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WO2011027319A1 - Procédé de préparation d'un produit intermédiaire de rameltéon - Google Patents

Procédé de préparation d'un produit intermédiaire de rameltéon Download PDF

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Publication number
WO2011027319A1
WO2011027319A1 PCT/IB2010/053959 IB2010053959W WO2011027319A1 WO 2011027319 A1 WO2011027319 A1 WO 2011027319A1 IB 2010053959 W IB2010053959 W IB 2010053959W WO 2011027319 A1 WO2011027319 A1 WO 2011027319A1
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WIPO (PCT)
Prior art keywords
formula
tetrahydro
indeno
furan
process according
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/IB2010/053959
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English (en)
Inventor
Suresh Babu Jayachandra
Preeti Walia
Chandra Has Khanduri
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Filing date
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Publication of WO2011027319A1 publication Critical patent/WO2011027319A1/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

  • the present invention relates to a process for the preparation of (2E)- 1,2,6,7- tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I,
  • the present invention further relates to a process for the preparation of ramelteon using (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I as an intermediate.
  • Ramelteon is chemically N- ⁇ 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8- yl] ethyl ⁇ prop anamide having the structure of Formula II,
  • Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTi and ⁇ 2 receptors and selectivity over the MT 3 receptor. Ramelteon acts as an oral hypnotic agent and it is available in the market for the treatment of insomnia characterized by difficulty with sleep onset.
  • U.S. Patent No. 6,034,239 provides a process for the preparation of ramelteon, wherein the process involves reducing (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I,
  • U.S. Patent No. 6,034,239 provides a process for the preparation of (2E)-1,2,6,7- tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I by reacting 1,2,6,7- tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V,
  • EP Patent Application No. 1 792 899 provides a process for the preparation of (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I by reacting l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V,
  • the present inventors have found that the use of a mixture of solvents, wherein at least one solvent is a urea derivative, provides a way for facile and simple isolation of (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I from the reaction mixture.
  • the present inventors have also found that, when a mixture of solvents, wherein at least one solvent is a urea derivative, is employed as a solvent system, the quantity of the solvents can be reduced tremendously compared to prior art processes while the yield can be increased to about 90% or above.
  • the present invention provides a simple, economic and efficient process for preparing ramelteon using (2E)- l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I as an intermediate.
  • a first aspect of the present invention provides a process for the preparation of (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I,
  • l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V is reacted with a dialkyl cyanomethylphosphonate, for example, diethyl cyanomethylphosphonate, in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative.
  • the mixture of solvents comprises at least two organic solvents, wherein at least one solvent is a urea derivative.
  • the mixture of solvents is used in a volume of about 2 times to about 15 times the weight of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V.
  • the mixture of solvents is, for example, used in a volume of about 5 times to about 10 times the weight of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V.
  • the organic solvent is selected from the group consisting of alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, cyclic ethers and sulfoxides.
  • the organic solvent may be, for example, tetrahydrofuran, toluene or methanol, or a mixture thereof.
  • the urea derivative may be an alkyl substituted urea derivative, for example, 1,1,3,3-tetramethylurea (TMU) or a cyclic urea derivative, for example, ⁇ , ⁇ '-dimethylpropyleneurea (DMPU) or ⁇ , ⁇ '- dimethylethyleneurea (DMEU).
  • TMU 1,1,3,3-tetramethylurea
  • DMPU ⁇ , ⁇ '-dimethylpropyleneurea
  • DMEU ⁇ , ⁇ '- dimethylethyleneurea
  • the reaction may be carried out in the presence of a base.
  • the base may be selected from the group consisting of alkali metal hydrides, alkali metal amides and alkali metal alkoxides.
  • the base may be, for example, sodium hydride or sodium methoxide.
  • the reaction is carried out at about -10° to about 50°C, for example, at about 0° to about 10°C.
  • (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I may be isolated from the reaction mixture by adding water to the reaction mixture or by adding the reaction mixture to water, followed by filtration and/or concentration.
  • the compound of Formula I is optionally dried further and crystallized from an organic solvent, for example, an alkanol.
  • a second aspect of the present invention provides a process for the preparation of ramelteon of Formula II,
  • l,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V may be prepared according to the methods provided in U.S. Patent No 6,034,239 or EP Patent Application No. 1,792,899.
  • l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V is reacted with a dialkyl cyanomethylphosphonate, for example, diethyl cyanomethylphosphonate, in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative.
  • the mixture of solvents comprises at least two organic solvents, wherein at least one solvent is a urea derivative.
  • the mixture of solvents is used in a volume of about 2 times to about 15 times the weight of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V.
  • the mixture of solvents is, for example, used in a volume of about 5 times to about 10 times the weight of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V.
  • the reaction may be carried out in the presence of a base.
  • the base may be selected from a group consisting of alkali metal hydrides, alkali metal amides and alkali metal alkoxides.
  • the base may be, for example, sodium hydride or sodium methoxide.
  • the organic solvent is selected from the group consisting of alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, cyclic ethers and sulfoxides.
  • the organic solvent may be, for example, tetrahydrofuran, toluene or methanol, or a mixture thereof.
  • the urea derivative may be an alkyl substituted urea derivative, for example, 1,1,3,3-tetramethylurea (TMU) or a cyclic urea derivative, for example, ⁇ , ⁇ '-dimethylpropyleneurea (DMPU) or ⁇ , ⁇ '- dimethylethyleneurea (DMEU).
  • TNU 1,1,3,3-tetramethylurea
  • DMPU ⁇ , ⁇ '-dimethylpropyleneurea
  • DMEU dimethylethyleneurea
  • (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I may be isolated from the reaction mixture or directly used in the subsequent step without isolation.
  • the isolation may be carried out by adding water to the reaction mixture or by adding the reaction mixture to water, followed by filtration and/or concentration.
  • the compound of Formula I may also be dried further and crystallized from an organic solvent, for example, an alkanol.
  • (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I is hydrogenated to obtain (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethanamine of Formula III or its salt.
  • the hydrogenation is carried out in the presence of a solvent.
  • the solvent may be water or an organic solvent selected from the group consisting of alcohols, hydrocarbons, ethers, formamides and acetamides, or a mixture thereof.
  • the hydrogenation may be carried out in the presence of a hydrogenation catalyst and/or a base.
  • the hydrogenation catalyst may be Raney nickel, Raney cobalt or palladium-carbon.
  • the base may be ammonia, sodium or potassium acetate, triethylamine, pyridine, or an alkali metal carbonate or bicarbonate.
  • the hydrogenation is carried out at a temperature of about 10° to 100°C, for example, about 40° to about 60°C.
  • the hydrogen pressure may be from about 1 Kg/cm 2 to about 100 Kg/cm 2 , for example, from about 2 Kg/cm 2 to about 7 Kg/cm 2 .
  • (2£)-2-(l,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethanamine of Formula III may be isolated from the reaction mixture as a free base or as a salt.
  • (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III is, for example, isolated as an acid addition salt by contacting with an acid.
  • (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt so obtained is subjected to asymmetric reduction in the presence of a suitable catalyst.
  • the catalyst for asymmetric reduction may be a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex.
  • the catalyst may be, for example, Ru 2 Cl 4 [(R)-BINAP]2N(C 2 H5)3, ⁇ RuCl(Benzene)[(R)-BINAP] ⁇ Cl, ⁇ RuCl(p-Cymene) [(R)- BINAP] ⁇ C1, ⁇ RuBr(p-Cymene) [(R)-BINAP] ⁇ Br, ⁇ RuI(p-Cymene)[(R)-BINAP] ⁇ I 3 or ⁇ Rul(p-Cymene) [(R)-BINAP] ⁇ I.
  • the asymmetric reduction is carried out in the presence of a solvent and in hydrogen atmosphere under pressure.
  • the solvent may be water or an organic solvent selected from the group consisting of alcohols, hydrocarbons, ethers, formamides and acetamides, or a mixture thereof.
  • the asymmetric reduction is carried out at a temperature of about 10° to 100°C, for example, about 40° to about 60°C.
  • the hydrogen pressure may be from about 1 Kg/cm 2 to about 100 Kg/cm 2 , for example, from about 50 Kg/cm 2 to about 75 Kg/cm 2.
  • the reaction mixture is optionally subjected further catalytic reduction to reduce the by-products.
  • the catalytic reduction may be carried out in the presence of a hydrogenation catalyst, which may be Raney nickel, Raney cobalt or palladium-carbon.
  • 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV may be isolated from the reaction mixture as a free base or as a salt.
  • 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV is, for example, isolated as an acid addition salt by contacting with an acid.
  • 2-[(85')-l,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV or its salt is treated with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon.
  • a reactive derivative of propionic acid is preferably employed.
  • the reactive derivative may be selected from the group consisting of halides, amides, anhydrides, active azides and active esters of propionic acid.
  • the reactive derivate may be a halide of propionic acid, for example, propionyl chloride.
  • the reaction may be carried out in the presence of a de-acidifying agent in order to remove the released hydrogen halide.
  • the de- acidifying agent may be a base selected from the group consisting of inorganic bases, tertiary amines and aromatic amines.
  • the de-acidifying agent may be, for example, triethylamine.
  • the reaction is carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides.
  • the temperature for the reaction may be from about -20°C to about 100°C, for example, from about 5°C to about 25°C.
  • Ramelteon is isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, precipitation or a combination thereof.
  • Diethyl cyanomethylphosphonate (12.20 g) was added drop-wise at 0° to 5°C to a suspension of sodium hydride (2.75 g) in tetrahydrofuran (70 mL) and ⁇ , ⁇ '- dimethylpropyleneurea (10 mL). The mixture was stirred for 10 minutes and 1,2,6,7- tetrahydro-8H-indeno[5,4-b]furan-8-one (10 g) was added to the mixture while
  • the catalyst was prepared by stirring a mixture of methanol (140 mL), [RuCl 2 (p- cymene)] 2 (0.74 g) and (R)-BINAP (1.49 g) at 50°C for 2 hours.) The solution was hydrogenated at 60 to 65 kg/cm at 50°C for 24 hours. The solvent was recovered under vacuum and toluene (595 mL) was added to the residue. The pH of the mixture was adjusted to 2 to 3 using ethanolic hydrogen chloride (10 to 12%) at 10° to 15°C. The solid was filtered and dried under vacuum at 40° to 45°C to obtain the title compound.
  • Propionyl chloride (1.06 g) was added to a suspension of 2-[(SS)- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (2.5 g) and triethylamine (5.8 mL) in dichloromethane (25 mL) at a temperature of 10° to 15°C. The solution was stirred at about 25°C for 1 hour. The reaction mixture was poured into water (15 mL). The organic layer was separated and the solvent was removed under reduced pressure. The solid obtained was dissolved in ethyl acetate (5 mL), and diisopropylether (20 mL) was added to the solution. The resultant solution was stirred at 10° to 15°C for 30 minutes. The solid was filtered to obtain the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé de préparation du composé (2E)- 1,2,6,7- tétrahydro-8H-indéno[5,4-b]furan-8-ylidèneéthanenitrile représenté par la formule (I). L'invention concerne de plus un procédé de préparation de rameltéon qui utilise le composé (2E)-1,2,6,7-tétrahydro-8H-indéno[5,4-b]furan-8-ylidèneéthanenitrile représenté par la formule (I) comme produit intermédiaire.
PCT/IB2010/053959 2009-09-03 2010-09-02 Procédé de préparation d'un produit intermédiaire de rameltéon Ceased WO2011027319A1 (fr)

Applications Claiming Priority (2)

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IN1822DE2009 2009-09-03
IN1822/DEL/2009 2009-09-03

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103396387A (zh) * 2013-08-07 2013-11-20 安徽联创药物化学有限公司 雷美替胺中间体的制备方法
CN113045524A (zh) * 2021-03-24 2021-06-29 河南牧业经济学院 一种雷美替胺中间体的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020914A1 (fr) * 1994-12-30 1996-07-11 Ligand Pharmaceuticals Incorporated Retinoides tricycliques et leurs procedes de production et d'utilisation
US6034239A (en) 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1792899A1 (fr) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Procédé de fabrication de dérivés d amines optiquement actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020914A1 (fr) * 1994-12-30 1996-07-11 Ligand Pharmaceuticals Incorporated Retinoides tricycliques et leurs procedes de production et d'utilisation
US6034239A (en) 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1792899A1 (fr) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Procédé de fabrication de dérivés d amines optiquement actifs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CANAN KOCH S S ET AL: "Identification of the First Retinoid X Receptor Homodimer Antagonist", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 39, no. 17, 1 January 1996 (1996-01-01), pages 3229 - 3234, XP002279258, ISSN: 0022-2623, DOI: DOI:10.1021/JM960311D *
MICHELLYS P-Y ET AL: "Design and synthesis of novel RXR-selective modulators with improved pharmacological profile", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 13, no. 22, 17 November 2003 (2003-11-17), pages 4071 - 4075, XP002418978, ISSN: 0960-894X, DOI: DOI:10.1016/J.BMCL.2003.08.048 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103396387A (zh) * 2013-08-07 2013-11-20 安徽联创药物化学有限公司 雷美替胺中间体的制备方法
CN113045524A (zh) * 2021-03-24 2021-06-29 河南牧业经济学院 一种雷美替胺中间体的合成方法
CN113045524B (zh) * 2021-03-24 2023-09-22 河南牧业经济学院 一种雷美替胺中间体的合成方法

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