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WO2017208132A1 - Procédé de préparation de galétérone - Google Patents

Procédé de préparation de galétérone Download PDF

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Publication number
WO2017208132A1
WO2017208132A1 PCT/IB2017/053147 IB2017053147W WO2017208132A1 WO 2017208132 A1 WO2017208132 A1 WO 2017208132A1 IB 2017053147 W IB2017053147 W IB 2017053147W WO 2017208132 A1 WO2017208132 A1 WO 2017208132A1
Authority
WO
WIPO (PCT)
Prior art keywords
diene
reaction
galeterone
benzimidazol
acetoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/053147
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English (en)
Inventor
Francesco BARBIERI
Roberto Lenna
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Industriale Chimica SRL
Original Assignee
Industriale Chimica SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from ITUA2016A004043A external-priority patent/ITUA20164043A1/it
Priority claimed from ITUA2016A004793A external-priority patent/ITUA20164793A1/it
Application filed by Industriale Chimica SRL filed Critical Industriale Chimica SRL
Priority to ES201890072A priority Critical patent/ES2697706R1/es
Priority to CH01484/18A priority patent/CH714035B1/it
Publication of WO2017208132A1 publication Critical patent/WO2017208132A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • 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 3P-hydroxy-17-(lH-benzimidazol-l-yl)androsta-5,16-diene, also known as Galeterone, an intermediate useful for the treatment of prostate cancer, a compound having the formula given below:
  • Galeterone 3 -hydroxy-17-(lH-benzimidazol-l-yl)androsta-5,16-diene was first described in article "Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy", O. Omoshile et al, J. Med. Chem. 2003, 46 (12), pages 2345-2351, in figure 1 on page 2347, with the code VN/124-1*. The article does not report an experimental description of the preparation of the molecules object of the text, among which Galeterone, but refers to several other publications for the synthesis.
  • the first synthetic step is described in "Novel C-17-Heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model", V. D. Handratta et al., J. Med. Chem., 2005, 48 (8), pages 2972-2984.
  • This synthetic step consists of a Vilsmeier-Haack reaction which uses as a starting material 3P-acetoxyandrost-5-en-17-one (1) to yield 3P-acetoxy-17-chloroandrost-5,16-diene (2) and 3P-acetoxy-17-chloro-16- formylandrost-5,16-diene (3), as shown in the following scheme:
  • intermediate (4) is obtained by flash chromatography (FCC) on silica gel.
  • Intermediate (4) is then thermally deformylated using 10% palladium on carbon (Pd/C) as catalyst in an amount e ual to 50% of the weight of intermediate (4):
  • intermediate (5) is obtained by flash chromatography (FCC) on silica gel. Finally, intermediate (5) is deacetylated in bases and the crude Galeterone (6) is crystallized from the ethyl acetate/me thanol mixture:
  • the object of the present invention is to provide a synthesis route for the preparation of Galeterone, that is simpler than the prior art processes and industrially applicable.
  • a further object of the invention is intermediate (V), 3P-acetoxy-17-(lH-benzimidazol-l yl)androsta-5, 16-diene dioxalate:
  • the invention relates to an industrially applicable process for the synthesis of Galeterone, comprising steps a)-e) described in detail hereinafter.
  • Step a) consists in the reaction of 3P-acetoxyandrost-5-en-17-one (1) and POCb, wherein a mixture of 3P-acetoxy-17-chloro-16-formylandrost-5,16-diene (3) and 3P-acetoxy-17- chloroandrost-5,16-diene (2) is obtained:
  • Compound (1), 3P-acetoxyandrost-5-en-17-one is also known by the usage name prasterone acetate, which will be used in the rest of the description.
  • the reaction is conducted in a single solvent selected from arylalkylamides and dialkylamides, such as N-phenyl-N-methylformamide or, preferably, N,N- dimethylformamide (also referred to simply as dimethylformamide or its abbreviation DMF) in the presence of an inorganic reagent such as phosphorus oxychloride, POCI3. 3 to 6 moles, preferably 4.5 moles of inorganic reagent per mole of prasterone acetate are used for the reaction.
  • arylalkylamides and dialkylamides such as N-phenyl-N-methylformamide or, preferably, N,N- dimethylformamide (also referred to simply as dimethylformamide or its abbreviation DMF)
  • an inorganic reagent such as phosphorus oxychloride, POCI3. 3 to 6 moles, preferably 4.5 moles of inorganic reagent per mole of prasterone acetate are used for the reaction.
  • the necessary amount of inorganic reagent is dissolved in the solvent, and the resulting solution is poured dropwise, over a time of between 15 minutes and 1.5 hours, on the suspension obtained by mixing the same solvent and prasterone acetate, keeping the temperature between 15 and 50 °C; preferably, the solution of the inorganic compound in DMF is poured dropwise on the suspension of prasterone acetate in DMF over a time of between 15 minutes and 45 minutes, keeping the temperature between 15 and 40 °C.
  • the total amount of amide solvent is higher than 10 moles per mole of prasterone acetate, preferably at least 16 moles per mole of prasterone acetate.
  • the mixture temperature is brought to between 60 and 90 °C, preferably between 70 and 80 °C.
  • the overall reaction time is between 1 and 5 hours, preferably between 2 and 4 hours.
  • Intermediate (3) is then purified by crystallization from an organic solvent selected from methanol, ethanol, isopropanol, chloroform and dichloromethane, either pure or mixed with each other; preferred solvents for this purification are the methanol/dichloromethane mixture or pure methanol.
  • organic solvent selected from methanol, ethanol, isopropanol, chloroform and dichloromethane, either pure or mixed with each other; preferred solvents for this purification are the methanol/dichloromethane mixture or pure methanol.
  • step b) intermediate (3) obtained as described above is reacted with benzimidazole in the presence of an alkali metal carbonate or alkaline earth metal carbonate to yield intermediate (4), 3P-acetoxy-17-(lH-benzimidazol-l-yl)-16-formylandrosta-5,16-diene:
  • the amount in moles of benzimidazole used for the reaction is of between 1.0 and 1.75 moles, preferably between 1.05 and 1.25 moles, with respect to the moles of intermediate (3).
  • the solvent for the reaction is selected from dimethylacetamide, dimethylsulfoxide and, preferably, dimethylformamide.
  • the volume amount of organic solvent used is between 4 and 6 times with respect to the amount by weight, measured in grams, of intermediate (3) reacted; preferably, the amount by volume of organic solvent used is of between 4.5 and 5.5 times the amount by weight of intermediate (3) reacted.
  • the volume of water used to quench the reaction is between 3 and 5 times, preferably between 3.5 and 4.5 times the volume of the organic solvent used in reaction.
  • the carbonate is selected from sodium, calcium and, preferably, potassium carbonate.
  • the reaction temperature is between 65 and 90 °C, preferably between 75 and 85 °C.
  • the reaction time is between 1 and 3 hours, preferably between 1 and 2 hours.
  • reaction conditions make possible obtaining an intermediate (4) having such a quality that it can be used for the subsequent reactions without the need for additional purification, in particular chromatographic purifications.
  • Step c) of the process of the invention consists in the reaction of intermediate (4) to yield intermediate (5), 3P-acetoxy-17-(lH-benzimidazol-l-yl)androsta-5,16-diene, referred to hereinafter as Galeterone acetate:
  • This step is conducted by reacting intermediate (4) with palladium on carbon (Pd/C) as a catalyst at temperatures above 100 °C.
  • catalysts different from Pd/C such as platinum on carbon (Pt/C), ruthenium on carbon (Ru/C), rhodium on carbon (Rh/C) and palladium on alumina (Pd/Al 2 03), did not provide useful results.
  • the amount by weight of catalyst is of between 5% and 20%, with respect to the weight of intermediate (4) reacted, and the percentage of palladium in the catalyst can range between 5 and 10%.
  • the reaction solvent is selected from: Dowtherm ® A (an eutectic mixture of diphenyl and diphenyl oxide; Dowtherm ® is a registered trademark of Dow Corning Corporation); phthalic esters of alcohols selected from linear or branched aliphatic Ci-Cio alcohols, aromatic alcohols and cyclic alcohols, symmetrical or asymmetrical, such as dimethylphtalate, diethylphtalate, dibutyl phthalate, dicyclohexyl phthalate, butyl benzyl phthalate, diisobutyl phthalate; benzonitrile, dimethylformamide and dimethylacetamide; said solvents can be pure or mixed with one another.
  • the preferred solvent for this reaction is Dowtherm A.
  • the reaction temperature depends on the boiling point of the solvent and the reaction time is reduced significantly for reaction temperatures higher than 200 °C.
  • the reaction temperature is higher than 200 °C and the reaction time ranges between 1 and 12 hours, preferably between 1 and 6 hours.
  • the catalyst must be added to the other components of the reaction mixture at a temperature lower than 100 °C, preferably lower than 50 °C; the inventors have observed that the addition of the catalyst when the temperature of the mixture is higher than 100 °C leads to an increase of impurities in the final product.
  • Galeterone acetate (5) can be separated from the crude reaction mixture using standard techniques known to the man skilled in the art; alternatively, after the elimination of the metal catalyst alone by filtration, the next step can be carried out by adding oxalic acid directly to the organic solution obtained in step c), which contains Galeterone acetate (5).
  • the solution can be treated with a metal scavenging agent to eliminate any residual amounts of metal possibly present;
  • a metal scavenging agent suitable for the purpose are the products of the QuadraSil ® family sold by Sigma-Aldrich, in particular the QuadraSil ® MP product, consisting of spherical particles of macroporous silica functionalized to remove residual metals from products containing them (QuadraSil ® is a registered trademark of the company Johnson Matthey).
  • step d) of the process by reaction of Galeterone acetate (5) with oxalic acid in an organic solvent solution, from which dioxalate separates as filterable solid:
  • the amount of oxalic acid used is at least two moles per mole of intermediate (4) used in the previous step.
  • the oxalic acid used is anhydrous or, preferably, dihydrate.
  • This reaction is conducted by adding a base to intermediate (V) suspended in an organic solvent inert in the reaction conditions; the base can be added either pure or dissolved in a solvent.
  • the organic solvent in which intermediate (V) is suspended is selected from xylene, toluene, cyclohexane, heptane, hexane and methylene chloride, either pure or mixed with each other; the preferred solvent for this operation is pure methylene chloride.
  • the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate or potassium carbonate dissolved in water or in an alcohol such as methanol, ethanol, isopropanol, preferably sodium hydroxide dissolved in methanol.
  • Rf and RRT adopted in the examples indicate the delay factor in thin layer chromatography (TLC) and the relative retention time of a compound in high pressure liquid chromatography (HPLC), respectively.
  • Mobile phase A methanol
  • Mobile phase B water
  • UV Detector 254 nm and 280 nm
  • TLC MERCK TLC silica gel 60 F 2 54 Aluminium sheets 20 x 20 cm, code 1.0554.0001.
  • UV light at 254 and 366 nm.
  • This example relates to step a) of the process of the invention:
  • DMF dimethylformamide
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the largely predominant formation of intermediate (3) with Rf 0.65, the formation of intermediate (2) in traces (Rf 0.68) and the permanence of a starting product residue (Rf 0.51).
  • the solution is poured onto a mixture of cold water (1.5 L) and ice (1 kg) under stirring for 1 hour at 0 ⁇ T ⁇ 5 °C; then, it is brought to 20 ⁇ T ⁇ 25 °C over 45 minutes.
  • the precipitated solid is filtered by washing with water at 20 °C.
  • the wet solid is dissolved in 1 L dichloromethane (DCM) and the spontaneously formed aqueous phase is separated.
  • step b) of the process of the invention formation of 3P-acetoxy-17- ( 1 H-benzimidazol- 1 -yl)- 16-formylandrosta-5 , 16-diene (4) :
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the formation of product (4) with Rf 0.27, and a trace of a less polar impurity with Rf 0.35.
  • reaction mixture is brought to 20 ⁇ T ⁇ 25 °C, 2 L of water are added and the system is cooled to 0 ⁇ T ⁇ 2 °C for 1 hour.
  • the precipitated solid is filtered by washing with water, then dried at 60 °C under reduced pressure for 20 hours.
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the disappearance of the start (4) (Rf 0.24), the formation of the product (5) (Rf 0.31) and the formation of some impurities (R f 0.55 - 0.79).
  • reaction mixture is brought to 20 ⁇ T ⁇ 25 °C and 360 mL of toluene are added.
  • the suspension is stirred for 1 hour at 20 ⁇ T ⁇ 25 °C and 1 hour at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 120 mL of toluene. The wet solid is dissolved with 600 mL of toluene.
  • the suspension is stirred for 15 minutes at 20 ⁇ T ⁇ 25 °C and 15 minutes at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 120 mL of toluene.
  • the TLC control shows the formation of compound (6) with Rf 0.44 (start R f 0.68).
  • the solid is loaded, suspended in tert-butanol (61 mL), brought to reflux. PPI water is added dropwise (61 mL) and it is again brought to reflux.
  • the solid is filtered and washed with 37 mL of precooled methanol.
  • ⁇ -NMRCCDCb ⁇ : 1.02 (s, 3H, I8-CH3), 1.06 (s, 3H, 19-CH 3 ), 1.06-1.17 (m, 2H, H aliphatic), 1.47-1.89 ( ⁇ m, 11H, H aliphatic), 2.08-2.45 ( ⁇ m, 5H, H aliphatic), 3.53-3.58 (m, 1H, 3aH), 5.41 (m, 1H, 6-H), 5.98 (dd, 1H, 16-H), 7.26-7.31 (m, 2H, H aromatic), 7.47-7.51 (m, 1H, H aromatic), 7.79-7.83 (m, 1H, H aromatic), 7.96 (s, 1H, H aromatic).
  • Example 3 The preparation of Example 3 is repeated, using however in the first step (conversion from intermediate (4) to intermediate (5)) an amount of Pd/C catalyst greater than the amounts allowed by the invention.
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the disappearance of the start (4) (Rf 0.24), the formation of the product (5) (Rf 0.31) and the formation of some impurities (R f 0.55 - 0.79).
  • reaction mixture is brought to 20 ⁇ T ⁇ 25 °C and 150 mL of toluene are added.
  • the suspension is stirred for 1 hour at 20 ⁇ T ⁇ 25 °C and 1 hour at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with toluene.
  • the wet solid is recovered with 250 mL of toluene.
  • the suspension is stirred for 15 minutes at 20 ⁇ T ⁇ 25 °C and 15 minutes at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with toluene.
  • the TLC control shows the formation of compound (6) with Rf 0.44 (start R f 0.68).
  • the solid is loaded to a flask, suspended in tert-butanol (44 mL), and brought to reflux. PPI water is added dropwise (44 mL) and it is again brought to reflux.
  • the solid is suspended in methanol and it is brought to reflux (complete solution with 142.5 mL). It is cooled to 20 ⁇ T ⁇ 25 °C until the start of precipitation of the product.
  • the solid is loaded to a flask, suspended in methanol (123.8 mL), and brought to reflux (complete solution).
  • Galeterone sample (6) is analysed in Lc/Ms/Ms (chemical ionization).
  • RRT 0.87 impurity remains at values of between 0.32 and 0.34%.
  • Example 3 The preparation of Example 3 is repeated, using however a catalyst other than Pd/C in the first step (conversion from intermediate (4) to intermediate (5)).
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the disappearance of the start (4) (Rf 0.24), the formation of the product (5) (Rf 0.31), and the formation of an impurity (Rf 0.36).
  • the system is kept under reflux for 1 hour.
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the disappearance of the start
  • reaction mixture is brought to 20 ⁇ T ⁇ 25 °C and 15 mL of toluene are added.
  • the suspension is stirred for 1 hour at 20 ⁇ T ⁇ 25 °C and 1 hour at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 5 mL of toluene. The wet solid is dissolved with 30 mL of toluene.
  • the suspension is stirred for 15 minutes at 20 ⁇ T ⁇ 25 °C and 15 minutes at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 5 mL of toluene.
  • the TLC control shows the formation of compound (6) with Rf 0.44 (start R f 0.68). It is diluted with 50 mL DCM, 100 mL water are charged and stirred for 15 minutes.
  • Example 6 the procedure of Example 6 is essentially repeated with the only difference that in step c) (conversion of intermediate (4) to intermediate (5)), the Pd/C catalyst is added when the reagent system is already at the final reaction temperature.
  • the TLC control (isopropyl acetate/heptane 8/2 eluent) shows the disappearance of the start (4) (Rf 0.24), the formation of the product (5) (Rf 0.31), and the formation of some impurities (R f 0.55 - 0.79).
  • reaction mixture is brought to 20 ⁇ T ⁇ 25 °C and 15 mL of toluene are added.
  • the suspension is stirred for 1 hour at 20 ⁇ T ⁇ 25 °C and 1 hour at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 5 mL of toluene. The wet solid is recovered with 30 mL of toluene.
  • the suspension is stirred for 15 minutes at 20 ⁇ T ⁇ 25 °C and 15 minutes at 0 ⁇ T ⁇ 5 °C, the solid is filtered by washing with 5 mL of toluene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un procédé de synthèse de 3β-hydroxy-17-(lH-benzimidazol-l-yl)androsta-5,16-diène est décrit, un composé également connu sous le nom de Galétérone et utilisé dans le traitement du cancer de la prostate, représenté par la formule donnée ci-dessous.
PCT/IB2017/053147 2016-06-01 2017-05-29 Procédé de préparation de galétérone Ceased WO2017208132A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
ES201890072A ES2697706R1 (es) 2016-06-01 2017-05-29 Proceso Para La Preparación De Galeterona.
CH01484/18A CH714035B1 (it) 2016-06-01 2017-05-29 Processo per la preparazione di 3Beta-idrossi-17-(1H-benzimidazol-1-il)androsta-5,16-diene.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITUA2016A004043A ITUA20164043A1 (it) 2016-06-01 2016-06-01 Processo per la preparazione di 3β-idrossi-17-(1H-benzimidazol-1-il)androsta-5,16-diene
IT102016000057001 2016-06-01
IT102016000068114 2016-06-30
ITUA2016A004793A ITUA20164793A1 (it) 2016-06-30 2016-06-30 Processo per la preparazione di 3β-idrossi-17-(1H-benzimidazol-1-il)androsta-5,16-diene

Publications (1)

Publication Number Publication Date
WO2017208132A1 true WO2017208132A1 (fr) 2017-12-07

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Application Number Title Priority Date Filing Date
PCT/IB2017/053147 Ceased WO2017208132A1 (fr) 2016-06-01 2017-05-29 Procédé de préparation de galétérone

Country Status (3)

Country Link
CH (1) CH714035B1 (fr)
ES (1) ES2697706R1 (fr)
WO (1) WO2017208132A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091306A1 (fr) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Nouveaux promédicaments à base d'inhibiteurs cyp17 stéroïdiens/anti-androgènes
US20110034428A1 (en) * 2009-08-07 2011-02-10 Tokai Pharmaceuticals, Inc. Treatment of Prostate Cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091306A1 (fr) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Nouveaux promédicaments à base d'inhibiteurs cyp17 stéroïdiens/anti-androgènes
US20110034428A1 (en) * 2009-08-07 2011-02-10 Tokai Pharmaceuticals, Inc. Treatment of Prostate Cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANDERSON ET AL: "TOOLS FOR PURIFYING THE PRODUCT: COLUMN CHROMATOGRAPHY, CRYSTALLIZATION AND RESLURRYING", PRACTICAL PROCESS RESEARCH AND DEVELOPMENT, ACADEMIC PRESS, SAN DIEGO, US, 1 January 2000 (2000-01-01), pages 223 - 247, XP002382432 *
HANDRATTA VENKATESH D ET AL: "Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens: Synthesis, in Vitro Biological Activity, Pharmacokinetics, and Antitumor Activity in the LAPC4 Human Prostate Cancer Xenograft Model", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 48, no. 8, 25 March 2005 (2005-03-25), pages 2972 - 2984, XP002535274, ISSN: 0022-2623, DOI: 10.1021/JM040202W *

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ES2697706R1 (es) 2019-02-08
ES2697706A2 (es) 2019-01-28
CH714035B1 (it) 2021-02-15

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