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WO2011027319A1 - Process for the preparation of an intermediate for ramelteon - Google Patents

Process for the preparation of an intermediate for ramelteon 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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formula
tetrahydro
indeno
furan
process according
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French (fr)
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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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    • 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

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

Abstract

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)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula (I) as an intermediate.

Description

PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR
RAMELTEON
Field of the Invention
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,
Figure imgf000002_0001
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.
Background of the Invention
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,
Figure imgf000002_0002
FORMULA II
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTi and ΜΤ2 receptors and selectivity over the MT3 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,
FORMULA I
to obtain (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III,
Figure imgf000003_0002
FORMULA III
asymmetrically reducing the compound of Formula III to obtain 2-[(85')-l,6,7,8 tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV,
Figure imgf000003_0003
FORMULA IV
and reacting 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV with propionyl chloride to obtain ramelteon.
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,
Figure imgf000004_0001
FORMULA V
with diethyl cyanomethylphosphonate in the presence of sodium hydride. Tetrahydrofuran is used as a solvent for this reaction and tetrahydrofuran is used in a quantity of about 27 times more than that of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V. (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I is isolated from the reaction mixture by column chromatography with 60% yield.
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,
Figure imgf000004_0002
FORMULA V
with diethyl cyanomethylphosphonate in the presence of sodium methoxide. Toluene is used as a solvent for this reaction in a quantity of about 22 times more than that of 1,2,6,7- tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V. (2E)-l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I is isolated with 84.4% yield by layer separation and crystallization.
The prior art processes for preparing (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-ylideneethanenitrile of Formula I involves excessive use of solvents such as tetrahydrofuran or toluene. While following the prior art processes for preparing (2E)- l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I, the present inventors have observed that a sludge or a semisolid mass is formed during the reaction, which makes the isolation process often unsuccessful and potentially impacts the yield. Thus, attaining the reported yield by following the prior art processes is found to be highly difficult. Summary of the Invention
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. Thus, 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.
Detailed Description of the Invention
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,
Figure imgf000005_0001
FORMULA I
wherein the process comprises a step of reacting l,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-one of Formula V,
Figure imgf000005_0002
FORMULA V
with a dialkyl cyanomethylphosphonate in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative, to obtain (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 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 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, Ν,Ν'-dimethylpropyleneurea (DMPU) or Ν,Ν'- dimethylethyleneurea (DMEU). 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,
Figure imgf000007_0001
FORMULA II
wherein the process comprises,
a) reacting l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V,
Figure imgf000007_0002
FORMULA V
with a dialkyl cyanomethylphosphonate in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative, to obtain (2E)- 1,2,6,7 -tetrahydro- 8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I
Figure imgf000007_0003
FORMULA I
b) hydrogenating (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I to obtain (2E)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt,
Figure imgf000007_0004
FORMULA III c) asymmetrically reducing (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-ylidene)ethanamine of Formula III or its salt, to obtain 2-[(85')-l, 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV or its salt,
Figure imgf000008_0001
FORMULA IV
d) reacting 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV or its salt with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon, and
e) isolating ramelteon from the reaction mixture thereof.
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, Ν,Ν'-dimethylpropyleneurea (DMPU) or Ν,Ν'- dimethylethyleneurea (DMEU). 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 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/cm2 to about 7 Kg/cm2. (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, Ru2Cl4[(R)-BINAP]2N(C2H5)3, {RuCl(Benzene)[(R)-BINAP] }Cl, {RuCl(p-Cymene) [(R)- BINAP] }C1, {RuBr(p-Cymene) [(R)-BINAP] }Br, {RuI(p-Cymene)[(R)-BINAP] }I3 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. In the case where a halide of propionic acid is used as the reactive derivate, 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.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES
Example 1: Preparation of (2E)-l,2,6,7-Tetrahydro-gH-indenor5,4-51furan-8- ylideneethanenitrile :
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 Ν,Ν'- 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
maintaining temperature at 5° to 10°C. The reaction mixture was stirred for 2 hours, poured into water (200 mL) and filtered. The solid obtained was dried under vacuum at 40° to 45°C and crystallized from methanol (50 mL) to obtain the title compound.
Yield: 10.4 g
Example 2: Preparation of Ramelteon:
A) Preparation of (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4- >]furan-8- ylidene)ethanamine h drochloride :
(2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile (60 g) was hydrogenated (5 kg/cm2) in ethanolic ammonia solution (8%, 480 mL) at 45° to 50°C for 6 to 7 hours. The reaction mixture was filtered and the solvent was recovered under vacuum. Ethanol (80 mL) and diisopropyl ether (290 mL) were added to the residue and cooled to 10° to 15°C. Ethanolic hydrochloride (10 to 12%; 120 mL) was added to the reaction mixture to adjust pH to about 2 and the solid was filtered, dried under vacuum at 40° to 45°C to obtain the title compound.
Yield: 60.2 g
B) Preparation of 2-[(85)-l,6,7,8-tetrahydro-2H-indeno[5,4- >]furan-8-yl]ethanamine hydrochloride:
A suspension of (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine hydrochloride (70 g) in toluene (700 mL) and water (350 mL) was treated with 10% aqueous sodium hydroxide to attain a pH of 8 to 8.5. The organic layer was separated and solvent was recovered under vacuum at 40° to 45°C. Methanol (59.5 mL), tetrahydrofuran (29.7 mL) and catalyst { [RuCl(p-cymene)(R) -BINAP]C1 in MeOH were added to the residue. (The catalyst was prepared by stirring a mixture of methanol (140 mL), [RuCl2(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.
Yield: 56 g
C) Preparation of Ramelteon:
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.
Yield: 2.2 g

Claims

We claim:
1. A process for the preparation of (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I,
Figure imgf000013_0001
FORMULA I
wherein the process comprises a step of reacting l,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-one of Formula V,
Figure imgf000013_0002
FORMULA V
with a dialkyl cyanomethylphosphonate in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative, to obtain (2E)-l,2,6,7-tetrahydro- 8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I.
2. A process according to claim 1, wherein the dialkyl cyanomethylphosphonate is diethyl cyanomethylphosphonate.
3. A process according to claim 1, wherein the mixture of solvents comprises at least two organic solvents, wherein at least one solvent is a urea derivative.
4. A process according to claim 1, wherein 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.
5. A process according to claim 4, wherein the organic solvent is selected from a group consisting of tetrahydrofuran, toluene and methanol, or a mixture thereof.
6. A process according to claim 1, wherein the urea derivative is selected from a group consisting of an alkyl substituted urea derivative and a cyclic urea derivative. 7. A process for the preparation of ramelteon of Formula II,
Figure imgf000014_0001
FORMULA II wherein the process comprises, a) reacting l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula V,
Figure imgf000014_0002
FORMULA V
with a dialkyl cyanomethylphosphonate in the presence of a mixture of solvents, wherein at least one solvent is a urea derivative, to obtain (2E)- 1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneethanenitrile of Formula I
Figure imgf000014_0003
FORMULA I b) hydrogenating (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylideneethanenitrile of Formula I to obtain (2E)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt,
Figure imgf000015_0001
FORMULA III c) asymmetrically reducing (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-ylidene)ethanamine of Formula III or its salt, to obtain 2-[(SS)- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV or its salt,
Figure imgf000015_0002
FORMULA IV d) reacting 2-[(85')-l,6,
7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IV or its salt with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon, and e) isolating ramelteon from the reaction mixture thereof.
8. A process according to claim 7, wherein the dialkyl cyanomethylphosphonate is diethyl cyanomethylphosphonate.
9. A process according to claim 7, wherein a mixture of solvents comprises at least two organic solvents, wherein at least one solvent is a urea derivative.
10. A process according to claim 7, wherein the hydrogenation is carried out in the presence of a hydrogenation catalyst and a base.
11. A process according to claim 10, wherein the hydrogenation catalyst is selected from a group consisting of Raney nickel, Raney cobalt or palladium-carbon.
12. A process according to claim 7, wherein the asymmetric reduction is carried out using a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex.
13. A process according to claim 7, wherein 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula IV or its salt is reacted with a reactive derivative of propionic acid.
14. A process according to claim 13, wherein the reactive derivative of propionic acid is selected from the group consisting of halides, amides, anhydrides, active azides and active esters of propionic acid.
15. A process according to claim 14, wherein the reactive derivative of propionic acid is propionyl chloride.
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