION OF 3A-HYDROXY-5A-PREGNAN-20-ONE |
    PCT/EP2019/078580|WO2020083839A1|2018-10-22|2019-10-21|Process for the preparation of 3alpha-hydroxy-5αlpha-pregnan-20-one |
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