WO2009106966A1 - Procédé de préparation du rameltéon - Google Patents

Procédé de préparation du rameltéon Download PDF

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Publication number
WO2009106966A1
WO2009106966A1 PCT/IB2009/000362 IB2009000362W WO2009106966A1 WO 2009106966 A1 WO2009106966 A1 WO 2009106966A1 IB 2009000362 W IB2009000362 W IB 2009000362W WO 2009106966 A1 WO2009106966 A1 WO 2009106966A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
solvate
ramelteon
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Application number
PCT/IB2009/000362
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English (en)
Inventor
Pelayo Camps Garcia
Ester Masllorens Llinas
Original Assignee
Medichem, S.A.
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.)
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Publication date
Application filed by Medichem, S.A. filed Critical Medichem, S.A.
Publication of WO2009106966A1 publication Critical patent/WO2009106966A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems

Definitions

  • Ramelteon is an active pharmaceutical substance with an empirical formula of C 16 H 2 ]NO 2 and a molecular weight of 259.344.
  • Ramelteon is the international common accepted name for (5)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4- ⁇ ]furan-8- yl)ethyl]propionamide, which is represented by a compound of formula (I):
  • Ramelteon is a commercially marketed pharmaceutically active substance known to be useful for treating or preventing sleep disorders.
  • Ramelteon is a melatonin agonist that selectively binds to the melatonin receptors in the suprachiasmatic nucleus.
  • ramelteon is marketed under the name RozeremTM for the treatment of insomnia.
  • Ramelteon and other compounds are disclosed in U.S. Patent No. 6,034,239 ("the '239 patent") which is incorporated herein by reference.
  • the '239 patent discloses synthetic strategies for the preparation of ramelteon, one of which is illustrated herein at Scheme 1.
  • Example 19 of the '239 patent describes a direct preparation of ramelteon by reacting enantiomerically pure compound (IV) hydrochloride with propionyl chloride in the presence of triethylamine as a base, and in the presence of Ny/V-dimethylformamide as a solvent. Further, the '239 patent describes the preparation of compound (IV) from compound (II) via two consecutive hydrogenation reactions (see reference Examples 27 and 20 of the '239 patent, in that order). Scheme 1
  • the present invention provides an improved process for preparing indane derivatives.
  • the present invention provides a process for preparing ramelteon from l,2,6,7-tetrahydro-8H-indeno[5,4- ⁇ ]furan-8-ylideneacetonitrile of formula (II), wherein a compound of formula (II), or a solvate or salt thereof, is converted to (8S)- l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8-ylacetonitrile of formula (III), or a solvate or salt thereof, which is converted to 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8- yl]ethanamine of formula (IV), or a solvate or salt thereof, which is converted to ramelteon.
  • the present invention provides an improved process for preparing ramelteon from a compound
  • the present invention provides improved processes for preparing indane derivatives, for example, ramelteon. Processes in accordance with the invention reduce or avoid the use of extensive amounts of hazardous hydrogen gas, which makes for safer operating conditions. In addition, the processes of the invention are cost-effective and suitable for industrial implementation.
  • the present invention provides a process for preparing ramelteon comprising the steps of: i) converting a compound of formula (II), or a solvate thereof, into a compound of formula (III), or a solvate thereof, by an enantioselective conjugate reduction reaction; ii) converting a compound of formula (III), or a solvate thereof, into a compound of formula (IV), or a salt or solvate thereof, by a nitrile reduction reaction; and iii) converting a compound of formula (IV), or a salt or solvate thereof, into ramelteon.
  • the present invention provides a process for preparing ramelteon which has industrial advantages, e.g., reducing or avoiding the use of extensive amounts of hydrogen gas and increased safety.
  • the present invention provides a process for preparing ramelteon as depicted in Scheme 2.
  • the conversion of a compound of formula (II) to a compound of formula (III) comprises an enantioselective conjugate reduction reaction.
  • the enantioselective conjugate reduction reaction employs a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand.
  • a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand in step i) above leads to an efficient and highly enantioselective conjugate reduction of compound (II), or a solvate thereof.
  • the enantionselective conjugate reduction reaction is conducted in a suitable solvent, e.g., a hydrocarbon solvent.
  • a suitable solvent e.g., a hydrocarbon solvent.
  • suitable hydrocarbon solvents are aromatic solvents, e.g., toluene.
  • the enantioselective conjugate reduction reaction is conducted at a suitable temperature, e.g., from about 0 °C to about room temperature.
  • the enantioselective conjugate reduction reaction of step i) comprises contacting compound of formula (II), or a solvate thereof, with a reducing agent, in the presence of a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand, and in the presence of a solvent.
  • the catalyst comprising copper of step i) is prepared from copper (II) acetate as the catalytic precursor.
  • the chiral ferrocenyl-based biphosphine ligand of step i) is (S)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ligand (i.e., generally referred as the Josiphos ligand), or a derivative thereof.
  • the Josiphos ligand is preferably prepared using (S)-I -[(R)-2-
  • the reducing agent of step i) is a siloxane compound, more preferably the reducing agent of step i) is polymethylhydrosiloxane.
  • the conversion of a compound of formula (III) to a compound of formula (IV) comprises a nitrile reduction reaction.
  • the nitrile reduction reaction of step ii) comprises contacting a compound of formula (III), or a solvate thereof, with either (a) hydrogen and a metal catalyst or (b) another reducing agent.
  • the term "contacting" refers to reacting one or more substances under suitable conditions to achieve the desired result.
  • a compound of formula (III), or a solvate or salt thereof is reacted with a suitable amount of a reducing agent in a suitable reaction vessel at a suitable temperature in a suitable solvent for a suitable period of time under suitable other conditions to form a compound of formula (IV).
  • the nitrile reduction reaction is conducted in a suitable solvent, e.g., polar aprotic solvents.
  • a suitable solvent e.g., polar aprotic solvents.
  • An illustrative polar aprotic solvent is THF.
  • the nitrile reduction reaction is conducted at a suitable temperature, e.g., from about 0 °C to about 40 °C.
  • the reducing agent of step ii) (a) is lithium aluminium hydride.
  • the metal catalyst of step ii) (b) is a palladium, platinum or nickel catalyst, more preferably a nickel catalyst, and even more preferably is Raney nickel.
  • the conversion of a compound of formula (IV), or a salt or solvate thereof, to ramelteon in step iii) comprises a propionylation reaction wherein a compound of formula (IV), or a salt or solvate thereof, is contacted with a propionylating agent.
  • the propionylating agent of step iii) is propionyl chloride or propionic anhydride.
  • the salt or solvate of a compound of formula (IV) of step iii) is any suitable organic or inorganic salt of compound (IV). More preferably, the compound of (IV), or a salt or solvate thereof, of step iii) is a hydrogen halide salt of compound (IV), most preferably the compound of (IV), or a salt or solvate thereof, of step iii) is the hydrogen chloride salt of compound (IV).
  • the propionylation reaction of a compound of formula (IV), or a salt or solvate thereof, of step iii) is preferably carried out in the presence of a base such as sodium hydrogen carbonate or sodium hydroxide.
  • the propionylation reaction of a compound of formula (IV), or a salt or solvate thereof, of step iii) is preferably carried out in the presence of a solvent comprising tetrahydrofuran, water, or mixtures thereof. More preferably, the solvent of step iii) of the process of the invention is water.
  • reaction medium or solvent is free or substantially free of class II solvents, e.g., DMF.
  • the present invention provides a process for preparing ramelteon, said process comprising contacting a salt of compound of formula (IV) with propionic anhydride as a propionylating agent, in the presence of a base, and in the presence of water as a solvent.
  • Applicants have surprisingly discovered that the propionylation of the hydrochloride salt of compound of formula (IV) can be carried out efficiently in the presence of water when propionic anhydride is used as a propionylating agent.
  • Water is an inexpensive, safe and non-toxic solvent, which is abundant in nature. Accordingly, the use of water as a solvent is desirable for a green chemical process.
  • the process for preparing ramelteon from the hydrochloride salt of a compound of formula (IV) avoids the use of organic solvents and is cost-effective and suitable for industrial implementation.
  • the use of water as a solvent in the process of the invention above entails a number of advantages which additionally increase the efficiency of the reaction.
  • the hydrochloride salt of compound of formula (IV) that is, the starting material for the reaction, is highly soluble in water and the ramelteon product is insoluble in water, and thus precipitates as the reaction proceeds.
  • the salt of compound of formula (IV) can be any suitable organic or inorganic salt of compound of formula (IV).
  • the salt of compound of formula (IV) is a hydrogen halide salt of compound of formula (IV). More preferably, the salt of compound of formula (IV) is the hydrogen chloride salt of compound of formula (IV).
  • the base used in the propionylation reaction of the invention can be any base suitable to liberate the compound from the salt, e.g., sodium hydrogen carbonate or sodium hydroxide.
  • the base should be used in amounts sufficient to liberate the compound of formula (IV) from the corresponding salt, as well as to permit the reaction to proceed efficiently.
  • the ramelteon obtained according to the processes of the invention has a high chemical and enantiomeric purity profile.
  • the chromatographic separation was conducted at 40 0 C using a Chiralpak ® IB, 5 ⁇ m, 250 x 4.6 mm I.D. column.
  • the mobile phase was prepared by mixing 950 mL of M-hexane with 40 mL of 2-propanol, 10 mL of ethanol, 4 mL of trifluoroacetic and 2 mL of triethylamine.
  • the chromatograph was equipped with a UV detector monitoring 225 nm and the flow rate was 1.2 mL per minute. Samples were prepared at a concentration of 2.5 mg/mL of mobile phase and 10 ⁇ L of sample were injected onto the column.
  • the chromatographic separations were conducted at 40 0 C using a Chiralpak AD-H, 5 ⁇ m, 250 x 4.6 mm I.D. column.
  • the mobile phase was prepared by mixing 950 mL of H-hexane with 40 mL of 2-propanol, 10 mL of ethanol, 4 mL of trifluoroacetic and 2 mL of triethylamine.
  • the chromatograph was equipped with a UV detector monitoring 225 nm and the flow rate was 1.2 mL per minute. Samples were prepared at a concentration of 1 mg/mL in a 1:1 mixture of H-hexane and 2-propanol and 10 ⁇ L of sample were injected onto the column.
  • This example illustrates a process for preparing (8iS)-l,6,7,8-tetrahydro-2H- indeno[5,4-6]furan-8-ylacetonitrile (compound of formula III) via enantioselective reduction of l,2,6,7-tetrahydro-8H-indeno[5,4-6]furan-8-ylideneacetonitrile (compound of formula II) in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing 2-[(8S)-1 ,6,7,8-tetrahydro-2H- indeno[5,4- ⁇ ]furan-8-yl]ethanamine (compound of formula IV) via nitrile reduction of (8S)- l,6,7,8-tetrahydro-2H-indeno[5,4- ⁇ ]furan-8-ylacetonitrile (compound of formula III) in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing 2-[(8S)- 1 ,6,7,8-tetrahydro-2H- indeno[5,4- ⁇ ]furan-8-yl]ethanamine hydrochloride (compound IV ⁇ C1) in accordance with an embodiment of the invention.
  • reaction mass was stirred for one hour at 0-5 0 C and then heated to 20 0 C.
  • the reaction mixture was maintained at this temperature for 3 hours.
  • Toluene was then removed under vacuum, 100 mL of water were added and the vacuum distillation was continued until complete removal of toluene.
  • the filter was washed with 10 mL of methanol and the methanolic solution was cooled until the solid crystallized (at about 30 0 C). Then, 180 mL of acetone were charged at room temperature and the mixture was cooled to 0 0 C and filtered. The solid was washed with some acetone and after drying 5.5 g of solid corresponding to compound (IV)-HCl were obtained.
  • This example illustrates a process for preparing (S,R)-N-[2-(l ,6,7,8-tetrahydro- 2H-indeno-[5,4-6]furan-8-yl)ethyl]propionamide (i.e., racemic ramelteon) in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing (5',/?)-N-[2-(l ,6,7,8-tetrahydro- 2H-indeno-[5,4-6]furan-8-yl > )ethyl]propionamide (i.e. racemic ramelteon) in accordance with an embodiment of the invention.
  • This example illustrates a process for recrystallizing (S,R)-N-[2-(l, 6,7,8- tetrahydro-2H-indeno-[5,4- ⁇ ]fura «-8-yl)ethyl]propionamide (i.e., racemic ramelteon) in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing (S)-N-[2-( ⁇ ,6,7,8-tetrahydro-2H- indeno-[5,4- ⁇ ]furan-8-yl)emyl]propionamide (i.e., ramelteon) in accordance with an embodiment of the invention.
  • 25.0 g (0.104 mol) of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8- yl)ethanamine hydrochloride (compound IV ⁇ C1) and 375 mL of water were loaded into a reaction flask.
  • the brownish solution was cooled to 10-15 0 C and 20.98 g (0.156 mol) of 97% propionic anhydride was added followed by 50% sodium hydroxide solution (22.77 g, 0.285 mol). The p ⁇ was 6.0-6.5. During the addition, a precipitate was quickly formed. Once the addition was complete, the suspension was heated to 20-25 0 C for 2 hours. Then, the suspension was heated to 60 ⁇ 5 0 C and maintained at this temperature for 1 hour. The suspension was then cooled to 40 ⁇ 2 0 C. The precipitate product was filtered at 40 ⁇ 2 0 C, and washed with water (2x20 mL).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation de dérivés d'indane incluant, par exemple, du rameltéon. L'invention fournit un procédé pour la préparation du rameltéon à partir d'un composé de formule (II), le procédé consistant à produire des réactions de réduction successives et à convertir un composé de formule (IV) en rameltéon. L'invention concerne également un procédé amélioré de conversion d'un composé de formule (IV) en rameltéon.
PCT/IB2009/000362 2008-02-28 2009-02-27 Procédé de préparation du rameltéon WO2009106966A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US3236408P 2008-02-28 2008-02-28
US61/032,364 2008-02-28
US3785508P 2008-03-19 2008-03-19
US61/037,855 2008-03-19
US9972208P 2008-09-24 2008-09-24
US61/099,722 2008-09-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010092107A1 (fr) * 2009-02-12 2010-08-19 Lek Pharmaceuticals D.D. Synthèse de (s)-n-[2-(1,6,7,8-tétrahydro-2h-indéno-[5,4-b]furan-8-yl)éthyl]propionamide
WO2010041271A3 (fr) * 2008-09-16 2011-06-16 Usv Limited Préparation de (s)-n-[2-(1,6,7,8-tétrahydro-2h-indéno[5,4-b]furan-8-yl)éthyl] propionamide et nouveaux intermédiaires de ce composé
US8084630B2 (en) 2007-05-31 2011-12-27 Teva Pharmaceutical Industries Ltd. Process for the synthesis of ramelteon and its intermediates
WO2012035303A2 (fr) 2010-09-17 2012-03-22 Cipla Limited Et Al Nouveau procédé de synthèse du ramelteon et intermédiaires clés pour la synthèse du ramelteon
JP2012520291A (ja) * 2009-03-10 2012-09-06 インダストリアレ チミカ ソシエタ ア レスポンサビリタ リミタータ ラメルテオンの調製方法
CN108072711A (zh) * 2016-11-18 2018-05-25 万特制药(海南)有限公司 高效液相色谱法分离测定雷美替胺中间体光学异构体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034239A (en) * 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1199304A1 (fr) * 1997-03-05 2002-04-24 Takeda Chemical Industries, Ltd. Composés bicycliques et composition pharmaceutique contenant un composé tricyclique pour le traitement ou la prévention de troubles de sommeil
WO2008106179A1 (fr) * 2007-02-26 2008-09-04 Teva Pharmaceutical Industries Ltd. Intermédiaires et procédés pour la synthèse de ramelteon
WO2008151170A2 (fr) * 2007-05-31 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédé de synthèse du rameltéon et ses intermédiaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034239A (en) * 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1199304A1 (fr) * 1997-03-05 2002-04-24 Takeda Chemical Industries, Ltd. Composés bicycliques et composition pharmaceutique contenant un composé tricyclique pour le traitement ou la prévention de troubles de sommeil
WO2008106179A1 (fr) * 2007-02-26 2008-09-04 Teva Pharmaceutical Industries Ltd. Intermédiaires et procédés pour la synthèse de ramelteon
WO2008151170A2 (fr) * 2007-05-31 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédé de synthèse du rameltéon et ses intermédiaires

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHILMAN-BLAIR K ET AL: "TAK-375: treatment of insomnia treatment of circadian rhythm disorders melatonin MT1/MT2 agonist", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 28, no. 10, 1 January 2003 (2003-01-01), pages 950 - 958, XP002495177, ISSN: 0377-8282 *
JELLIMANN CAROLE ET AL: "Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors", JOURNAL OF MEDICINAL CHEMISTRY,, vol. 43, no. 22, 2 November 2000 (2000-11-02), pages 4051 - 4062, XP002526737 *
UCHIKAWA ET AL: "Synthesis of a Novel Series of Tricyclic Indan Derivatives as Melatonin Receptor Agonists", JOURNAL OF MEDICINAL CHEMISTRY,, vol. 45, no. 19, 1 January 2002 (2002-01-01), pages 4222 - 4239, XP002518028 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8084630B2 (en) 2007-05-31 2011-12-27 Teva Pharmaceutical Industries Ltd. Process for the synthesis of ramelteon and its intermediates
WO2010041271A3 (fr) * 2008-09-16 2011-06-16 Usv Limited Préparation de (s)-n-[2-(1,6,7,8-tétrahydro-2h-indéno[5,4-b]furan-8-yl)éthyl] propionamide et nouveaux intermédiaires de ce composé
WO2010092107A1 (fr) * 2009-02-12 2010-08-19 Lek Pharmaceuticals D.D. Synthèse de (s)-n-[2-(1,6,7,8-tétrahydro-2h-indéno-[5,4-b]furan-8-yl)éthyl]propionamide
JP2012520291A (ja) * 2009-03-10 2012-09-06 インダストリアレ チミカ ソシエタ ア レスポンサビリタ リミタータ ラメルテオンの調製方法
WO2012035303A2 (fr) 2010-09-17 2012-03-22 Cipla Limited Et Al Nouveau procédé de synthèse du ramelteon et intermédiaires clés pour la synthèse du ramelteon
CN108072711A (zh) * 2016-11-18 2018-05-25 万特制药(海南)有限公司 高效液相色谱法分离测定雷美替胺中间体光学异构体

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