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    • 专利摘要:
    The present invention relates to a new process for the synthesis of 17ß-hydroxy- des-A-androst-9,10-en-5-one, the compound of the following formula (1), which can be used as an intermediate in the synthesis of retroprogesterones.
    公开号:ES2670477A2
    申请号:ES201890028
    申请日:2016-10-28
    公开日:2018-05-30
    发明作者:Roberto Lenna；Roberto DI BRISCO
    申请人:Industriale Chimica SRL；
    IPC主号:
    专利说明:

    Procedure for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5-one
    5 Field of the invention
    The present invention relates to the field of processes for the synthesis of active ingredients for pharmaceutical use and, in particular, to a process for the industrial scale preparation of 17β-hydroxy-des-A-androst-9,10-en -5-one, a
    10 intermediate useful for the synthesis of retroprogesterones.
    Previous Technique
    Retroprogesterones are a class of steroids with hormonal activity used in the therapy and treatment of dysfunctions of the female genital tract and in pregnancy. The precursor compound of the family is retroprogesterone, a compound that has a 4-ring steroid structure of the type shown in the following figure:
    in which the spatial orientation of the hydrogen atoms in positions 8 and 9 is beta while that of the methyl in position 10 is alpha; this structure differs from that of progesterone, which has the so-called "natural" configuration shown in the following figure, in the opposite orientation of the hydrogen atom in position 9 (alpha) and that of methyl in position 10 (beta) .
    Useful retrotroprogesterones in the therapeutic field are, for example, didrogesterone and trengestone, which has the following structural formulas:
    5 Didrogesterone has been shown to be effective in the treatment of various conditions associated with a progesterone deficiency, including infertility due to an insufficiency of the corpus luteum, abortion (threatened abortion or recurrent abortion), menstrual disorders, premenstrual syndrome and endometriosis, while Trengestone has been used to treat cycle-related disorders
    10 menstrual An intermediate useful in the synthesis of retroprogesterones is the compound with the following formula (1), whose chemical name is 17β-hydroxy-des-A-androst-9,10-en-5one:
    described in J. Org. Chem, 32, 3008 (1967); The use of the compound as a precursor to the synthesis of retroprogesterones was reported in J. Org. Chem, 33 (9), 1968.
    The compound (1) can be synthesized according to the formulas given in J. Org. Chem, 32, 3008 (1967) starting from a bicyclic intermediate (2) with a series of chemical reactions that lead to a racemic mixture of the compound (1):
    5 Such a racemic mixture cannot be used as such for the preparation of retroprogesterones since it is a mixture of the two optical antipodes.
    In the aforementioned article, the authors also reported that compound (1) had previously been obtained in the "optically active" form by chemical degradation of testosterone acetate. This method only has scientific value, since
    10 which allows obtaining the optically pure product for the first time but cannot be applied to industrial steroid production: in fact, testosterone acetate (4-ring structure) must be synthesized and the first ring (3-ring structure) You must degrade and rebuild later. The preparation of the compound of formula (1) in its optically active form is
    15 describes in Tetrahedron vol. 24, p. 2039-2046, 1968; in accordance with the described method, starting from the racemic intermediate (3) and resolving the optical antipodes throughout the synthesis with brucine salts, the compound (1) is obtained in optically pure form:
    Although this synthesis can be applied for the preparation of retroprogesterones, it has the disadvantage that part of a racemic reagent; The resolution of a racemate, even in the ideal case of a quantitative separation yield, leads to a maximum of 50% yield.
    In J MED CHEM 1985, 28, 1796-1803, scheme (1), the compounds of general structure (5) are prepared in order to study them and verify their potential pharmacological activity. According to the teachings of the article, these compounds can be prepared starting from the precursor (4):
    In turn, the compounds of general formula (4) can be prepared, such as
    It is described in US 3413314, by total synthesis according to the
    scheme:
    This route of synthesis, however, also presents the problem that one of
    The steps (US 3413314, column 2, step d) consist of the separation of the optical antipodes by salification with a chiral amine, with the consequent loss of at least half of the starting material.
    The object of the present invention is to provide an improved synthesis route for the preparation of 17β-hydroxy-des-A-androst-9,10-en-5-one, in particular simpler than that of the processes of the prior art and that can be applied
    industrially.
    Summary of the invention
    This and other objects are achieved by the present invention which, in a first aspect thereof, refers to a process for the synthesis of the 17β-hydroxy-des-A-androst-9,10-en-5-one, compound (1), which comprises the following stages:
    a) reaction of the compound (4aR, 6aS, 9aS, 9bS) -decahydro-6a-methylcyclopenta [f] [1] benzopyran-3,7-dione, compound (II), with ethylmagnesium bromide or ethylmagnesium chloride to give the mixture of isomers (4S, 5R, 7aS) -5-hydroxy-7a-methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one and (4S, 5S, 7aS) -5-hydroxy-7a- methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one, mixture of intermediates (III):
    b) oxidation of the mixture of intermediates (III) to give the (4S, 7aS) -7a-methyl-4- (3oxopentyl) hexahydro-1H-inden-1,5 (4H) -dione, intermediate (IV):
    c) cyclization of intermediate (IV) to give the des-A-androst-9,10-en-5,17-dione, intermediate (V):
    d) reduction of intermediate (V) to give 17β-hydroxy-des-A-androst-9,10-en-5-one 15 (1):
    A further object of the present invention is the mixture of intermediates (III), reaction product of step a) of the process.
    5 Brief description of the figures
    - Fig. 1 shows the 1H NMR spectrum of the mixture of intermediates (III); - Fig. 2 shows the XRD diffraction pattern of the compound (1) obtained according to the invention. 10 Detailed description of the invention
    In the present description and in the claims, in the case of a discrepancy between the name of a compound and the structural formula given to it, the latter must be considered correct.
    The starting material of the process of the invention is the compound (II), the (4aR, 6aS, 9aS, 9bS) -decahydro-6a-methyl-cyclo-penta [f] [1] benzopyran-3,7-dione] , also known as sitolactone, name that will be adopted hereinafter in the description; the structure of the compound, complete with all the information
    20 relevant stereochemistry, shown below:
    Sitolactone is a commercially available product obtained by microbiological degradation of phytosterols that are a residual product from soybean processing.
    The reaction of step a) is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, or methyltrahydrofuran, either pure or mixed together, which operates in an inert atmosphere at a temperature between -50 ° C and 0 ° C Preferably, it is carried out in tetrahydrofuran at a temperature between
    5 -45 ° C and -20 ° C, in a mild stream of nitrogen.
    The sitolactone is reacted with an organometallic reagent (Grignard reagent) in which the organic part is the ethyl radical, selected from ethylmagnesium chloride and ethylmagnesium bromide in solution. Preferably, ethylmagnesium bromide in tetrahydrofuran is used, adding this solution in portions to the mixture
    10 reaction. The amount of reagent to be added and the reaction time are defined by the reaction controls that show the progress thereof, for example controls by TLC or HPLC; The mixture of intermediates (III) is suitable for the subsequent reaction when the residue of sitolactone is ≤ 5% of the starting amount. The
    The molar ratio between the organometallic reagent and the sitolactone is between 1 and 2, preferably between 1.05 and 1.25. The reaction time between the organometallic reagent and the sitolactone is generally between 30 minutes and 2 hours, preferably between 40 and 90 minutes.
    The mixture of intermediates (III) is formed by the two isomers (4S, 5R, 7aS) -5hydroxy-7a-methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one and (4S, 5S, 7aS) -5-hydroxy-7amethyl-4- (3-oxopentyl) octahydro-1H-inden-1-one, which carry the OH group at position 5 of the molecule in the two possible orientations, as shown below. in the present document:
    This mixture can be used as such without the need to separate the two components. Surprisingly, under the reaction conditions, the carbonyl at position 7 of the sitolactone reacts only to a small degree with the organometallic reagent 30, making this protection not necessary.
    The reaction of step b) is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, acetone, methyl isobutyl ketone, toluene, pure heptane or mixture of isomers, cyclohexane, dimethylacetamide, dimethylformamide, chloroform, chloride of methylene, dimethyl sulfoxide and water, very pure
    5 or mixed together.
    As the oxidant, trichloroisocyanuric acid (TCCA) can be used in the presence of an organic base such as pyridine or triethylamine; chromium (VI) compounds in the presence of bases such as pyridine, 3,5-dimethylpyrazole or triethylamine, or acids such as sulfuric acid, perchloric acid, acetic acid or hydrochloric acid; the radical
    2,2,6,6-tetramethylpiperidin-1-oxyl, commonly known as TEMPO, or a derivative thereof such as the 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical, the 4methoxy radical -2,2,6,6-tetramethylpiperidin-1-oxyl and the radical 4- (benzoyloxy) -2,2,6,6-tetramethylpiperidin-1-oxyl in the presence of a basic aqueous solution and a co-oxidant such as oxygen or hypochlorite of sodium or calcium; hypochlorites like
    15 main oxidants such as sodium hypochlorite, calcium hypochlorite or tetrabutylammonium hypochlorite; gaseous oxygen or oxygen-nitrogen mixtures in the presence of copper (I) salts such as CuCl; KHSO5 potassium peroxonosulfate, marketed under the name of Oxone® (registered trademark of E.I. du Pont de Nemours and Company); gaseous chlorine dissolved in a halogenated solvent, such
    20 as chloroform or carbon tetrachloride; aluminum isopropylate in the presence of a carbonyl compound such as cyclohexanone, benzaldehyde, benzophenone or acetone; dimethylsulfoxide and an activator such as oxalyl chloride, benzoic anhydride, trifluoroacetic anhydride, P2O5 and the SO3-pyridine complex in the presence of a base such as triethylamine or diisopropylethylamine; hypervalent iodine compounds such as
    Iodobenzoic acid, also known with the acronym IBX, Dess-Martin periodio, also known with the acronym DMP, or IBX stabilized with benzoic acid and isophthalic acid, also known with the acronym SIBX.
    Preferably, it is carried out using trichloroisocyanuric acid (TCCA) as an oxidant in acetone at a temperature between 5 and 40 ° C in the presence of water 30 and pyridine.
    The oxidant is added in portions to the reaction solution; the amount of reagent and the reaction time are defined by the reaction controls that show the progress thereof. The quality of intermediate (IV) is adequate for the subsequent reaction when the residue of the mixture of intermediates (III) unreacted ≤
    35 5% of the starting amount.
    In the preferred case of using TCCA, the required moles of this reagent with respect to the moles of intermediate (III) to be oxidized are in the range between 0.5 and 5, preferably between 0.5 and 1.5; The reaction time, after the addition of the TCCA, is between 30 minutes and 3 hours, preferably between 45 minutes and 1.5 hours.
    The cyclization reaction of step c) can be carried out both on intermediate (IV), which can be obtained directly from the previous reaction, and on the isolated product.
    The reaction is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, toluene, cyclohexane, n-heptane,
    10 mixture of isomers of heptane, methanol, ethanol, isopropanol, acetic acid, acetonitrile, methylene chloride, water, either pure or mixed with each other, which operate in the presence of basic catalysts such as NaOCH3, KOCH3, KOH, NaOH, Na2CO3 , K2CO3 or NaNH2, or acid catalysts such as HClO4, H2SO4 or HCl.
    The reaction temperature is between 0 and 40 ° C, preferably between 10 and 30 ° C. The reaction is preferably carried out using KOH as a catalyst in alcoholic or hydroalcoholic solution, preferably methanol and water. Preferably, it is carried out directly on the organic solution of the
    Intermediate (IV) obtained in the previous stage, without isolation. Cycling requires a time of between 1 and 4 hours, preferably between 1.5 and 3 hours. The quality of intermediate (V) is suitable for the subsequent reaction when the unreacted intermediate (IV) residue is ≤ 5% of the starting amount.
    The reduction of step d) is carried out using sodium, lithium or potassium metal hydrides, such as sodium borohydride, potassium borohydride, or lithium aluminum hydride; sodium borohydride is preferred. The reaction temperature is between -10 and 40 ° C, preferably between 10 and 20 ° C.
    The reaction is carried out in a solvent selected from alcohols, in particular methanol, ethanol, isopropanol or cyclohexanol; or alcohols mixed with solvents such as ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, methylene chloride, toluene, cyclohexane, n-heptane, mixture of heptane isomers, dimethylformamide or dimethylacetamide. The preferred solvent is methanol.
    The hydride is added in portions to the reaction solution; the amount of
    reagent and reaction time are defined by the reaction controls that show the progress thereof. The moles of sodium borohydride used with respect to the moles of intermediate (IV) are in the range of between 0.3 and 1.5, preferably between 0.35 5 and 0.9; The reaction time is between 1 and 5 h, preferably between 2 and 3.5 h. The quality of the compound (1) is considered acceptable when the unreacted intermediate (V) residue is ≤ 5% of the starting amount. The invention will be described below by the following examples, provided for illustrative, non-limiting purposes.
    The reagents used in the examples are normally commercially available and are used without the need for purification to increase their purity.
    EXPERIMENTAL METHODS AND CONDITIONS
    15 NMR: JEOL 400 YH NMR spectrometer (400 MHz); Aldrich® ColorSpec® NMR tubes; JEOL Delta v5.1.1 software;
    20 Spectra recorded in Sigma-Aldrich deuterated chloroform: Chloroform-d, 99.8% atomic D, containing 0.1% (v / v) tetramethylsilane (TMS) as internal standard; and chloroform-d, "100%", D 99.96% atomic, containing 0.03% (v / v) of TMS.
    MS
    25 HP SLC-API 2000 LC / MS / MS AB-mass system; Samples injected directly and chemically ionized (CI) with formic acid.
    DSC
    Perkin Elmer instrument mod. Diamond;
    30 Perkin Elmer standard aluminum caps and caps, code 02190041; Scanning speed: 10 ° C / min; Temperature range: from 20 ° C to 200 ° C.
    GO
    Thermo Scientific Nicolet 6700 spectrometer; 35 FT-IR spectra registered in KBr (solid) and diffuse reflectance iTR
    smart (ATR); Potassium bromide Sigma-Aldrich Code 221864 (for IR analysis). HPLC
    Agilent model 1200 chromatographic system5 1260 DAD VL MODEL UV Detector and 1290 Infinity ELSD Laser Detector
    FTA
    MERCK: TLC 60 F254 silica gel Aluminum plates 20 x 20 cm, code 1.0554.0001. HPTLC
    10 MERCK: HPTLC 60 F254 silica gel with concentration zone 10 x 2.5 cm, code 1,13727,0001. TLC-RP
    MERCK: Silica gel TLC 60 RP-18 F254S, code 1.15685.0001. TLC detectors
    15 Cerium phosphomolibdate acid solution;
    Preparation: 25 g of phosphomolibic acid hydrate (Aldrich P7390), 10 g of cerium (IV) sulfate (Aldrich 31606) and 600 ml of water are stirred until dissolved with 60 ml of 95-98% sulfuric acid (Aldrich 258105); this is brought to a final volume of 1000 ml with water; the plate is then impregnated with the solution,
    20 and subsequently heated until it is dyed blue. Light UV at 254 and 366 nm.
    XRD
    Bruker D2Phaser;X-ray source, copper tube with λ = 1.54184 [Å] powered with 30 kV and
    25 mA; Scanning speed: 0.02 ° 2θ / second Scanning interval from 5 ° to 35 ° 2θ; Test time 1478 stages in 1704 seconds; Rotation 10 ° [1 ° / min];
    30 SSD160 detector (1D mode) with PSD (position sensitive detector) opening
    of 4.6 °.The following abbreviations are used in the examples:EtMgBr: ethylmagnesium bromide;MTBE: methyl tert-butyl ether;
    TCCA: trichloroisocyanuric acid;
    THF: tetrahydrofuran;Rf: delay factor in thin layer chromatography. EXAMPLE 1
    This example refers to step a) of the process of the invention. 5 300 g of sitolactone are placed under stirring with 3.6 l of THF in an inert atmosphere. The solution is cooled to a temperature between -40 and -30 ° C (the sitolactone partially precipitates again) with stirring. 1.35 L of EtMgBr in THF (1 M solution) is added for 90 minutes and with stirring, maintaining the reaction temperature between -40 <T <-30 ° C (exotherm during addition). After the addition, stirring is continued for 20 minutes keeping the reaction temperature between -40 <T <-30 ° C. Progress is checked by HPTLC (eluent 100% acetate
    15 isopropyl) still detecting approximately 20% of sitolactone and the formation of a spot at an Rf greater than that of sitolactone and some intensity spots barely detectable.
    An additional 300 ml of EtMgBr in THF (1 M solution) is added, keeping the reaction temperature between -40 <T <-30 ° C. 20 After the addition, stirring is continued for 20 minutes keeping the reaction temperature between -40 <T <-30 ° C.
    Progress is checked by HPTLC (eluent 100% isopropyl acetate) by detecting a residual amount of sitolactone less than 5% with respect to the starting amount, increasing the intensity of the stain to a higher Rf and the
    25 persistence of some intensity spots barely detectable.
    The reaction solution is then poured slowly and with stirring into 3.4 L of 4% aqueous solution of ammonium chloride previously cooled to 0 <T <5 ° C. The phases are separated.
    The aqueous phase is first extracted with MTBE (3 x 1.5 L), and then
    30 combined organic phases are washed with 1.5 L of aqueous NaCl solution and made anhydrous with sodium sulfate. It is filtered and the filter is washed with 1 L of MTBE and concentrated to dryness at reduced P, thereby obtaining 350.7 g of a yellow residue that can be used as such in the next step.
    1 g of the residue is purified for analytical purposes by flash chromatography on silica gel, eluting with a 1: 1 mixture of isopropyl acetate
    heptane isomers, and dried under reduced pressure to constant weight (colorless solid of low melting point). NMR (CDCI3): it is confirmed that the sample is a 54:46 mixture of the two isomers in the hydroxyl of mixture (III) (broad singlet at 4,166 ppm and wide singlet
    5 to 3,736 ppm). The full 1 H NMR spectrum is shown in Figure 1. Mass spectrum (CI): [M ++ 1] = 253; [M ++ 1] - H2O = 235; [M ++ 1] - 2H2O = 217;
    [M ++ 1] - 3H2O = 199.FT-IR (ATR): 1735 cm-1 and 1702 cm-1.
    EXAMPLE 2 This example refers to steps b) and c) of the process of the invention. 63.42 g of the mixture of intermediates (III), obtained as it has been dissolved
    described in the previous example, by stirring in 286 ml of acetone in an inert atmosphere. 15 120 ml of pyridine and 2.95 ml of water are added. The temperature is adjusted to 20 ° C. In another vessel, a solution with 29.24 g of TCCA with 95.3 ml of acetone is prepared and slowly poured over the intermediate mixture solution
    (III) while maintaining the temperature at <25 ° C. At the end of the addition, stir for 1 h (solid formation already during the dropwise addition) and mild exotherm; the temperature is maintained at ≤ 25 ° C.
    Progress is checked by HPTLC (eluent MTBE / heptane 8: 2) by detecting the complete disappearance of the starting reagent, the formation of a main spot at an Rf lower than that of the starting mixture (III) and some stains
    25 intensity barely detectable.
    The mixture is cooled to T = 0 ° C and filtered, washing the solid on the filter with 60 ml of acetone. The solution is kept at 0 ° C for 1 h, the precipitated solid is filtered again and washed with 60 ml of acetone.
    The organic phase is poured dropwise, while maintaining the T ≤ 20 ° C, in an aqueous solution prepared with 97.3 g of Na2CO3, 117 g of Na2SO3 and 672 ml of water. The resulting suspension is filtered and the solid is washed on the filter with 100 ml of
    acetone and the presence of two phases is observed. The phases are separated, the organic phase is concentrated to a small volume and set aside. The aqueous phase is extracted with 482 ml of toluene and the organic phase is added.
    then to the organic phase set aside above (organic solution C).
    In another vessel, a solution of 103.5 g of KOH, 92 ml of water and 434 ml of methanol is prepared and slowly poured slowly into the organic solution C obtained previously. The mixture is stirred keeping the T <25 ° C for 1 h and 40
    5 minutes.
    Progress is checked by TLC-RP (eluent acetone / water 7: 3) by detecting the complete disappearance of intermediate (IV), and the formation of a visible UV spot (main product) and some spots of barely detectable intensity.
    The phases are separated and the aqueous phase is extracted with 380 ml of toluene. The organic phases are combined and washed first with 160 ml of a 10% aqueous solution of NaCl and then concentrated under reduced pressure to give 51.34 g of an oily product that, over time, crystallizes spontaneously at temperature. ambient.
    The residue is recovered by adding a mixture of 100 ml of heptane and 5 ml of MTBE, stirring for 30 minutes and evaporating the solvents at reduced P to dryness. The solid residue is recovered again by adding a mixture of 100 ml of heptane and 5 ml of MTBE, stirring for 30 minutes at room temperature.
    The solid is then filtered in a Büchner funnel and washed with 20 ml of a heptane / MTBE 4: 1 mixture previously cooled to 0 ° C. The product is dried at 40 ° C at reduced P to give 39.4 g of a yellow solid (intermediate V). 3.28 g of orange oil are obtained from the mother liquor after removal of the solvent. The oil was checked by TLC showing the
    25 presence of product and other stains. Analysis: 1H NMR (CDCl3): 1.03 ppm, singlet, 3H; 1.41-1.54 ppm, multiplet, 2H; 1,541.74 ppm, multiplet, 2H; 1.80-1.82 ppm, 3H, triplet, J = 1.83 Hz; 1.92-1.97 ppm, doublet doublets, 1H; 2.01-2.1 ppm, multiplet, 1H; 2.1-2.4 ppm, multiplet, 4H; 2.4
    2.6 2.6 ppm, multiplet, 3H; 2.86-2.91 ppm, 1H, doublet doublets. 13C NMR (CDCl3): 219.6 ppm, 198.65 ppm; 156.92 ppm; 130.89 ppm; 50.56 ppm; 47.08 ppm; 38.32 ppm; 36.89 ppm; 35.85 ppm; 30.61 ppm; 26.43 ppm; 21.98 ppm; 12.99 ppm; 11.21 ppm. Mass spectrum (CI): [M ++ 1] = 233.
    35 FT-IR (KBr): 1735 cm-1; 1652 cm -1; 1604 cm-1.
    The DRX spectrum shows the presence of a crystalline phase (main peaks at values of 11,178 °, 11,435 °, 14,501 °, 16,332 °, 18,671 °, 19,579 °, 21,553 °, 28,738 ° of angle 2θ) and an amorphous product.
    DSC: the transition begins at 121 ° C and is maximum at 124 ° C.
    5 EXAMPLE 3 This example refers to step b) of the process of the invention. The procedure of the previous example is repeated until the organic solution is obtained
    C which, in this case evaporates (liquid residue). A sample is purified for analytical purposes by flash chromatography.
    10 on silica gel, eluting with a 1: 1 mixture of isopropyl acetate-heptane isomers, and dried under reduced pressure to constant weight (a yellow solid, intermediate IV is obtained).
    1H NMR (CDCl3): 1.04-1.08 ppm, 3H, triplet doublet, J = 7.8 Hz; 1.17 ppm, 3H, singlet; 1.6-1.86 ppm, 5H, multiplet; 1.96-2.12 ppm, 2H, multiplet; 2.1815 2.28 ppm, 1H, multiplet; 2.38-2.72 ppm, 8H, multiplet.
    13C NMR (CDCl3): 218.1 ppm, 211.54 ppm; 211,102 ppm; 49.59 ppm; 49.14 ppm; 47.59 ppm; 39.84 ppm; 37.54 ppm; 36.19 ppm; 35.99 ppm; 30.51 ppm; 22.36 ppm; 20.28 ppm; 13.62 ppm; 7.89 ppm.
    Mass spectrum (CI): [M ++ 1] = 251. 20 FT-IR (ATR): 1730 cm-1
    EXAMPLE 4
    This example refers to step b) of the process of the invention. 500 mg of intermediate (III) are dissolved at 20 ° C in 38 ml of acetone 1 ml of Jones reagent is added with stirring for 50 min keeping
    25 the reaction temperature between 15 and 25 ° C. The Jones reagent was prepared in advance by dissolving 27 g of chromic anhydride (CrVIO3) in 100 ml of water by adding 23 ml of 98% sulfuric acid. At the end of the addition, the mixture is stirred for 10 min, then the end of the reaction is checked by TLC (eluent MTBE / n-heptane 8: 2). 30 20 ml of MTBE and 40 ml of a 5% aqueous NaHCO3 solution are added to
    the reaction mixture. The solid is filtered and washed with 10 ml of MTBE. The phases are separated and the organic phase is washed with 20 ml of a solution.
    5% aqueous NaHCO3 and with 20 ml of a saturated aqueous NaCl solution. The organic phase is concentrated at reduced P to give 370 mg of intermediate (IV).
    EXAMPLE 5
    This example refers to step b) of the process of the invention.100 mg of intermediate (III) is dissolved at 20 ° C in 5 ml of dichloromethane.205 mg of Dess-Martin periodine is added portionwise with stirring
    5 for 2.5 h maintaining the reaction temperature between 15 and 25 ° C. The end of the reaction (intermediate residue (III) less than 5% with respect to the
    starting amount) is checked by TLC (eluent MTBE / n-heptane 8: 2). The reaction suspension is filtered and the solid is washed with 5 ml of dichloromethane. The organic phase is concentrated at reduced P and chromatographed on gel.
    10 silica (eluent MTBE / n-heptane 8: 2) to give, after solvent removal, 60 mg of intermediate (IV).
    EXAMPLE 6
    This example refers to step d) of the process of the invention. 5 g of intermediate (V), obtained as described in Example 2, is dissolved with stirring in 50 ml of methanol at room temperature. The solution is cooled to T <15 ° C and, without ever exceeding this temperature, 204 mg of NaBH4 is added with stirring in 4 portions for 20 minutes. The mixture is stirred for 30 minutes at 10 <T <15 ° C and then the progress is checked by HPTLC (eluent heptane / isopropyl acetate 1: 1)
    20 detecting the formation of a main spot at an Rf less than that of intermediate (V), the presence of intermediate (V) and some spots with barely detectable intensity.
    The reaction is maintained with stirring at 10 <T <15 ° C, adding 50, 20 and 10 mg of NaBH4, respectively, at 30 minute intervals.
    The progress of the reaction is checked after each addition by HPTLC as described above. The reaction, checked 30 minutes after the last addition, is considered completed.
    It is cooled to 0 <T <5 ° C and, while stirring, 100 ml of water are added. Stir at 0 <T <5 ° C for 1 h and the precipitated solid is filtered on a 30 Büchner funnel. After drying at reduced P to constant weight, 4.2 g of compound are obtained
    (1) in the form of a yellow solid, which contains less than 5% of unreacted intermediate (V).
    EXAMPLE 7
    This example refers to step d) of the process of the invention.
    294 g of intermediate (V), obtained as described in example 2, is suspended in 2.5 ml of methanol and stirred for 30 min at room temperature (incomplete solution).
    The solution is cooled to T <15 ° C and, never exceeding this temperature, it
    5 adds a total of 18 g of NaBH4 in 10 portions for 160 minutes, checking the progress of the reaction by HPTLC (eluent heptane / isopropyl acetate 1: 1).
    At the end of the addition, it is cooled to 0 <T <5 ° C and, while stirring, 5 l of water are added. 10 Stir at 0 <T <5 ° C for 1 h and the precipitated solid is filtered on a Büchner funnel by washing it with water (600 ml).
    After drying at 45 ° C and at reduced P to constant weight, 241 g of compound (1) (yellow solid) are obtained, containing less than 5% of unreacted intermediate (V).
    A sample of the product thus obtained is purified for analytical purposes by flash chromatography on silica gel, eluting with the 60:40 mixture of heptane isomers: isopropyl acetate.
    The product was recovered by evaporation of the elution solvent and then suspended in MTBE at 0 <T <5 ° C for 30 minutes. After filtering and drying (T = 45 ° C, P <1 atm) at constant weight, a white solid is obtained.
    1H NMR (CDCl3): 0.91 ppm, 3H, singlet; 1.11-1.72 ppm, 7H, multiplet; 1,791.80 ppm, 3H, triplet J = 1.6 Hz, J = 2 Hz; 1.9-2.05 ppm, 2H, multiplet; 2.08-2.2 ppm, 1H, multiplet; 2.2-2.37 ppm, 3H, multiplet; 2.45-2.54 ppm, 1H, triplet doublet;
    2.79-2.84 ppm, 1H, doublet doublets; 3.68-3.72 ppm, 1H, triplet, J = 8.8 Hz. 13C NMR (CDCl3): 199.16 ppm, 158.59 ppm; 130.10 ppm; 81.28 ppm; 50.48 ppm; 42.44 ppm; 39 ppm; 37.1 ppm; 35.7 ppm; 30.5 ppm; 27.04 ppm; 27 ppm; 23.5 ppm; 11.1 ppm; 10.3 ppm Mass spectrum (CI): [M ++ 1] = 235.
    30 FT-IR (KBr): 3451 cm-1, 1647 cm-1, 1604 cm-1 The DRX spectrum shows the presence of a crystalline phase with characteristic peaks at values of 11,482 °, 16,958 °, 17,899 °, 18,483 ° , 19,401 ° and 24,583 ° of angle 2θ. The full diffraction pattern is shown in Figure 2.
    35 DSC: the transition begins at 167.5 ° C, maximum at 169.5 ° C.

    [α] 25 D = -37.5 ° (1% CH3Cl).
    权利要求:
    Claims (7)
    [1]
    1. Process for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5one, compound (1), characterized in that it comprises the following steps:
    5 a) reaction of compound (4aR, 6aS, 9aS, 9bS) -decahydro-6a-methylcyclopenta [f] [1] benzopyran-3,7-dione, compound (II), with ethylmagnesium bromide or ethylmagnesium chloride to give the mixture of isomers (4S, 5R, 7aS) -5-hydroxy-7a-methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one and (4S, 5S, 7aS) -5-hydroxy-7a -methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one,
    10 mixture of intermediates (III):
    b) oxidation of the mixture of intermediates (III) to give the (4S, 7aS) -7a-methyl-4 (3-oxopentyl) hexahydro-1H-inden-1,5 (4H) -dione, intermediate (IV):
    c) cyclization of intermediate (IV) to give the des-A-androst-9,10-en-5,17-dione, intermediate (V):
    d) reduction of intermediate (V) to give 17β-hydroxy-des-A-androst-9,10-en5-one, compound (1):
    Method for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5one, according to claim 1, characterized in that step a) is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran or mixtures thereof, in an inert atmosphere and at a temperature between -50 ° C and 0 ° C.
    [3]
    3. Process for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, according to any one of claims 1 or 2, characterized in that in step a) the molar relationship between the ethylmagnesium bromide or ethylmagnesium chloride and the compound (II) is between 1 and 2.
    [4]
    4. Process for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5one, according to claim 3, characterized in that said ratio is between 1.05 and 1.25.
    Method for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, according to any one of the preceding claims, characterized in that step b) is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, acetone, methyl isobutyl ketone, toluene, pure heptane or mixture of isomers, cyclohexane, dimethylacetamide,
    Dimethylformamide, chloroform, methylene chloride, dimethylsulfoxide, water and mixtures thereof.
    [6]
    Method for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, according to any one of the preceding claims, characterized
    because in stage b) the oxidizer is used: trichloroisocyanuric acid (TCCA) in the presence of an organic base; chromium (VI) compounds in the presence of bases or acids; the radical 2,2,6,6-tetramethylpiperidin-1-oxyl or a derivative thereof in the presence of a basic aqueous solution and a co-oxidant selected from oxygen 5 and sodium hypochlorite or calcium hypochlorite; sodium hypochlorite, calcium hypochlorite
    or tetrabutylammonium hypochlorite; gaseous oxygen or oxygen-nitrogen mixtures in the presence of copper (I) salts; KHSO5 potassium peroximonosulfate; gaseous chlorine dissolved in a halogenated solvent; aluminum isopropylate in the presence of a carbonyl compound; dimethylsulfoxide and an activator selected from chloride
    Oxalyl, benzoic anhydride, trifluoroacetic anhydride, P2O5 and the SO3-pyridine complex in the presence of a base; a hypervalent iodine compound selected from Dess-Martin's periodonanane, and iodobenoic acid possibly stabilized with benzoic acid and isophthalic acid.
    Method for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, according to any one of the preceding claims, characterized in that step b) is carried out using 0.5 to 5 moles of trichloroisocyanuric acid (TCCA) in acetone per mole of mixture of intermediates (III) at a temperature between 5 and 40 ° C.
    [8]
    8. Process for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, according to any one of the preceding claims, characterized in that step c) is carried out in a solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, toluene, cyclohexane, n-heptane,
    25 isomer mixture of heptane, methanol, ethanol, isopropanol, acetic acid, acetonitrile, methylene chloride, water and mixtures thereof, in the presence of an acidic or basic catalyst, at a temperature between 0 and 40 ° C.
    [9]
    9. Procedure for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5
    30a, according to any one of the preceding claims, characterized in that step d) is carried out with a metal hydride at a temperature between -10 and 40 ° C in a solvent selected from alcohols or a mixture of a alcohol and a second solvent selected from ethyl ether, isopropyl ether, tetrahydrofuran, methyltrahydrofuran, methylene chloride, toluene, cyclohexane, n
    Heptane, mixture of heptane, dimethylformamide and dimethylacetamide isomers.
    [10]
    10. Process for the preparation of 17β-hydroxy-des-a-androst-9,10-en-5ona, characterized in that it comprises the Mixture (III) of the isomers (4S, 5R, 7aS) -5hydroxy-7a- methyl-4- (3-oxopentyl) octahydro-1H-inden-1-one and (4S, 5S, 7aS) -5-hydroxy-7amethyl-4- (3-oxopentyl) octahydro-1H-inden-1-one:
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    US10189765B2|2019-01-29|
    RU2018119620A|2019-12-02|
    DE112016004993T5|2018-07-12|
    AR106516A1|2018-01-24|
    GB2561089B|2020-05-20|
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    RU2018119620A3|2020-01-30|
    GB2561089A|2018-10-03|
    ITUB20155260A1|2017-04-30|
    RU2715720C2|2020-03-03|
    US20180339956A1|2018-11-29|
    ES2670477R1|2018-06-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE657261A|1962-03-06|
    SU780435A1|1979-02-26|1985-02-28|Институт биоорганической химии АН БССР|3,4-dihydro-10oxy-1-phenanthrenones as semi-product in synthesis of steroids or their analogues and method of obtaining same|
    TW200611909A|2004-08-04|2006-04-16|Akzo Nobel Nv|Process for the preparation 2-substituted-derivatives of estrone and estradiol|IT201700004904A1|2017-01-18|2018-07-18|Ind Chimica Srl|PROCESS FOR THE PREPARATION OF 9β, 10α-PROGESTERONE |
    CN112409434B|2020-11-27|2021-10-26|厦门欧瑞捷生物科技有限公司|Synthesis method of dehydroprogesterone|
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