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    • 专利摘要:
    The present invention refers to a new process for the synthesis of (9β, 10α) -pregn-4-ene-3,20-dione, commonly known as retroprogesterone, of formula (1) reported below:
    公开号:CH714701B1
    申请号:CH00919/19
    申请日:2018-01-18
    公开日:2021-09-30
    发明作者:Lenna Roberto；Rigamonti Davide；Delfrate Claudio
    申请人:Ind Chimica Srl；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [0001] The present invention relates to the sector of processes for the synthesis of active ingredients for pharmaceutical use, and in particular to a process for the preparation on an industrial scale of 9β, 10α-progesterone, also known as retroprogesterone.
    STATE OF ART
    [0002] Retroprogesterones are a class of steroids endowed with hormonal activity which are used in the treatment and treatment of dysfunctions of the female reproductive system and of pregnancy.
    [0003] The parent compound of the family is retroprogesterone, a compound having the 4-ring steroid structure shown in the following figure: in which the spatial orientation of the hydrogen atoms in positions 8 and 9 is β while that of methyl in position 10 is α ; this structure differs from that of progesterone, having the so-called „natural“ configuration of the following figure, due to the opposite orientation of the hydrogen atom in position 9 (α) and of the methyl atom in position 10 (β).
    [0004] The four rings that make up the basic steroid skeleton are indicated in the sector with the letters A to D, as shown in the following figure:
    [0005] Retroprogesterones useful in the therapeutic field are for example dydrogesterone and trengestone, having the following structural formulas:
    Dydrogesterone has been shown to be effective in treating various conditions associated with a progesterone deficiency, including infertility due to luteal insufficiency, spontaneous (threatened or recurrent) miscarriages, menstrual disorders, premenstrual syndrome and endometriosis, while trengestone has been used for the treatment of problems related to the menstrual cycle.
    [0007] The compound of formula (1) reported below, whose chemical name is 17β-hydroxy-des-A-androst-9,10-en-5-one, is an intermediate useful in the synthesis of retroprogesterones:
    This compound is described in various publications including J. Org. Chem, 32, 3008 (1967) and PCT patent application WO 2017/072719 A1 filed on 28/10/2016.
    [0009] Compound (I) is obtained by hydrogenation of (1): the use of which for the synthesis of retroprogesterone is described in Journal of Organic Chemistry, Vol 33, N ° 9, September 1968, pp. 3548-51.
    The key reaction of this process is the creation of the A ring of the steroid skeleton by ringing the intermediate (V) with methylvinylketone (MVK) to give retroprogesterone (VI), as shown in the following diagram:
    [0011] This process scheme therefore follows the sequence:BCD → BCD-C4 → ABCDindicating that the steroid of interest (ABCD) is obtained by reaction between an intermediate comprising the rings B, C and D and a four-carbon reagent.
    [0012] In the synthesis route of the aforementioned article, starting from 2.64 g of compound (V), after reaction 1.16 g of intermediate (V) and 380 mg of ringed product (VI) are recovered by means of chromatography it is then oxidized with Cr (VI) in acetone obtaining, after purifications, 124 mg of pure retroprogesterone.
    [0013] The reaction yield is very low, lower than 4% by mol. It is therefore evident that this synthetic procedure has only academic value but no practical applicability in a large-scale production that has the synthesis of an API as its final goal.
    [0014] The same sequence of reactions (cyclization and oxidation) described in the same article to obtain retroprogesterone presents similar criticalities to those above for retroprogesterone.
    [0015] The indication that can be obtained from reading the aforementioned article is of a process useful for preparing a sample for analytical purposes, but of no industrial applicability.
    [0016] The object of the present invention is to provide a synthesis route for the preparation of Retroprogesterone (VI) which is simpler than the processes of the known art and applicable industrially.
    SUMMARY OF THE INVENTION
    [0017] This and other purposes are achieved with the present invention, which relates to a process for the synthesis of Retroprogesterone, compound (VI), comprising the following steps:a) reaction of compound (7), (3S, 3aS, 5aR, 6R, 9aR, 9bS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyldodecahydro-7H-cyclopenta [a] naphthalen-7 -one, with acrylonitrile to give compound (6), 3 - ((3S, 3aS, 5aR, 6S, 9aS, 9biS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyl-7- oxododecahydro-1 H-cyclopenta [a] naphthalen-6-yl) propanonitrile:
    b) reaction of compound (6) with a strong base to give compound (5), acid 3 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3 - ((S) -1-hydroxyethyl) - 3a, 6-dimethyl-7-oxododecahydro-1H-cyclopenta [a] naphthalen-6-yl) propanoic:
    c) reaction of compound (5) with acetic anhydride to give compound (4), (S) -1 - ((4aS, 4bR, 6aS, 7S, 9aS, 9bS) -4a, 6a-dimethyl-2-oxo- 2,3,4,4a, 4b, 5,6,6a, 7,8,9,9a, 9b, 10-tetradecahydroindene [5,4-f] cromen-7-yl) ethyl acetate:
    d) reaction of compound (4) with an organometallic reagent C1a to give compound (3), (S) -1 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3a, 6-dimethyl-7-bone -6- (3-oxobutyl) dodecahydro-1H-cyclopenta [a] naphthalen-3-yl) ethyl acetate: wherein the term "organometallic reactive Ci" is understood to mean an organometallic compound in which the organic fraction comprises only one carbon atom;e) reaction of compound (3) with a strong base to give compound (2), (8S, 9R, 10S, 13S, 145.17S) -17 - ((S) -1-hydroxyethyl) -10.13- dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta [a] phenanthren-3-one:
    f) oxidation of the intermediate (2) to obtain Retroprogesterone:
    [0018] The process of building the steroid skeleton according to the present invention can be summarized in the sequence:BCD → BCD-C3 → BCD-C4 → ABCDdifferent from that of the known art, as reported above.
    Further objects of the present invention are the intermediates (6), (5), (4) and (3), the structural formula of which is shown in the reaction sequence illustrated above.
    DETAILED DESCRIPTION OF THE INVENTION
    [0020] In the present description and in the claims, in the event of a discrepancy between the name of a compound and the structural formula reported for it, the latter must be considered correct.
    [0021] The starting material of the process of the invention is compound (7), obtainable by hydrogenation at atmospheric pressure and room temperature of the following unsaturated precursor: using rhodium on alumina as a catalyst in an acid alcoholic solution.
    [0022] The reaction of step a) is carried out in a solvent selected from linear or branched C1-C10 aliphatic alcohols, pure or mixed together, in the presence of an inorganic base and acrylonitrile. The preferred solvent 2-methyl-2-butanol (also referred to in the art as tert-amyl alcohol).
    [0023] The reaction temperature is between 25 ° C and the boiling point of the reaction mixture, preferably between 45 and 75 ° C.
    [0024] The base used is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide; the preferred base is sodium hydroxide.
    [0025] The reaction time is between 4 and 24 hours, preferably 16 hours.
    [0026] The quantity in moles of acrylonitrile used is comprised between 1 and 5 moles, preferably between 2 and 4 moles, per mol of starting compound (7). The acrylonitrile can be added in portions during the reaction or, preferably, in a single addition.
    [0027] The reaction of step b) is carried out in a basic aqueous solution in the presence of a reactive which favors the mixing of the phases (phase transfer reagent).
    [0028] The reaction temperature is between 50 ° C and the boiling temperature of the reaction solution; preferably boiling is carried out.
    [0029] The base used is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide; the preferred base is sodium hydroxide.
    A reagent useful for promoting the mixing of the phases (phase transfer reagent) is a quaternary ammonium salt, preferably benzyltrimethylammonium hydroxide (also known as Triton B).
    [0031] The reaction of step c) is carried out until the disappearance of the intermediate (5) in acetic anhydride at a temperature between 100 ° C and the boiling temperature of the reaction mixture.
    [0032] Acetic anhydride (Ac2O) has the double function of solvent and reactive.
    [0033] The reaction time is generally between 60 and 120 minutes, typically about 90 minutes.
    [0034] A base selected from sodium and potassium acetate (preferably sodium acetate) is then added to the reaction mixture, and refluxed for a time ranging from 60 to 120 minutes, preferably 90 minutes.
    [0035] The reaction of step d) is carried out at a temperature between -50 ° C and -20 ° C, preferably between -35 ° C and -25 ° C in an inert solvent under the reaction conditions.
    [0036] The solvent is selected from ethyl ether, isopropyl ether, dibutyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tertbutyl ether and toluene, pure or mixed together. Preferably, terahydrofuran is used, pure or mixed with a second solvent.
    [0037] Methylmagnesium chloride, methylmagnesium bromide or methylmagnesium iodide dissolved in organic solvent inert under the reaction conditions can be used as organometallic reagent C1; preferably methylmagnesium bromide in tetrahydrofuran is used.
    [0038] Between 1.5 and 5 moles, preferably between 3 and 4 moles, of organometallic C1 reactive are used per mole of intermediate (4).
    [0039] The reaction of step e) is carried out in a solvent selected from methanol, ethanol, isopropanol, tert-butanol, n-butanol, cyclohexanol, ethylene glycol, dioxane, tetrahydrofuran, methyltherohydrofuran, pure or mixed together, and which can be used anhydrous or in the presence of water.
    [0040] The hydroxides of lithium, sodium or potassium, or the carbonates of lithium, sodium, potassium or cesium can be used as the strong base.
    [0041] The preferred solvent / base combination for carrying out the reaction of step e) is methanol and sodium hydroxide.
    [0042] The reaction temperature is between 40 ° C and the boiling temperature of the reaction mixture, and preferably between 60 ° C and said boiling temperature.
    [0043] The reaction of step f) is carried out in water or a solvent devoid of oxidizable functional groups, such as: esters (for example ethyl acetate or isopropyl acetate); ketones (e.g. acetone, methyl isobutyl ketone or cyclohexanone); aliphatic or aromatic hydrocarbons (e.g. heptane, toluene or cyclohexane); and halogenated solvents (such as methylene chloride or chloroform); these solvents can be used pure or mixed together.
    [0044] Chromium (VI) compounds can be used as oxidants; dimethyl sulfoxide in the presence of an activator, such as the pyridine-SO3 complex or N-chlorosuccinimide (NCS; in the latter case the reaction is also known as Swern oxidation); alkoxides of aluminum or magnesium under the conditions known as Oppenauer oxidation; periodinans such as triacetoxyperiodinan, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one known as Dess-Martin periodinan, o-iodoxybenzoic acid (known as IBX) and o- stabilized iodoxybenzoic (known as SIBX).
    [0045] The retroprogesterone thus obtained can be used as an intermediate for the preparation of other steroids having pharmacological activity, such as for example Dydrogesterone, following the indications reported in the literature, for example in 79 (1960) Recueil 771-783.
    [0046] The invention will be further illustrated by the following examples, which are given for illustrative purposes only and which are not to be considered as limiting thereof.
    [0047] The reagents used in the examples are commonly commercially available and are used without the need for further purifications.
    EXPERIMENTAL METHODS AND CONDITIONS
    NMR:
    [0048] JEOL 400 YH NMR spectrometer (400 MHz); Aldrich NMR tubes <®> ColorSpec <®>; JEOL Delta software v5.1.1; Spectra recorded in Sigma-Aldrich deuterated chloroform: Chloroform-d, D 99.8 atom%, containing 0.1% (v / v) tetramethylsilane (TMS) as internal standard; and Chloroform-d, „100%“, D 99.96 atom%, containing 0.03% (v / v) TMS.
    MS:
    [0049] HPLC-bulk system: AB Sciex API 2000 LC / MS / MS; Samples directly injected and chemically ionized (CI) with formic acid.
    DSC:
    [0050] Perkin Elmer instrument mod. Diamond; Perkin Elmer Standard aluminum capsules and lids, cod. 02190041; Scanning speed: 10 ° C / min; Temperature range: 20 ° C to 200 ° C.
    IR:
    [0051] Thermo Scientific Nicolet 6700 spectrometer; FT-IR spectra recorded in KBr (solid) and in smart-iTR-diffuse reflectance (ATR); Potassium Bromide Sigma-Aldrich Code 221864 (for IR analysis).
    HPLC:
    [0052] Chromatographic system: Agilent model 1200 UV Detector MODEL 1260 DAD VL and laser detector 1290 Infinity ELSD
    TLC:
    [0053] MERCK: TLC silica gel 60 F254 Aluminum sheets 20 × 20 cm, cod. 1.0554.0001.
    HPTLC:
    [0054] MERCK: HPTLC silica gel 60 with concentration zone 10 × 2.5 cm, cod. 1.13727.0001.
    TLC-RP:
    [0055] MERCK: TLC silica gel 60 RP-18 S, cod. 1.15685.0001.
    TLC detectors:
    [0056] Acid solution of cerium phosphomolybdate; Preparation: 25 g of phosphomolybdic acid hydrate (Aldrich P7390), 10 g cerium (IV) sulfate hydrate (Aldrich 31606) and 600 mL of water are stirred to dissolve with 60 mL of 95-98% sulfuric acid (Aldrich 258105); it is brought to a final volume of 1000 mL with water; the plate is immersed in the solution, then heated to a blue color. UV lamp at 254 and 366 nm.
    XRD:
    [0057] Bruker D2Phaser; X-ray source: copper tube with λ = 1.54184 [Å] powered at 30 kV and 10 mA; Scan speed 0.02 ° 2θ / second Scan interval 5 ° to 35 ° 2θ; Analysis time: 1478 steps in 1704 seconds; Rotation 10 ° [1 ° / min]; Detector SSD160 (1D mode) with a 4.6 ° opening of the PSD (Position Sensitive Detector).
    EXAMPLE 1
    [0058] This example relates to step a) of the process of the invention.
    [0059] 180 mg of sodium hydroxide and 180 mL of tert-amyl alcohol are loaded into a 1 L flask, under a nitrogen flow. It is left under stirring at 50 ° C for 60 minutes.
    A solution of intermediate (7) (12 g dissolved in 120 mL of tert-amyl alcohol) is added. It is left under stirring for 60 minutes at 50 ° C.
    [0061] A solution of acrylonitrile (7.24 g in 108 mL of tert-amyl alcohol) is added by dropping over 30 minutes. It is left under stirring at 50 ° C for 16 hours.
    [0062] After TLC control (eluent: isopropyl acetate / heptane 7/3; plate: silica gel; detector: UV / cerium phosphomolybdate - Sample: reaction mixture poured into acidic water and extracted with isopropyl acetate) the formation of intermediate (6) with respect to the unreacted intermediate (7).
    [0063] The mixture is brought to 20-25 ° C and 200 mL of water containing 0.25 mL of acetic acid are added, stirring for 10 minutes. The pH is verified to be between 5 and 6.
    [0064] The solvent is removed in a rotavapor at 45 ° C under vacuum and the aqueous phase is then extracted with isopropyl acetate (2 × 100 mL).
    [0065] The combined organic phases are first washed with water (100 mL), then the solvent is removed in the rotavapor at 45 ° C under vacuum, obtaining a brown oil (20.08 g) which is used as such in the subsequent reaction.
    A small portion of the brown oil is purified by silica gel chromatography (eluent: heptane / isopropyl acetate 50:50 → 40:60) for analytical purposes. After elimination of the solvent at constant weight, the residue obtained is analyzed.
    [0067] The results of the analytical tests performed are in agreement with the structure identified in the text as intermediate (6): M <+> = 317 = C20H31NO2:Ms (Cl): M <+> + 1 = 318; M <+> + 1 - H2O = 300; M <+> + 1 - 2H2O = 282; M <+> + 1 - H2O - CH3CHO = 256
    [0068] As regards the starting product (7) M <+> = 264 = C17H28O2 the analytical tests performed provide the following results in accordance with the structure:Ms (Cl): M <+> + 1 = 265; M <+> + 1 - H2O = 247; M <+> + 1 - 2H2O = 229
    EXAMPLE 2
    [0069] This example relates to step b) of the process of the invention.
    [0070] The intermediate (6) obtained from the previous reaction (19.9 g) is stirred with 200 mL of an aqueous 4 M sodium hydroxide solution and 5 mL of 40% Triton B in water, resulting in reflux.
    [0071] After 6 h the degree of progress of the reaction is checked with TLC (eluent: isopropyl acetate / heptane 7/3, with 0.1% acetic acid; plate: silica gel; detector: UV / cerium phosphomolybdate - Sample : reaction mixture in acidic water, extracted with MTBE): complete reaction.
    [0072] It is cooled to 20-25 ° C and extracted with 250 mL of MTBE (organic phase A).
    [0073] The organic phase A is washed with 100 mL of aqueous solution of NaOH 2 M.
    [0074] The basic aqueous phases are combined, cooled to 10-15 ° C and acidified to pH = 2 with 3 M HCl, maintaining the T <30 ° C.
    The acidic aqueous phase is extracted with 400 mL of MTBE (organic phase B).
    [0076] The organic phase B is washed with water and then with a saturated aqueous solution of NaCl.
    [0077] The solvent is removed in a rotavapor at 45 ° C under vacuum, obtaining 19.2 g of yellow oil (intermediate 5).
    [0078] The organic phase A is washed with water and then with a saturated aqueous solution of NaCl.
    [0079] After elimination of the solvent with the rotavapor, 2 g of yellow oil are obtained which are mainly composed of intermediate (6).
    A small portion of intermediate (5) is purified by silica gel chromatography (80:20 ethyl acetate / heptane + 0.1% acetic acid) for analytical purposes. After elimination of the solvent at constant weight, the residue obtained is analyzed.
    [0081] The results of the analytical tests performed are in agreement with the structure identified in the text as intermediate (5): M <+> = 336 = C20H32O4:Ms (Cl): M <+> + 1 = 337; M <+> + 1 - H2O = 319; M <+> + 1 - 2H2O = 301; M <+> + 1 - H2O - CH3CHO = 275.
    EXAMPLE 3
    [0082] This example relates to step c) of the process of the invention.
    [0083] The intermediate (5) obtained as described in the previous example (18.9 g) is suspended in 80 mL of acetic anhydride, obtaining an opalescent solution; the solution is filtered on cotton by washing the filter with another 300 mL of acetic anhydride.
    [0084] The solution is brought to reflux for 90 minutes (T = 135 ° C), checking the progress of the reaction with TLC: the starting material has disappeared and the formation of two distinct products is highlighted (Sample: reaction mixture in water, extracted with MTBE; eluent: isopropyl acetate / heptane 7/3 with 0.1% acetic acid; plate: silica gel; detector: UV / cerium phosphomolybdate).
    [0085] 9.7 g of anhydrous sodium acetate are charged and refluxed for a further 90 '.
    [0086] It is cooled to about 40 ° C and the acetic anhydride is removed under reduced pressure.
    [0087] The residue is dissolved in 300 mL of MTBE, washed with 200 mL of saturated aqueous solution of NaHCO3 and the aqueous phase is extracted again with 200 mL of MTBE.
    The combined organic phases are washed with 200 mL of saturated aqueous solution of NaCl. The organic solvent is removed in a rotavapor under vacuum at 45 ° C, obtaining a brown oil (18.6 g) containing the intermediate (4).
    [0089] The brown oil is purified by medium pressure chromatography on silica gel (eluent heptane / ethyl acetate 85:15) obtaining, after drying at constant weight, 8.2 g of intermediate (4) as a white solid.
    [0090] The results of the analytical tests performed are in agreement with the structure identified in the text as intermediate (4): M <+> = 360 = C22H32O4:Ms (Cl): M <+> + 1 = 361; M <+> + 1 - CH3COOH = 301; M <+> + 1 - CH3COOH - H2O = 283.
    EXAMPLE 4
    [0091] This example relates to step d) of the process of the invention.
    [0092] 5.5 g of intermediate (4) obtained as described in the previous example and dissolved in THF (66 mL) are loaded into a flask.
    [0093] It is cooled to a temperature between -30 and -35 ° C and a 1 M solution of methylmagnesium bromide, CH3MgBr, prepared by diluting 18.4 mL of a commercial solution of methylmagnesium bromide at a concentration of 3 M with 36.8 mL of THF while maintaining the temperature below -25 ° C.
    [0094] At the end of the addition it is kept at T = -30 ± 5 ° C for 30 minutes.
    [0095] The progress of the reaction is checked with TLC (Sample: reaction mixture in aqueous solution of ammonium chloride, extracted with MTBE - Eluent: isopropyl acetate / heptane 7/3; plate: silica gel; detector: UV / cerium phosphomolybdate): complete reaction, intermediate (4) disappeared.
    [0096] It is poured onto an aqueous solution of 15% NH4Cl (200 mL), pre-cooled to 0-5 ° C, maintaining the T <10 ° C and stirring for 10 minutes.
    [0097] 200 mL of MTBE are added and the mixture is kept under stirring for 1 h at T = 25 ° C.
    The phases are separated and the aqueous phase is re-extracted with 100 mL of MTBE.
    The combined organic phases are washed with 250 mL of water. The organic phases are evaporated under vacuum at 45 ° C, obtaining 5.3 g of intermediate (3).
    [0100] A small portion of intermediate (3) is purified by silica gel chromatography (eluent heptane / ethyl acetate 70/30) for analytical purposes. After elimination of the solvent at constant weight, the residue obtained is analyzed.
    [0101] The results of the analytical tests performed are in agreement with the structure identified in the text as intermediate (3): M <+> = 376 = C23H36O4;Ms (Cl) M <+> + 1 = 377; M <+> + 1 - H2O = 359; M <+> + 1 - 2H2O = 341; M <+> + 1 - CH3COOH = 317; M <+> + 1 - CH3COOH - H2O = 299; M <+> + 1 - CH3COOH - 2H2O = 281.
    EXAMPLE 5
    [0102] This example relates to step e) of the process of the invention.
    [0103] A solution of intermediate (3) in methanol (5.2 g in 364 mL) is loaded into a flask, an aqueous solution of 10% NaOH (36.4 mL) is added and heated to reflux (T = 65 ° C) for 1 h.
    [0104] The progress of the reaction is checked with TLC: intermediate (3) disappeared. (Sample: reaction mixture diluted in methanol; Eluent: isopropyl acetate / heptane 7/3; plate: silica gel; detector: UV / cerium phosphomolybdate).
    [0105] The methanol is removed in a rotavapor at 45 ° C under vacuum and the residue is taken up with 320 mL of 10% aqueous NaOH solution. It is extracted with MTBE (320 mL + 150 mL). The combined organic phases are washed with a saturated aqueous solution of NaCl.
    [0106] The organic solvent is evaporated under vacuum at 45 ° C obtaining 3.9 g of a solid (intermediate 2).
    [0107] A small portion of intermediate (2) is purified by silica gel chromatography (eluent heptane / ethyl acetate 85:15) for analytical purposes. After elimination of the solvent at constant weight, the residue obtained is analyzed.
    [0108] The results of the analytical tests performed are in agreement with the structure identified in the text as intermediate (2): M <+> = 316 = C21H32O2;Ms (Cl) M <+> + 1 = 317; M <+> + 1 - H2O = 299; M <+> + 1 - 2H2O = 281.
    EXAMPLE 6
    [0109] This example relates to step e) of the process of the invention.
    [0110] In a flask, 3.8 g of intermediate (2) obtained as described in the previous example are dissolved in isopropyl acetate, heating to about 60 ° C.
    [0111] SIBX (8.96 g) is loaded and refluxed (88 ° C) for 6 h. TLC: complete (Sample: reaction mixture treated with aqueous solution of NaHCO3 and extracted with isopropyl acetate. Eluent: isopropyl acetate / heptane 7/3; plate: silica gel; detector: UV / cerium phosphomolybdate).
    [0112] The reaction mixture is cooled to 25 ° C and filtered on Celite washing with 20 mL of isopropyl acetate.
    [0113] 50 mL of saturated aqueous solution of NaHCO3 are added and the mixture is left under stirring for 10 minutes. The phases are separated and 50 mL of an aqueous solution of sodium metabisulphite at 15% are added to the organic one, stirring for 10 minutes.
    [0114] The phases are separated and the organic one is washed with 50 mL of saturated aqueous solution of NaCl.
    [0115] The phases are separated and the solvent is removed in a rotavapor under vacuum at 45 ° C, obtaining 3.6 g of retroprogesterone (yellow solid).
    A portion of retroprogesterone is purified by silica gel chromatography using a 7/3 to 6/4 heptane / ethyl acetate gradient.
    [0117] The results of the analytical tests performed on the sample, dried at constant weight, are in agreement with the structure of retroprogesterone: C21H30O2 = 314:Ms (Cl): M <+> + 1 = 315; M <+> + 1 - H2O = 297FT-IR (KBr): 1693 cm <-1>; 1664 cm <-1>; 1610 cm <-1>.<1> H-NMR (CDCl3): 5.73 ppm, s, 1H; 2.14 ppm, s 3H; 1.37 ppm, s, 3H; 0.68 ppm, s, 3H.<13> C-NMR (CDCl3): 209.2; 199.5; 172.2; 123.9; 64.7; 47.7; 45.5; 44.3; 39.9; 37.9; 37.4; 35.2; 33.7; 31.5; 29.1; 28.9; 24.9; 22.9; 22.3; 22.2; 12.7 (ppm).
    权利要求:
    Claims (5)
    [1]
    1. Process for the synthesis of retroprogesterone, comprising the following steps:a) reaction of compound (7), (3S, 3aS, 5aR, 6R, 9aR, 9bS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyldodecahydro-7H-cyclopenta [a] naphthalen-7 -one, with acrylonitrile to give compound (6), 3 - ((3iS, 3aS, 5aR, 6S, 9aS, 9bS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyl-7- oxododecahydro-1H-cyclopenta [a] naphthalen-6-yl) propanonitrile:
    b) reaction of compound (6) with a strong base to give compound (5), acid 3 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3 - ((S) -1-hydroxyethyl) - 3a, 6-dimethyl-7-oxododecahydro-1H-cyclopenta [a] naphthalen-6-yl) propanoic:
    c) reaction of compound (5) with acetic anhydride, Ac2O, to give compound (4), (S) -1 - ((4aS, 4bR, 6aS, 7S, 9aS, 9bS) -4a, 6a-dimethyl-2 -osso-2,3,4,4a, 4b, 5,6,6a, 7,8,9,9a, 9b, 10-tetradecahydroindene [5,4-f] cromen-7-yl) ethyl acetate:
    d) reaction of compound (4) with an organometallic reagent C1a to give compound (3), (S) -1 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3a, 6-dimethyl-7-bone -6- (3-oxobutyl) dodecahydro-1H-cyclopenta [a] naphthalen-3-yl) ethyl acetate: wherein the term "organometallic reactive Ci" is understood to mean an organometallic compound in which the organic fraction comprises only one carbon atom;e) reaction of compound (3) with a strong base to give compound (2), (8S, 9R, 10S, 135,145,175) -17 - ((S) -1-hydroxyethyl) -10,13-dimethyl-1, 2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta [a] phenanthren-3-one:
    f) oxidation of the intermediate (2) to obtain retroprogesterone:
    [2]
    2. 3 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyl-7-oxododecahydro-1H-cyclopenta [a] naphthalen-6 -yl) propanonitrile, compound of formula (6) intermediate of the process of claim 1:
    [3]
    3. Acid 3 - ((3S, 3aS, 5aR, 6S, 9aS, 9bS) -3 - ((S) -1-hydroxyethyl) -3a, 6-dimethyl-7-oxododecahydro-1H-cyclopenta [a] naphthalen- 6-yl) propanoic, compound of formula (5) intermediate of the process of claim 1:
    [4]
    4. (S) -1 - ((4aS, 4bR, 6aS, 7S, 9aS, 9bS) -4a, 6a-dimethyl-2-oxo-2,3,4,4a, 4b, 5,6,6a, 7 , 8,9,9a, 9b, 10-tetradecahydroindene [5,4-f] cromen-7-yl) ethyl acetate, compound of formula (4) intermediate of the process of claim 1:
    [5]
    5. (S) -1 - ((3S, 3aS, 5aR, 6S, 9a5,9biS) -3a, 6-dimethyl-7-oxo-6- (3-oxobutyl) dodecahydro-1H-cyclopenta [a] naphthalen- 3-yl) ethyl acetate, compound of formula (3) intermediate of the process of claim 1:
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    同族专利:
    公开号 | 公开日
    CN110198949A|2019-09-03|
    IT201700004904A1|2018-07-18|
    ES2722574A2|2019-08-13|
    ES2722574B2|2020-01-15|
    US10654885B2|2020-05-19|
    WO2018134278A1|2018-07-26|
    ES2722574R1|2019-08-27|
    US20200040029A1|2020-02-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3766213A|1966-04-19|1973-10-16|Hoffmann La Roche|Retrosteroid a ring formation|
    US3496199A|1968-06-17|1970-02-17|Hoffmann La Roche|Process for the preparation of 9beta,10alpha-steroids|
    CN102532236B|2012-01-05|2014-04-16|中国药科大学|Steroid 5Alpha-reductase inhibitors, preparation methods thereof and medical applications thereof|
    EP3083656A1|2013-12-20|2016-10-26|Prevacus Inc.|Synthesis of ent-progesterone and intermediates thereof|
    US20160108081A1|2014-09-17|2016-04-21|Prevacus, Inc.|Synthesis of ent-progesterone and intermediates thereof|
    ITUB20155260A1|2015-10-30|2017-04-30|Ind Chimica Srl|PROCESS FOR THE PREPARATION OF 17? -Hydroxy-des-A-androst-9,10-en-5-one|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT102017000004904A|IT201700004904A1|2017-01-18|2017-01-18|PROCESS FOR THE PREPARATION OF 9β, 10α-PROGESTERONE |
    PCT/EP2018/051147|WO2018134278A1|2017-01-18|2018-01-18|Process for the preparation of 9 beta,10 alpha-progesterone |
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