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WO2011027323A1 - Process for the preparation of ramelteon - Google Patents

Process for the preparation of ramelteon Download PDF

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Publication number
WO2011027323A1
WO2011027323A1 PCT/IB2010/053963 IB2010053963W WO2011027323A1 WO 2011027323 A1 WO2011027323 A1 WO 2011027323A1 IB 2010053963 W IB2010053963 W IB 2010053963W WO 2011027323 A1 WO2011027323 A1 WO 2011027323A1
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Prior art keywords
formula
furan
ethanamine
tetrahydro
indeno
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PCT/IB2010/053963
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French (fr)
Inventor
Suresh Babu Jayachandra
Preeti Walia
Raghuram Morampudi
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

Definitions

  • the present invention relates to a process for the preparation of ramelteon using 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof as an intermediate.
  • Ramelteon is chemically described as N- ⁇ 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethyl ⁇ propanamide, having the structure of Formula II.
  • Ramelteon is a melatonin receptor agonist with high affinity for both melatonin MTi and ⁇ 2 receptors and selectivity over the MT 3 receptor. Ramelteon acts as an oral hypnotic agent and 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 asymmetric reduction of (2E)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru-BINAP catalyst in the presence of methanol and hydrogen gas up to 100 atmospheric pressure followed by treatment with hydrochloric acid,
  • hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is further reacted with propionyl chloride to obtain ramelteon.
  • European Patent No. EP 1 792 899 provides an improved process for the preparation of the hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan- 8-yl]ethanamine of Formula I.
  • the process involves asymmetric reduction of (2E)-2- (l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru- BINAP catalyst in the presence of toluene and methanol under hydrogen atmosphere of 4.9 MPa; this is followed by treatment with concentrated hydrochloric acid.
  • This method subsequently employs an additional catalytic hydrogenation with palladium-carbon in the presence of sodium hydroxide to convert 2-[(8S)-7,8-dihydro-6H-indeno[5,4-b]furan-8- yl]ethanamine of Formula IA into the desired compound of Formula I.
  • European Patent No. EP 1 792 899 also employs further crystallization steps to achieve acceptable purity levels.
  • the present inventors have also observed that the hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained by the asymmetric reduction step described in the prior art suffers from low chiral purity.
  • the present inventors have developed an advantageous process for the preparation of 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts.
  • the present process does not require an additional reduction step with palladium- carbon as described in the prior art and at the same time provides 2-[(85')-l , 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts with a better purity and yield.
  • the present inventors have also found that the chiral purity of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I can be tremendously improved, without compromising the yield, by treating the hydrochloride salt of 2-[(SS)- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I with a solvent system comprising ethanol.
  • the present invention provides a simple, economic and efficient process for preparing ramelteon using 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I or its hydrochloride salt as an intermediate.
  • the present invention provides for a process for the preparation of ramelteon of Formula II.
  • the process includes:
  • step a) is carried out in the presence of a catalyst and the suitable catalyst may be a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex.
  • the catalyst may be Ru 2 Cl 4 [(R)-BINAP]2N(C 2 H5)3, ⁇ RuCl(Benzene)[(R)- BINAP] ⁇ C1, ⁇ 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 solvent system in step a) may include an additional organic solvent.
  • an additional organic solvent for example, a mixture of methanol and tetrahydrofuran is used as a solvent system.
  • the present invention provides for a process for the preparation of ramelteon of Formula II.
  • the process includes:
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity at least 1% higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I; b) optionally, converting the second hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base;
  • step a) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
  • Embodiments of this aspect may include one or more of the following features.
  • the solvent system in step a) utilizes ethanol as the only solvent.
  • Step a) the process may further include dissolving the first hydrochloride salt of 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I in the solvent system that includes ethanol, partially removing the solvent and isolating the second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I from the mixture thereof.
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about .05% more than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I.
  • a first aspect of the present invention provides a process for the preparation of ramelteon of Formula II
  • Formula III or its salt may be prepared according to the method provided in European Patent No. EP 1 792 899 or U.S. Patent No. 6,034,239. (2£)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt is subjected to asymmetric reduction in the presence of a solvent system, which includes tetrahydrofuran and 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 solvent system may additionally contain an organic solvent selected from the group consisting of alcohols, hydrocarbons, ethers, formamides and acetamides, or a mixture thereof.
  • the solvent may be, for example, a mixture of methanol and tetrahydrofuran.
  • the asymmetric reduction is carried out in a hydrogen atmosphere under pressure at a temperature of about 10°C to 100°C; for example, about 40°C to about 60°C.
  • the hydrogen pressure may be from about 1 Kg/cm to about 100 Kg/cm 2 , for example, from about 50 Kg/cm 2 to about 75 Kg/cm 2. No additional steps of catalytic reduction are needed.
  • (2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof may be isolated from the reaction mixture.
  • 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is isolated as a hydrochloride salt by treating with
  • hydrochloric acid for example, ethanolic hydrochloric acid.
  • 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I 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 may be employed.
  • the reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid.
  • the reactive derivate may be, 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 may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides.
  • the organic solvent may be, for example, dichloromethane.
  • 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 may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent precipitation, or a combination thereof.
  • a second aspect of the present invention provides a process for the preparation of ramelteon of Formula II,
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
  • step b) optionally converting the second hydrochloride salt of 2-[(85')-l, 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base,
  • step a) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon; and
  • the first hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I may be prepared according to the methods provided in U.S. Patent No. 6,034,239 or European Patent No. EP 1 792 899 or the previous aspect of the present invention.
  • the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I is treated with a solvent system that includes ethanol.
  • the solvent system may contain ethanol as the only solvent.
  • the treatment with the solvent system that includes ethanol comprises the steps of dissolving the first hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I in the solvent system of ethanol, partially removing the solvent, specifically, for example, from about 50% to about 80% of the solvent, stirring the resultant mixture at a temperature range of from about 0° to about 25°C, and isolating the second hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I by filtration, decantation, solvent evaporation, concentration or a combination thereof.
  • the second hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I.
  • the second hydrochloride salt of 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about 1% more than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I.
  • the second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I may optionally be converted into free base by treating with an organic or inorganic base.
  • the second hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its free base is treated with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon.
  • a reactive derivative of propionic acid may be employed.
  • the reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid.
  • the reactive derivate may be, 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 may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides.
  • the organic solvent may be, for example, dichloromethane.
  • 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 may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent precipitation, or a combination thereof.
  • 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 hydrochloride (10 to 12%) at 10°C to 15°C. The solid was filtered and dried under vacuum at 40°C to 45 °C to obtain the title compound. Yield: 48.03 g
  • Example 2 Purification of 2-r(8 t S')-l,6,7,8-tetrahydro-2H-Indenor5,4-blfuran-8- yllethanamine Hydrochloride: 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (chemical purity 99.42% and chiral purity 98.54%; 47 g) was dissolved in ethanol (1175 ml) at 50°C to 55°C. Approximately 75% of the ethanol was recovered at 50°C to 55°C under vacuum (not less than 650 mmHg). The mixture was cooled slowly to 10°C to 15°C and stirred for 1 hour. The solid obtained was filtered, washed with cold ethanol (47 ml) and dried under vacuum at 40°C to 45 °C to obtain the title compound.

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Abstract

The present invention relates to a process for the preparation of ramelteon using 2- [(8S)-1, 6,7, 8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof as an intermediate.

Description

PROCESS FOR THE PREPARATION OF RAMELTEON
Field of the Invention
The present invention relates to a process for the preparation of ramelteon using 2- [(85,)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof as an intermediate.
Figure imgf000003_0001
FORMULA I
Background of the Invention
Ramelteon is chemically described as N-{2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethyl}propanamide, having the structure of Formula II.
Figure imgf000003_0002
FORMULA II
Ramelteon is a melatonin receptor agonist with high affinity for both melatonin MTi and ΜΤ2 receptors and selectivity over the MT3 receptor. Ramelteon acts as an oral hypnotic agent and 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 asymmetric reduction of (2E)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru-BINAP catalyst in the presence of methanol and hydrogen gas up to 100 atmospheric pressure followed by treatment with hydrochloric acid,
Figure imgf000004_0001
FORMULA III
to obtain the hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I.
Figure imgf000004_0002
FORMULA I
The hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is further reacted with propionyl chloride to obtain ramelteon.
According to European Patent No. EP 1 792 899, the above process is not suitable for an industrial production method as it results in by-products, specifically an impurity, 2- [(85,)-7,8-dihydro-6H-indeno[5,4-b]furan-8-yl]ethanamine of Formula IA.
Figure imgf000004_0003
FORMULA IA
European Patent No. EP 1 792 899 provides an improved process for the preparation of the hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan- 8-yl]ethanamine of Formula I. The process involves asymmetric reduction of (2E)-2- (l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru- BINAP catalyst in the presence of toluene and methanol under hydrogen atmosphere of 4.9 MPa; this is followed by treatment with concentrated hydrochloric acid. This method subsequently employs an additional catalytic hydrogenation with palladium-carbon in the presence of sodium hydroxide to convert 2-[(8S)-7,8-dihydro-6H-indeno[5,4-b]furan-8- yl]ethanamine of Formula IA into the desired compound of Formula I. European Patent No. EP 1 792 899 also employs further crystallization steps to achieve acceptable purity levels. The present inventors have also observed that the hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained by the asymmetric reduction step described in the prior art suffers from low chiral purity. The purification of the hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H-indeno[5,4-b]furan- 8-yl]ethanamine of Formula I with solvents such as methanol, acetone or ethyl acetate either decreases the yield or still yields a chirally less pure material.
The present inventors have developed an advantageous process for the preparation of 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts. The present process does not require an additional reduction step with palladium- carbon as described in the prior art and at the same time provides 2-[(85')-l , 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts with a better purity and yield.
The present inventors have also found that the chiral purity of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I can be tremendously improved, without compromising the yield, by treating the hydrochloride salt of 2-[(SS)- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I with a solvent system comprising ethanol.
Thus, the present invention provides a simple, economic and efficient process for preparing ramelteon using 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I or its hydrochloride salt as an intermediate. Summary of the Invention
In one general aspect, the present invention provides for a process for the preparation of ramelteon of Formula II.
Figure imgf000006_0001
FORMULA II
The process includes:
a) asymmetrically reducing (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethanamine of Formula III or its salt in the presence of a solvent system comprising tetrahydrofuran,
Figure imgf000006_0002
FORMULA III
to obtain 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof;
Figure imgf000006_0003
FORMULA I
b) reacting 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
c) isolating ramelteon from the reaction mixture thereof. Embodiments of the present aspect may include one or more of the following features. For example, step a) is carried out in the presence of a catalyst and the suitable catalyst may be a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex. In particular, the catalyst may be Ru2Cl4[(R)-BINAP]2N(C2H5)3, {RuCl(Benzene)[(R)- BINAP] }C1, {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 solvent system in step a) may include an additional organic solvent. For example, a mixture of methanol and tetrahydrofuran is used as a solvent system.
In another aspect, the present invention provides for a process for the preparation of ramelteon of Formula II.
Figure imgf000007_0001
FORMULA II
The process includes:
a) treating a first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I with a solvent system that includes ethanol to obtain a second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
Figure imgf000007_0002
FORMULA I
wherein the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity at least 1% higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I; b) optionally, converting the second hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base;
c) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
d) isolating ramelteon from the reaction mixture thereof.
Embodiments of this aspect may include one or more of the following features. For example, the solvent system in step a) utilizes ethanol as the only solvent.
Step a) the process may further include dissolving the first hydrochloride salt of 2- [(85,)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I in the solvent system that includes ethanol, partially removing the solvent and isolating the second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I from the mixture thereof.
In this aspect, the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about .05% more than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of ramelteon of Formula II,
Figure imgf000008_0001
FORMULA II wherein the process includes:
a) asymmetrically reducing (2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethanamine of Formula III or its salt in the presence of a solvent system which includes tetrahydrofuran,
Figure imgf000009_0001
FORMULA III
to obtain 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof,
Figure imgf000009_0002
FORMULA I
b) reacting 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
c) isolating ramelteon from the reaction mixture thereof.
(2E)-2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of
Formula III or its salt may be prepared according to the method provided in European Patent No. EP 1 792 899 or U.S. Patent No. 6,034,239. (2£)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt is subjected to asymmetric reduction in the presence of a solvent system, which includes tetrahydrofuran and 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 solvent system may additionally contain an organic solvent selected from the group consisting of alcohols, hydrocarbons, ethers, formamides and acetamides, or a mixture thereof. The solvent may be, for example, a mixture of methanol and tetrahydrofuran. The asymmetric reduction is carried out in a hydrogen atmosphere under pressure at a temperature of about 10°C to 100°C; for example, about 40°C to about 60°C. The hydrogen pressure may be from about 1 Kg/cm to about 100 Kg/cm 2 , for example, from about 50 Kg/cm 2 to about 75 Kg/cm 2. No additional steps of catalytic reduction are needed. (2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof may be isolated from the reaction mixture. For example, 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is isolated as a hydrochloride salt by treating with
hydrochloric acid, for example, ethanolic hydrochloric acid.
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salt is treated with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon. For example, a reactive derivative of propionic acid may be employed. The reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid. The reactive derivate may be, for example, propionyl chloride. In the case where the 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 may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides. The organic solvent may be, for example, dichloromethane. 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 may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent precipitation, or a combination thereof.
A second aspect of the present invention provides a process for the preparation of ramelteon of Formula II,
Figure imgf000011_0001
FORMULA II
wherein the process includes:
a) treating a first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I with a solvent system that includes ethanol to obtain a second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
Figure imgf000011_0002
FORMULA I
wherein the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
b) optionally converting the second hydrochloride salt of 2-[(85')-l, 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base,
c) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon; and
d) isolating ramelteon from the reaction mixture thereof. The first hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I may be prepared according to the methods provided in U.S. Patent No. 6,034,239 or European Patent No. EP 1 792 899 or the previous aspect of the present invention. The first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I is treated with a solvent system that includes ethanol. The solvent system may contain ethanol as the only solvent. The treatment with the solvent system that includes ethanol comprises the steps of dissolving the first hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I in the solvent system of ethanol, partially removing the solvent, specifically, for example, from about 50% to about 80% of the solvent, stirring the resultant mixture at a temperature range of from about 0° to about 25°C, and isolating the second hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I by filtration, decantation, solvent evaporation, concentration or a combination thereof. The second hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I. For example, the second hydrochloride salt of 2- [(85,)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about 1% more than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I.
The second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I may optionally be converted into free base by treating with an organic or inorganic base. The second hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its free base is treated with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon. For example, a reactive derivative of propionic acid may be employed. The reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid. The reactive derivate may be, for example, propionyl chloride. In the case where the 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 may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides. The organic solvent may be, for example, dichloromethane. 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 may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent 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.
Example 1 : Preparation of 2-\(SS)- 1,6,7, 8-tetrahydro-2H-Indenor5,4-blfuran-8- yllethanamine 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 the solvent was recovered under vacuum at 40°C to 45 °C. Methanol (59.5 ml), tetrahydrofuran (29.7 mL) and the catalyst { [RuCl(p-cymene)(R) -BINAP]C1 in methanol 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 hydrochloride (10 to 12%) at 10°C to 15°C. The solid was filtered and dried under vacuum at 40°C to 45 °C to obtain the title compound. Yield: 48.03 g
Chiral purity: 98.54%
Chemical purity: 99.42%
Example 2: Purification of 2-r(8tS')-l,6,7,8-tetrahydro-2H-Indenor5,4-blfuran-8- yllethanamine Hydrochloride: 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (chemical purity 99.42% and chiral purity 98.54%; 47 g) was dissolved in ethanol (1175 ml) at 50°C to 55°C. Approximately 75% of the ethanol was recovered at 50°C to 55°C under vacuum (not less than 650 mmHg). The mixture was cooled slowly to 10°C to 15°C and stirred for 1 hour. The solid obtained was filtered, washed with cold ethanol (47 ml) and dried under vacuum at 40°C to 45 °C to obtain the title compound.
Yield: 83%
Chiral purity: 99.66%
Chemical purity (HPLC): 99.92%
Example 3: Purification of 2-r(8S)-l,6J,8-tetrahvdro-2H-Indenor5,4-blfuran-8- yllethanamine Hydrochloride
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (5 g; chiral purity: 89.82%) was dissolved in ethanol (120 ml) at 60°C. Approximately 75% of the ethanol was recovered at 50°C to 55°C under vacuum (not less than 650 mmHg). The mixture was stirred at 25 °C to 25 °C for 2 hours and the stirring was continued for 1 hour at 0° to 5°C. The solid obtained was filtered to obtain the title compound.
Yield: 82%
Chiral purity: 99.2%
Example 4: Preparation of Ramelteon
A mixture of dichloromethane (250 ml), 2-[(8S)- 1,6,7, 8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine hydrochloride as prepared in Example 2 (25 g) and tri-ethylamine (28.8 mL) was cooled to 10°C to 15°C. Propionyl chloride (10.62 g) was added drop-wise at 10°C to 15°C to the mixture and stirred at 20°C to 25 °C for 60 minutes. Water (125 ml) was added to the reaction mixture and the organic layer was separated. The solvent was removed under reduced pressure at 40°C. The residue was treated with carbon in ethyl acetate (125 ml) at 50°C to 55°C for 30 minutes and filtered. Ethyl acetate (about 50 ml) was removed under reduced pressure and diisopropylether (200 ml) was added to the residue. The mixture was stirred at 10°C to 15°C for 1 hour. The solid obtained was filtered, washed with diisopropylether (50 m) and dried under vacuum at 60°C to 65 °C to obtain the title compound.
Yield: 90%
Chiral Purity: 100%
Chemical purity (HPLC):99.56
Comparative Example 1: Purification of 2-\(SS)- 1,6,7, 8-tetrahvdro-2H-Indenor5,4- b\ furan- 8 -yll ethanamine Hydrochloride
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (5 g; chiral purity: 89.82%) was dissolved in methanol (25 ml) at 60°C. The solution was stirred at 0°C to 5°C for 1 hour and filtered to obtain the title compound.
Yield: 51%
Chiral purity: 98.1%
Comparative Example 2: Purification of 2-IY8S)- 1,6,7, 8-tetrahvdro-2H-Indenor5,4- b\ furan- 8 -yll ethanamine Hydrochloride
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride
(5 g; chiral purity: 89.82%) was dissolved in methanol (25 ml) at 60°C. Acetone (50 ml) was added to the solution, stirred at 0°C to 5°C for 1 hour and filtered to obtain the title compound.
Yield: 52%
Chiral purity: 99.14%
Comparative Example 3: Purification of 2-r(8tS,)-l,6,7,8-tetrahydro-2H-Indenor5,4- b\ furan- 8 -yll ethanamine Hydrochloride
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (5 g; chiral purity: 89.82%; Chemical purity: NA) was dissolved in methanol (25 ml) at 60°C. Acetone (100 ml) was added to the solution, stirred at 0°C to 5°C for 1 hour and filtered to obtain the title compound.
Yield: 64%
Chiral purity: 98.3% Comparative Example 4: Purification of 2-r(8tSr)-l,6,7,8-tetrahydro-2H-Indenor5,4- bl furan- 8 - yll ethanamine Hydrochloride
2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (5 g; chiral purity: 89.82%) was dissolved in methanol (15 ml) at 60°C. Acetone (50 ml) was added to the solution, stirred at 0°C to 5°C for 1 hour and filtered to obtain the title compound.
Yield: 64%
Chiral purity: 98.7%
Comparative Example 5: Purification of 2-r(8tS,)-l,6J,8-tetrahydro-2H-Indenor5,4- b\ furan- 8 - yll ethanamine Hydrochloride
A mixture of 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (1 g; chiral purity: 89.82%) and ethyl acetate (30 ml) were stirred at 60°C for 30 minutes. The stirring was further continued at 20°C to 25 °C for 1 hour and filtered to obtain the title compound.
Yield: 70%
Chiral purity: 91.3%

Claims

WE CLAIM:
A process for the preparation of ramelteon of Formula II,
Figure imgf000017_0001
FORMULA II
wherein the process comprises:
a) asymmetrically reducing (2E)-2-(l,
2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethanamine of Formula III or its salt in the presence of a solvent system comprising tetrahydrofuran,
Figure imgf000017_0002
FORMULA III
to obtain 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof;
Figure imgf000017_0003
FORMULA I
b) reacting 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
c) isolating ramelteon from the reaction mixture thereof.
A process according to claim 1, wherein step a) is carried out in the presence of a catalyst.
3. A process according to claim 2, wherein the catalyst comprises a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex.
4. A process according to claim 3, wherein the catalyst comprises Ru2C [(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.
5. A process according to claim 1, wherein the solvent system in step a) comprises an additional organic solvent.
6. A process according to claim 5, wherein the solvent system in step a) comprises a mixture of methanol and tetrahydrofuran.
7. A process for the preparation of ramelteon of Formula II,
Figure imgf000018_0001
FORMULA II
wherein the process comprises:
a) treating a first hydrochloride salt of 2-[(8S)- 1,6,7, 8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I with a solvent system comprising ethanol to obtain a second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
Figure imgf000018_0002
FORMULA I
wherein the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity at least 1% higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I;
b) optionally, converting the second hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base;
c) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
d) isolating ramelteon from the reaction mixture thereof.
8. A process according to claim 7, wherein the solvent system in step a) comprises ethanol as the only solvent.
9. A process according to claim 7, wherein step a) further comprises dissolving the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl] ethanamine of Formula I in the solvent system comprising ethanol, partially removing the solvent and isolating the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I from the mixture thereof.
10. A process according to claim 7, wherein the second hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about .05% more than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I.
PCT/IB2010/053963 2009-09-03 2010-09-02 Process for the preparation of ramelteon Ceased WO2011027323A1 (en)

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Cited By (2)

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CN106632177A (en) * 2016-12-05 2017-05-10 万特制药(海南)有限公司 Preparation method of ramelteon intermediate
CN113045524A (en) * 2021-03-24 2021-06-29 河南牧业经济学院 Synthesis method of ramelteon intermediate

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US6034239A (en) 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1792899A1 (en) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Process for production of optically active amine derivatives
WO2009093133A1 (en) * 2008-01-25 2009-07-30 Medichem, S.A. Method for determining the enantiomeric purity of indane derivatives

Patent Citations (3)

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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
EP1792899A1 (en) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Process for production of optically active amine derivatives
WO2009093133A1 (en) * 2008-01-25 2009-07-30 Medichem, S.A. Method for determining the enantiomeric purity of indane derivatives

Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN106632177A (en) * 2016-12-05 2017-05-10 万特制药(海南)有限公司 Preparation method of ramelteon intermediate
CN113045524A (en) * 2021-03-24 2021-06-29 河南牧业经济学院 Synthesis method of ramelteon intermediate
CN113045524B (en) * 2021-03-24 2023-09-22 河南牧业经济学院 A kind of synthetic method of ramelteon intermediate

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