WO2019020508A1 - Procédé de préparation de rucaparib à pureté élevée - Google Patents

Procédé de préparation de rucaparib à pureté élevée Download PDF

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Publication number
WO2019020508A1
WO2019020508A1 PCT/EP2018/069740 EP2018069740W WO2019020508A1 WO 2019020508 A1 WO2019020508 A1 WO 2019020508A1 EP 2018069740 W EP2018069740 W EP 2018069740W WO 2019020508 A1 WO2019020508 A1 WO 2019020508A1
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Prior art keywords
formula
compound
process according
xxi
acid
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PCT/EP2018/069740
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English (en)
Inventor
Gianluca Belogi
Andrea Mazzoni
Stefano Serra
Barbara NOVO
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Olon S.P.A.
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Publication of WO2019020508A1 publication Critical patent/WO2019020508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to a novel process for the synthesis of high-purity rucaparib with a low environmental impact.
  • Rucaparib (I) is a poly(ADP ribose) polymerase (PARP) inhibitor used as an antitumoral for the treatment of ovarian cancer.
  • PARP poly(ADP ribose) polymerase
  • This synthesis method suffers from poor atom economy as a halogen is introduced into the molecule which does not appear in the end product, and requires the use of toxic, environmentally harmful reagents such as pyridinium tribromide for the bromination reaction and environmentally harmful solvents such as dichloromethane in the Suzuki reaction step.
  • the main step of a second rucaparib synthesis method comprises coupling with the Sonogashira reaction between triflate XII and alkyne XIII, followed by reduction of the nitro group to amine and ring closure to give the indole structure.
  • a series of further steps designed to construct the azepine ring, including Raney nickel reduction rucaparib I is obtained (Scheme 3).
  • the process can be performed in high yields, producing high-purity rucaparib with greater atom economy and avoiding the use of environmentally harmful organic solvents in the key step of the process.
  • the use of the bromine atom employed in the synthesis method previously described is avoided, as the coupling reaction is conducted starting directly from the indole with a palladium-catalyzed regioselective coupling reaction.
  • the solvent dichloromethane normally used in the Suzuki reaction is replaced with water.
  • the process is advantageous from the industrial standpoint as it provides high regioselectivity without the use of complex intermediates or potentially toxic, environmentally harmful solvents.
  • the object of the present invention is a process for the preparation of rucaparib having the following formula (I) or a pharmaceutically acceptable salt thereof:
  • Ri is straight or branched Ci-C 6 alkyl, and a compound of formula XIX:
  • R 2 is as defined above;
  • Ri is preferably methyl, ethyl, n-propyl, sec-propyl, n-butyl or tert-butyl, more preferably methyl.
  • R 2 is preferably methyl, ethyl, n-propyl, sec-propyl, n-butyl or tert-butyl, more preferably tert-butyl.
  • X is F, CI, Br or I, more preferably I.
  • the preferred salt of rucaparib of formula (I) is the camphorsulphonic acid salt.
  • Indole IX and iodo-aryl XIX are commercially available.
  • the reaction can be conducted using palladium or a salt or complex thereof, such as palladium acetate and palladium chloride, as catalyst.
  • the reaction can preferably be performed using palladium acetate as catalyst.
  • the palladium acetate catalyst is preferably used in a ratio ranging from 0.05 to 0.001 to compound IX.
  • the reaction can be conducted using a monodentate or bidentate phosphine as ligand, such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-ortho-toluylphosphine, 2,2'-bis(diphenylphosphino)-l, -binaphthyl (BINAP), tri(2-furyl)phosphine (TFP), 4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine (APhos), l,2,3,4,5-pentaphenyl- -(di-tert-butylphosphino)ferrocene (QPhos),
  • a monodentate or bidentate phosphine as ligand, such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphin
  • the reaction can preferably be performed using dppm as ligand.
  • the bidentate ligand dppm is preferably used in a stoichiometric ratio to palladium acetate ranging from 1.1 to 1.
  • the reaction can be performed using potassium acetate and sodium acetate as base.
  • the reaction can preferably be performed using potassium acetate as base.
  • Potassium acetate is preferably used in a stoichiometric ratio to compound IX ranging from 10 to 1.
  • the reaction is preferably performed using compound XIX in a stoichiometric ratio to compound IX ranging from 1.5 to 1.
  • the reaction can be performed in water or protic organic solvents such as ethanol, methanol, isopropanol or mixtures thereof, and preferably using water as the solvent.
  • the reaction can be performed at a temperature from room temperature to 120°C.
  • the regioselectivity of the reaction can be obtained to a surprisingly high extent by operating at a temperature ranging from 80°C to 110°C.
  • the reaction time is from 2 to 48 hours, preferably from 12 to 36 hours, and more preferably from 16 to 30 hours.
  • the reaction can be performed at a pressure ranging from 1 to 2 bars, preferably from 1 to 1.2 bars.
  • reaction mixture is extracted in ethyl acetate.
  • the ethyl acetate solution is concentrated under vacuum, preferably at a pressure of less than 100 mBars and in a time of less than 2 hours.
  • the product is obtained as an oil, and it is purified by silica-gel column chromatography to obtain a white solid.
  • Compound XXI is prepared by reacting compound XX with N-phthalimido- ethylamino-acetaldehyde in an aprotic solvent at a controlled temperature in the presence of an acid and a reducing agent which are suitable to promote the reaction.
  • This step is performed by the method described in Righi et al., Journal of Organic
  • the reaction can be performed using trifluoroacetic acid, trichloroacetic acid and acetic acid, for example, as the acid. Trifluoroacetic acid is preferably used as the acid.
  • the reaction can be performed using triethylsilane, diphenylsilane, triethoxysilane or tetramethyldisiloxane, for example, as reducing agent, preferably triethylsilane.
  • the stoichiometric ratio of N-phthalimido-ethylamino-acetaldehyde to compound XX is from 2.0 to 1.0, preferably from 1.5 to 1.0, and more preferably from 1.2 to 1.0.
  • the molar ratio of the acid to compound XX usually ranges from 10.0 to 1.0; preferably from 8.0 to 2.0, and more preferably from 6.0 to 3.0.
  • the molar ratio of reducing agent to compound XX usually ranges from 6.0 to 1.0; preferably from 5.0 to 1.0, and more preferably from 4.0 to 1.0.
  • the reaction can be performed in aprotic solvents including dichloromethane, ethyl acetate, toluene, acetonitrile, dimethylformamide, tetrahydrofuran, dioxane or mixtures thereof.
  • the reaction is preferably performed in dichloromethane.
  • the sequence of operations preferably involves adding the acid and the reducing agent in succession to a solution of compound XX in the reaction solvent.
  • the mixture of compound XX with the acid and the reducing agent is maintained at a temperature ranging from 0°C to the boiling point of the solvent, preferably from 10 to 30°C, and more preferably from 15 to 25°C.
  • the reaction mixture is kept under stirring for a time ranging from 1 hour to 36 hours, preferably from 2 to 24 hours.
  • the reaction mixture is cooled to a temperature ranging from -10 to 10°C, preferably from -5 to 5°C.
  • the reaction mixture is neutralised by adding an organic base such as triethylamine, pyridine or diisopropylethylamme or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate, preferably sodium bicarbonate.
  • organic base such as triethylamine, pyridine or diisopropylethylamme
  • an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate, preferably sodium bicarbonate.
  • the solution of compound XXI in dichloromethane is concentrated under vacuum, preferably at a pressure of less than 100 mBars and in a time of less than 2 hours.
  • Compound XXI can be isolated by crystallisation from organic solvent. Step c): conversion of compound XXI to compound XXII by removal of the phthalimido group and formation of a lactam
  • Compound XXII is prepared by deprotection of the phthalimido group followed by formation of lactam to give the azepine ring.
  • the reaction is performed in a pro tic solvent such as water, ethanol, methanol or isopropanol.
  • a pro tic solvent such as water, ethanol, methanol or isopropanol.
  • the reaction is preferably performed in water.
  • the reaction is performed using a reagent such as methylamine, hydrazine, phenylhydrazine, methylhydrazine or hydroxylamine, preferably methylamine.
  • a reagent such as methylamine, hydrazine, phenylhydrazine, methylhydrazine or hydroxylamine, preferably methylamine.
  • the stoichiometric ratio of methylamine to compound XXI ranges from 10 to 50, preferably from 20 to 40.
  • the reaction is performed at a temperature generally ranging from 0 to 40°C, preferably from 15°C to 30°C, and more preferably from 20°C to 30°C.
  • the reaction is performed for a time ranging from 0.5 to 4 hours, preferably from 0.5 to 2 hours.
  • the reaction is performed by adding compound XXI to the methylamine solution.
  • Compound XXII is recovered by filtration from the reaction mixture.
  • Compound XXII can be purified by crystallisation from water or organic solvents.
  • the hydrolysis reaction of the tert-butyloxycarbonyl (BOC) protecting group of compound XXII is preferably performed in a mixture of an aprotic solvent such as dichloromethane, ethyl acetate, toluene or THF with a protic solvent such as methanol, ethanol or isopropanol.
  • the reaction is preferably performed in a mixture of dichloromethane and methanol.
  • the reaction is promoted by an acid such as trifluoroacetic acid or hydrochloric acid in methanol.
  • the stoichiometric ratio of hydrochloric acid to compound XXII ranges from 20 to 5, preferably from 10 to 5.
  • the reaction is performed by adding hydrochloric acid dissolved in methanol to the solution of compound XXII in dichloromethane and methanol.
  • the reaction is performed at a temperature generally ranging from 0 to 40°C, preferably from 15°C to 30°C, and more preferably from 20°C to 30°C.
  • the reaction is performed for a time ranging from 1 to 24 hours, preferably from 2 to 6 hours.
  • an inorganic base such as sodium hydroxide, potassium hydroxide or sodium bicarbonate is added.
  • Sodium hydroxide added in the form of a concentrated aqueous solution, is preferably used as inorganic base.
  • the stoichiometric ratio of inorganic base to hydrochloric acid added to the reaction is from 1.5 to 1.
  • the resulting precipitate is recovered by filtration.
  • This step is performed, for example, by the method described in Gillmore et al, Organic Process Research & Development, 2012, 16, 1897-1904.
  • camphorsulphonic acid salt of rucaparib (I) is performed in a mixture of water with protic solvents, such as methanol, ethanol or isopropanol.
  • the formation of the camphorsulphonic acid salt of rucaparib (I) is preferably performed in a water and isopropanol mixture.
  • a solution of camphorsulphonic acid in water is added to a suspension of rucaparib (I) in water and isopropanol.
  • the suspension is heated to a temperature ranging from 60 to 80°C until completely dissolved.
  • the solution is cooled to a temperature ranging from 50 to 20°C to precipitate the product.
  • the suspension is cooled to a temperature ranging from 0 to 20°C.
  • the precipitated product is isolated by filtration.
  • a further object of the invention is the reaction intermediate of formula XXI:
  • Ri is straight or branched Ci-C 6 alkyl and R 2 is straight or branched Ci-C 6 alkyl, and its use in processes for the preparation of rucaparib of formula (I) or a pharmaceutically acceptable salt thereof.
  • the resulting mixture is kept under stirring at room temperature for 3-16 hours.
  • the reaction is cooled to 0°C, carefully neutralised with a sodium bicarbonate saturated solution (15 mL) and diluted with dichloromethane (20 mL).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé à faible impact environnemental pour la synthèse de rucaparib avec un rendement et une pureté élevés, ledit procédé comprenant une réaction de couplage régiosélective entre un indole et un iodo-aryle, réalisée dans de l'eau en présence d'un catalyseur. Le procédé de l'invention est avantageux sur le plan industriel, car dans l'étape de couplage clé, une régiosélectivité élevée est obtenue sans utiliser d'intermédiaires complexes ou de solvants potentiellement toxiques et nuisibles pour l'environnement.
PCT/EP2018/069740 2017-07-26 2018-07-20 Procédé de préparation de rucaparib à pureté élevée WO2019020508A1 (fr)

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IT102017000085789A IT201700085789A1 (it) 2017-07-26 2017-07-26 Metodo per la preparazione di rucaparib ad elevata purezza

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824677A (zh) * 2019-04-03 2019-05-31 江苏开元药业有限公司 治疗卵巢癌药物瑞卡帕布的制备方法
CN111004244A (zh) * 2019-12-27 2020-04-14 重庆市碚圣医药科技股份有限公司 一种瑞卡帕布樟脑磺酸盐的合成方法
CN114133396A (zh) * 2022-01-04 2022-03-04 浙江乐普药业股份有限公司 8-氟-1,3,4,5-四氢-氮杂卓并[5,4,3-cd]吲哚-6-酮的合成方法
WO2023013974A1 (fr) * 2021-08-03 2023-02-09 고려대학교 산학협력단 Nouvelle méthode de production de rucaparib qui est un inhibiteur de parp et intermédiaire de celui-ci

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6977298B2 (en) 1999-01-11 2005-12-20 Agouron Pharmacetucals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US7323562B2 (en) 2004-09-22 2008-01-29 Agouron Pharmaceuticals, Inc. Method of preparing poly(ADP-ribose) polymerases inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6977298B2 (en) 1999-01-11 2005-12-20 Agouron Pharmacetucals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US7323562B2 (en) 2004-09-22 2008-01-29 Agouron Pharmaceuticals, Inc. Method of preparing poly(ADP-ribose) polymerases inhibitors

Non-Patent Citations (6)

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Title
ADAM T. GILLMORE ET AL: "Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 16, no. 12, 21 December 2012 (2012-12-21), US, pages 1897 - 1904, XP055250298, ISSN: 1083-6160, DOI: 10.1021/op200238p *
ARCH. PHARM. (WEINHEIM, vol. 328, 1995, pages 329 - 332
CHEM.PHARM.BULL., vol. 36, no. 3, 1988, pages 1162 - 1168
GILLMORE ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 16, 2012, pages 1897 - 1904
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 16, 2012, pages 1897 - 1904
RIGHI ET AL., JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 14, 2012, pages 6351 - 6357

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824677A (zh) * 2019-04-03 2019-05-31 江苏开元药业有限公司 治疗卵巢癌药物瑞卡帕布的制备方法
CN109824677B (zh) * 2019-04-03 2021-09-03 江苏开元药业有限公司 治疗卵巢癌药物瑞卡帕布的制备方法
CN111004244A (zh) * 2019-12-27 2020-04-14 重庆市碚圣医药科技股份有限公司 一种瑞卡帕布樟脑磺酸盐的合成方法
WO2023013974A1 (fr) * 2021-08-03 2023-02-09 고려대학교 산학협력단 Nouvelle méthode de production de rucaparib qui est un inhibiteur de parp et intermédiaire de celui-ci
CN114133396A (zh) * 2022-01-04 2022-03-04 浙江乐普药业股份有限公司 8-氟-1,3,4,5-四氢-氮杂卓并[5,4,3-cd]吲哚-6-酮的合成方法

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