Field of the invention

The present invention relates to a novel process for synthesis of ramelteon, and key intermediates for the synthesis of ramelteon.

Background of the invention

ROZEREM (ramelteon) is an orally active hypnotic, chemically designated as (S)-N-[2- (l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propio namide, and contains one chiral center. The compound is produced as the (S)-enantiomer, with an empirical formula of C ₁₆ H ₂₁ N0 ₂ , molecular weight of 259.34, and the following chemical structure (I):

(I) -Ramelteon

Ramelteon is used to help patients who have sleep-onset insomnia (difficulty falling asleep) to fall asleep more quickly. It is the first in a new class of sleep agents that selectively binds to the MT] and MT ₂ receptors in the suprachiasmatic nucleus (SCN), in a class of medications called melatonin receptor agonists with both high affinity for melatonin MT _! and MT ₂ receptors and selectivity over the MT ₃ receptor. It works similarly to melatonin, a natural substance in the brain that is needed for sleep.

Ramelteon was first disclosed in European patent EP 885210, which also disclosed a process for synthesizing ramelteon, as shown in scheme 1 : Scheme 1

Ramelteon

The processes of the prior art suffer from many disadvantages, some of which result from the fact that they involve several steps.

For instance, in US patent US 6034239, which is related to EP 885210, there is disclosed a process for preparing an intermediate compound of Formula (IV), which involves conversion of diethylcyano methyl phosphonate in the presence of 60% sodium hydride. Disadvantages of this particular reaction include the need for the highly flammable and corrosive base sodium hydride, the use of toxic triethyl phosphate for the formation of diethylcyano methyl phosphonate (which also has a high boiling point), and low yield of 60%. Such disadvantages mean that the disclosed process is difficult to implement industrially or economically. A further problem associated with prior art preparation techniques is the formation of dimeric impurities at the nitrile reduction stage (i.e. where the intermediate of Formula (IV) is reduced). For instance, US 6034239 discloses reduction of (l,2,6,7-Tetrahydro-8H-indeno-[5,4- b]furan-8-ylidene)-acetonitrile of formula (IV) by means of H ₂ over Raney nickel in in a solvent medium of ethanol NH ₃ to provide compound of formula (IIA). The reaction is carried out by applying 5 kg of hydrogen pressure, which results in the formation of the byproduct and impurity Dimer A, which in turn affects the yield and purity of the product of formula (IIA).

Dimer A

Similarly, (l,2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8-ylidene)-aceton itrile of formula (IV) may be reduced by means of H ₂ over Raney cobalt in a solvent medium of ethanol/ NH ₃ to afford compound of formula (IIB). The reaction, which is carried out by applying hydrogen pressure, is not selective, and results in the formation of the by-product and impurity Dimer B, which in turn affects the yield and purity of product of formula (IIB).

Dimer B

Repeated purifications are required to remove impurities such as Dimer A and B to obtain ramelteon having the desired purity, which results in the poor yield of ramelteon.

Several other approaches are also described in the literature to make ramelteon and related compounds in WO2006030739, WO208062468, WO2008106179, US 2010152468, WO2009106966 and WO2010/055481. However, all processes of the prior art for the preparation of ramelteon are cumbersome; the processes employ a plurality of reagents and involve multiple steps, which make the overall processes uneconomical. Therefore there is a need for a more economical, efficient and industrially suitable method of making ramelteon, whereby address the problems associated with prior art, some of which are discussed above.

The present invention provides a new process for the synthesis of ramelteon which addresses the problems associated with the prior art. Object of the invention

The object of the present invention is to provide a novel process for preparing ramelteon, and key intermediates therefor. Another object of the present invention is to provide ramelteon which is substantially free from dimeric impurities.

A further object of the present invention is to a process for the synthesis of ramelteon which reduces or substantially eliminates the formation of dimeric impurities.

Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale-up.

Summary of the Invention

In a first aspect, the present invention provides a process for preparing ramelteon of formula (I)

(I)

comprising catalytic reduction of a compound of formula (IV)

(IV)

in the presence of a metal borohydride and propionyl halide and/or propionic anhydride and a catalytic amount of a metal salt, preferably at a temperature ranging from about 0°C to 5 about 30°C, to form an enantiomeri ixture defined by formula (II)

(II)

and separating ramelteon of formula (I) from the enantiomeric mixture.

The compound of formula (IV) may be reduced at a temperature in the range of from about 10 25°C to about 30°C to yield the enantiomeric mixture defined by formula (II). An intermediate of formula (IIA)

(IIA)

may form during the reduction of the compound of formula (IV) to the enantiomeric mixture defined by formula (II), and said intermediate of formula (IIA) may not be isolated. The 15 catalytic reduction may be carried at a temperature in the range of from about 0°C to about 5°C to yield intermediate N-[2-(l,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)eth yl] propionamide of formula (III)

(III) which intermediate of formula (III) is then treated with a catalyst and a metal borohydride to produce the enantiomeric mixture of formula (II), wherein the catalyst is a palladium catalyst or a platinum catalyst, preferably a palladium catalyst. An intermediate of formula (IIB)

(IIB)

may form during the reduction of the compound of formula (IV) to the enantiomeric mixture of formula (II), and said intermediate of formula (IIB) may not be isolated. The metal borohydride may comprise NaBEL,, L1BH4, NaCNBHU (sodium cyanoborohydride), sodium trifluoro acetoxy borohydride, or any combination thereof; the metal borohydride preferably comprises NaBH^ The propionyl halide may comprise propionyl iodide, propionyl fluoride, propionyl chloride, propionyl bromide, or a combination thereof; propionyl chloride and/or propionyl bromide is preferred. The metal salt may comprise a transition metal salt; the transition metal preferably comprises Iron, Cobalt, Nickel, or a combination thereof. The metal salt may comprise a Ni (II) salt, preferably nickel (II) chloride. The metal salt may be present in an amount in the range of from 0.5 % to 5 % by weight of the compound of formula (IV). The catalytic reduction may be carried in the presence of a solvent, which preferably comprises a dry alcohol, more preferably methanol. The molar ratio of the compound of formula (IV) to the metal borohydride or the propionyl halide or propionic anhydride may vary from 1 :1 to 1 :10 equivalence, preferably 1 :1 to 1:8 equivalence. The molar ratio of the metal borohydride to the propionyl halide or propionyl anhydride may vary in the range of from 1 : 2 to 2:1, preferably 1 :1. The metal borohydride and propionyl halide or propionic anhydride may be added in lots. The step of separating ramelteon from the enantiomeric mixture may comprise optical resolution of the mixture of enantiomers defined by formula (II), preferably by means of high performance column chromatography, to obtain ramelteon of formula (I). The optical resolution may be carried out by packed column supercritical fluids chromatography. The process may further comprise the step of reacting a compound of formula (VI)

(VI)

with cyano acetic acid of formula (V)

(V)

in the presence of a base, preferably comprising a primary amine, a secondary amine, a tertiary amine, a heterocyclic amine, or a combination thereof, to obtain the compound of formula (IV). The base may comprise a heterocyclic amine, preferably piperidine and/or pyrrolidine. This reaction may be is carried out at a temperature ranging from about 80°C to about 150°C, preferably in the range of from about 100°C to about 120°C. The ramelteon produced in accordance with the present invention may be substantially free from a dimer of formula A and/ or B .

Dimer B

In another aspect, the present invention provides a process for the preparation of compound of formula (III), comprising: catalytic reduction of a compound of formula (IX)

using a metal borohydride and propionyl halide and/or propionic anhydride in the presence of a catalytic amount of a metal salt, at a temperature in the range from about 0°C to about 30°C to form a compound diethyl(2-ethyl propionamide)phosphonate of formula (VII).

(VII)

The catalytic reduction may be carried out in the presence of a dry alcohol, preferably methanol, and/or at a temperature in the range of from about 25°C to about 30°C.The compound of formula (VII) may be condensed with compound l,2,6,7-tetrahydro-8H- indeno-[5,4-b]furan-8-one of formula (VI) in the presence of a base in a suitable solvent to yield the compound of formula (III). The base may be an organic base, preferably comprising a primary amine, a secondary amine, a tertiary amine, or a combination thereof, and/or an inorganic base, preferably comprising a metal hydroxide, a metal alkoxide, a metal hydride, or a combination thereof, wherein the inorganic base preferably comprises a metal alkoxide, and more preferably sodium methoxide. The solvent may comprise alcohol, toluene, dimethylformamide, dimethylsulfoxide, or a combination thereof. The solvent may comprise alcohol, preferably methanol. The condensation may be carried out at a temperature ranging from about 40°C to about 100°C, preferably about 50°C to about 60°C. The compound of formula (III) may be reduced to provide the enantiomeric mixture defined by formula (II). Ramelteon of formula (I) may be separated from the enantiomeric mixture.

In another aspect the present invention provides a process for preparing a compound of formula (VII) comprising by reacting a compound diethyl(2-ethylamino)phosphonate of formula (VIII)

with propionyl halide and/or propionic anhydride in the presence of suitable solvent.

The reaction may be carried out using propionic anhydride. The solvent may comprise a non polar solvent, preferably dichloromethane. The reaction may be carried out in the presence of a base, preferably triethylamine. The reaction may be carried out at a temperature in the range of from about 0°C to about 30°C. The compound of formula (VII) may be condensed with compound l,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8-one of formula (VI) in the presence of a base in a suitable solvent to yield the compound of formula (III). The compound of formula (III) may be is reduced to provide the enantiomeric mixture defined by formula (II). The ramelteon of formula (I) thereby formed may be separated from the enantiomeric mixture. The compound of formula (VII) may be substantially free of a dimer of formula C.

Dimer C In another aspect the present invention provides a compound of formula (VII)

(VII)

In another aspect the present invention provides a process substantially as herein described with reference to the examples. In another aspect the present invention provides ramelteon obtainable by the processes substantially as herein described with reference to the examples.

In another aspect the present invention provides a use of ramelteon obtainable by the process of the present invention for the manufacture of therapeutic agent. In another aspect the present invention provides a use of ramelteon obtainable by the process of the present invention, for treating a sleep disorder.

In another aspect the present invention provides a method of treating sleep disorder, comprising administering the ramelteon obtainable by a process of the present invention.

Further features are defined in the dependent claims.

Description of the drawing

FIG 1 shows an overview of an example of the process of the present invention.

Brief Description of the present Invention According to a first aspect of the present invention, there is provided a process for preparing enantiomerically pure ramelteon of formula (I),

(I)

comprising catalytic reduction of the intermediate compound of formula (IV)

(IV)

using a metal borohydride and propionyl halide or propionic anhydride in the presence of catalytic amount of a metal salt to form an enantiomeric mixture defined by formula (II)

and separating ramelteon of formula (I) te from the enantiomeric mixture of formula (II). An example of this reaction is shown schematically on the right hand side of figure 1.

The catalytic reduction of the compounds from formula (IV) to formula (II) may be carried 5 out at a temperature ranging from about -10°C to about 40°C, or preferably in the range of from about 0°C to about 30°C.

The reduction is optionally carried out in the presence of a catalyst, such as a palladium catalyst or a platinum catalyst; a palladium catalyst is preferred. Particularly useful 10 reduction conditions include, for example, 10% (w/w) palladium on carbon and a metal borohydride, or 10% (w/w) palladium on carbon and hydrogen gas.

In an alternative embodiment of the invention, the compound of formula (IV) may be catalytically reduced to yield the intermediate N-[2-(l,6,7,8-Tetrahydro-2H-indeno[5,4-

15 b]furan-8-ylidene)ethyl] propionamide of formula (III). This reduction may be carried out at a temperature in the range of from about -10°C to about 5°C, or more preferably in the range of from about 0°C to about 5°C. The compound of formula (III) may then be reduced using a metal borohydride to produce a compound of formula (II). When the reduction is carried out at a temperature in the range of about -10°C to about 5°C or about 0°C to about 5°C, a

20 catalyst is preferably present. The catalyst is a palladium catalyst or a platinum catalyst, preferably a palladium catalyst, such as 10% (w/w) palladium on carbon.

In a preferred embodiment, the compound of formula (IV) is reduced at a temperature of from about 25°C to about 40°C, or more preferably about 25°C to about 30°C, to yield 25 intermediate of formula (II). When the reduction is carried out at a temperature in the range of about 25°C to about 40°C or about 25°C to about 30°C, the presence of the catalyst (such as the palladium catalyst) is optional.

The compound of formula can also be reduced at a temperature in the range of from about - 30 10°C to about 25°C, or about 0°C to about 25°C, or about 5°C to about 25°C; when the reduction is carried out at a temperature falling within any of these ranges, the catalyst (such as the palladium catalyst) is preferably present. Without wishing to be limited by theory, at a temperature in the range of from about 5°C to about 25°C, it is thought that both the intermediate of formula (III) and the enantiomeric mixture defined by formula (II) are formed during the catalytic reduction of the compound of formula (IV). The catalyst (such as the palladium catalyst) is preferably present at these temperatures, to ensure the intermediate of formula (III) is further reduced to form the enantiomeric mixture defined by formula (II).

The catalytic reduction may be achieved using a variety of metal borohydrides as reducing agents, such as, but not limited to, NaBRj (sodium borohydride), NaCNBH ₄ (sodium cyanoborohydride), LiBH ₄ (lithium borohydride), sodium trifluoro acetoxy borohydride, or a mixture thereof, in combination with a catalytic metal salt, such as, but not limited to a salt of a transition metal, such as a salt of Iron, Cobalt and Nickel. Preferably, the catalytic reduction is carried out using sodium borohydride in the presence of a Ni (II) salt. A preferred Ni (II) salt is dry nickel (II) chloride.

The amount of the metal salt used, such as nickel (II) chloride, may vary in the range of from about 0.5 to about 5 % by weight, based on the nitrile of formula (IV).

The process of the present invention is advantageous over the prior art as the catalytic reduction may be carried out without isolating intermediate (IIA) when the reaction is carried out at ambient temperature, for instance, in the range of from about 25°C to about 30°C, and without isolating intermediate (IIB) when the reaction is carried out at a temperature in the range of from about 0°C to about 5°C. Similarly, when the reduction is carried out at a temperature in the range of from about 5°C to about 25°C, whereby it is thought that both intermediates of formula (IIA) and (IIB) are formed, neither intermediate (IIA) or (IIB) needs to be isolated. This is achieved by the in situ treatment of intermediates (IIA) or (IIB) with propionyl halide or propionic anhydride, i.e. where the intermediates (IIA) or (IIB) are not isolated from the reaction medium before they are reacted with propionyl halide or propionic anhydride. The metal borohydride and propionyl halide or propionic anhydride may be added directly to the reaction medium before the formation of intermediates (IIA) or (IIB) to avoid isolating the intermediates.

The addition of the propionic anhydride or propionic halide and sodium borohydride helps to ensure complete conversion of the intermediate (IV) to intermediates (IIA) or (IIB) and further conversion to the corresponding compounds (II) and (III). In a preferred embodiment, the reagents are added simultaneously, and in lots (i.e. stepwise).

Not isolating the intermediates (IIA) or (IIB) simplifies the overall process, and increases yield, since it removes a purification step. Further, the use of propionyl halide or propionic anhydride reduces or substantially eliminates the dimeric impurities A and B, which increases the yield of product and simplifies purification of the product. This improvement in yield and purity and the simplification of the process forms one aspect of the present invention.

Further, the additives propionyl halide or propionic anhydride not only reduces or substantially eliminates the formation of the dimer impurities, but also act as amidation reactants to form intermediate compounds (II) or (III) and this forms another aspect of the present invention.

The molar ratio of the metal borohydride to the propionyl halide or propionyl anhydride may vary in the range of from about 1 : 2 to about 2:1, preferably about 1:1. The molar ratio of the nitrile intermediate of formula (IV) to sodium borohydride or to the propionyl halide or propionic anhydride, may vary in the range of from about 1 :1 to about 1:10 equivalence. Preferably, a ratio of about 1 :1 to about 1 :8 equivalence of these reagents may be used to convert nitrile of formula (IV).

Molar equivalent quantities of the metal borohydride (such as sodium borohydride) and propionyl halide or propionic anhydride may be added in lots, i.e. stepwise (as opposed to adding the metal borohydride and propionyl halide or propionic anhydride in one step). The propionyl halide may comprise propionyl chloride, propionyl bromide, propionyl iodide, propionyl fluoride, or a combination thereof, preferably propionyl chloride and/or propionyl bromide. The use of propionyl halides, such as propionyl chloride or propionyl bromide, and propionic anhydride, reduce or substantially eliminate the formation of the dimer impurities, as well as to providing an amidation reactant. Propionic anhydride is the most preferred reagent. Any polar, protic and aprotic solvents may be employed as the medium for the conversion of the compound of formula (IV) to formula (II) or (III); however, a dry alcohol is preferably used, more preferably methanol.

According to another aspect of the present invention, there is provided a novel process for preparing the intermediate compound (l,2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8- ylidene)-acetonitrile of formula (IV), which is useful key intermediate in the preparation of ramelteon, which method comprises reaction of cyano acetic acid of formula (V)

Formula V

with compound 1, 2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8-one of formula (VI)

Formula VI

in the presence of base comprising a primary amine, secondary amine, tertiary amine, a heterocyclic amine, or a combination thereof, to yield compound of formula (IV).

Preferably, the reaction is carried out in the presence of a base comprising a heterocyclic amine, such as piperidine and pyrrolidine; piperidine is preferred. Preferably, the reaction is carried out at a temperature ranging from about 80°C to about 150°C, more preferably at in the range of about 100°C to about 120°C.

Optionally, the process may be carried out in the presence of a polar solvent such as DMSO (Dimethyl sulfoxide), DMF (Dimethylformamide), Sulfolane, or a mixture thereof.

The present invention is advantageous as the process for preparing the intermediate (IV) involves use of a readily and cheaply available solid reagent cyano acetic acid, which has a low melting point and is relatively less toxic ; this forms one aspect of the present invention.

The present invention provides a clear improvement over the prior art, in that the overall yield of compound (IV) is increased, compared to the processes of the prior art. In particular, the present invention typically provides yields of around 80-90%, as compared to the reported yield of 60% for the corresponding steps in the prior art; this forms another aspect of the present invention.

The reaction conditions as described for the process of the present invention above, i.e. for the catalytic reduction of the nitrile intermediate of formula (IV) to amide of formula (II), using a metal borohydride and propionyl halide or propionic anhydride, in the presence of a catalytic amount of metal salt at a suitable temperature, may be applied to the corresponding steps of the catalytic reduction of the nitrile intermediate of formula (IV) to the amide of formula (III).

According to yet another aspect of the present invention there is provided a process for the preparation of a compound of formula (III), which process comprises: catalytic reduction of an intermediate compound diethylcyanomethyl phosphonate of formula (IX) using a metal borohydride and propionyl halide or propionic anhydride in the presence of a catalytic amount of a metal salt to form the novel intermediate diethyl(2-ethyl propionamide)phosphonate of formula (VII).

(VII)

An example of the reaction is provided on the left hand side of Figure 1. The catalytic reduction may be conducted at a temperature in the range of from at a temperature in the range of from about -10°C to about 40°C, preferably in the range about 0°C to about 30°C, or more preferably in the range of from about 25 °C to about 30°C. The metal borohydride may comprise NaBIi _t , Lithium borohydride (LiBH ₄ ), NaCNBH, (sodium cyanoborohydride), sodium trifluoro acetoxy borohydride, or a mixture thereof; sodium borohydride is preferred. The metal salt may comprise a salt of a transition metal, such as a salt of Iron, Cobalt and Nickel; Nickel (II) chloride is preferred. The reduction may be carried out in the presence of a solvent.

Preferably, the catalytic reduction of the intermediate of formula (IX) is carried using molar equivalent quantities of the metal borohydride to propionyl halide or propionic anhydride; however the ratio of the metal borohydride to propionyl halide or propionic anhydride may vary in the range of 2:1 to 1:2. The reduction of the intermediate of formula (IX) yields the novel intermediate diethyl(2-ethyl propionamide)phosphonate of formula (VII). The present invention reduces the rapid decomposition of the catalyst, as well as preventing the formation of dimer impurity of formula C

Dimer C

and thus forms one aspect of the present invention. The formation of the intermediate of formula (VII) may be followed by condensation with the compound l,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8-one of formula (VI) in the presence of a base in a suitable solvent, to yield compound of formula (III). The condensation of the compound of formula (VII) with the compound of formula (VI) may be carried out in the presence of an organic base, preferably comprising a primary amine, a secondary amine, a tertiary amine, or any combination thereof, and/or an inorganic base, preferably comprising a metal hydroxide, a metal alkoxide, a metal hydride, or any combination thereof. Preferably the condensation is carried out using a metal alkoxide, more preferably sodium methoxide.

The condensation may be carried out in the presence of a solvent comprising an alcohol, toluene, dimethylformamide, dimethylsulfoxide, or a mixture thereof. The alcohol may comprise methanol, ethanol, isopropyl alcohol, butanol, or a combination thereof. Preferably the alcohol comprises methanol.

The condensation may be carried out at a temperature in the range of from about 40°C to about 100°C, more preferably in the range of from about 50°C to about 60°C. Alternatively, the novel intermediate diethyl(2-ethyl propionamide)phosphonate of formula (VII) may be prepared by reacting the compound diethyl(2-ethylamino)phosphonate of formula (VIII)

with propionyl halide or propionic anhydride in the presence of suitable solvent.

The reaction may be carried out in a non-polar solvent in the presence of a base at a temperature in the range from about 0°C to about 30°C. The non-polar solvent may comprise dichloromethane. The base may comprise triethylamine. According to another aspect of the present invention, there is provided a process for preparing ramelteon of formula (I)

(I)

which process comprises preparing an enantiomeric mixture defined by formula (II) according to any process of the present invention as described in the present disclosure, and optically resolving the compound of formula (II) by means of high performance column chromatography to yield enantiomerically pure ramelteon of formula (I). The optical resolution to ramelteon (I) may be carried out using packed column supercritical fluids chromatography (SFC) or liquid chromatography. Most preferably the separation is performed using SFC, using carbon dioxide modified by methanol containing diethylamine (DEA) as mobile phase. One important advantage of using supercritical fluids instead of liquids as the solvent medium is the reduction in the overall volume of organic solvent required during the course of the optical resolution, so that significantly less solvent is used, in turn meaning less solvent is wasted, or requires recovery. Alternatively, optical resolution of the compound of formula (II) may be carried out in accordance with the process described in US 6034239, the relevant disclosure of which is incorporated herein by reference.

According to a further aspect of the present invention, there is provided a compound of formula (II) obtainable by (or obtained by) a process according to any process of the present invention as described in the present disclosure. According to a further aspect of the present invention, there is provided a compound of formula (III) obtainable by (or obtained by) a process according to any process of the present invention as described in the present disclosure. According to a further aspect of the present invention, there is provided ramelteon of formula (I) obtainable by (or obtained by) a process according to any process of the present invention as described in the present disclosure.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising ramelteon, obtainable by (or obtained by) any process of the present invention as described in the present disclosure, optionally together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art. According to another aspect of the present invention, there is provided the use of ramelteon, obtainable by (or obtained by) any process of the present invention as described in the present disclosure, in the treatment of insomnia.

According to another aspect of the present invention, there is provided a method of treating depression in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of ramelteon, obtainable by (or obtained by) any process of the present invention as described in the present disclosure.

In accordance with the invention as herein described, there is provided a process for preparation of ramelteon which is simple, economical and suitable for industrial scale-up.

In an embodiment of the present invention, there is provided an improved synthesis of ramelteon, as depicted below in reaction scheme 2.

Scheme 2

0-30°C

Metal salt Propionyl halide/

Propionc anhydride

Ramelteon (I)

Accordingly, in an embodiment, the present invention provides a process for the preparation of ramelteon of formula (I), comprising: reacting cyano acetic acid of formula (V) with compound l,2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8-one of formula (VI) in the presence of base to obtain compound (IV); reducing the intermediate of formula (IV) using a metal borohydride and propionyl halide or propionic anhydride in the presence of catalytic amount of a metal salt, at a temperature in the range of about 0°C to about 30°C; optionally reacting with a catalyst, such as a palladium catalyst or a platinum catalyst, preferably a palladium catalyst, (for instance 10% (w/w) palladium on carbon) and a metal borohydride; to form compound of formula (II); and optically resolving the enantiomeric mixture defined by formula (II) by means of high performance column chromatography to yield enantiomerically pure ramelteon of formula (I).

In the process of the present invention, a catalyst, such as a palladium catalyst or a platinum catalyst, preferably a palladium catalyst (for instance 10% (w/w) palladium on carbon) and a metal borohydride may be used optionally when the reaction is carried out at a temperature ranging from about 0°C to about 5°C to yield intermediate N-[2-(l„6,7,8-Tetrahydro-2H- indeno[5,4-b]furan-8-ylidene)ethyl] propionamide of formula (III), before compound of formula (II) is produced.

The catalytic reduction of the compound of formula (IV) to (III) at a temperature of from about 0°C to about 5°C is carried out in one step, i.e. without isolating any intermediate formed in the step, more particularly, the intermediate of formula (IIB). In a preferred embodiment the process comprises reducing compound of formula (IV) to yield the intermediate of formula (II), wherein the catalytic reduction is carried out in one step, i.e. without isolating any intermediate formed in the step, more particularly, the intermediate of formula (IIA). The catalytic reduction is preferably carried out at a temperature in the range of about 25°C to about 30°C.

The optical resolution of formula (II) to ramelteon (I) may be carried out by packed column supercritical fluids chromatography (SFC) or liquid chromatography.

Alternatively, the optical resolution may be performed according to the process described in US 6034239.

According to another aspect of the present invention, there is provided an alternate process for preparing a compound of formula (III) as exemplified in Scheme 3.

Accordingly, in an embodiment, the invention provides an improved process for the preparation of compound of the formula (III) which comprises; catalytic reduction of the intermediate compound diethylcyanomethyl phosphonate of formula (IX) using a metal borohydride and propionyl halide or propionic anhydride in the presence of catalytic amount of a metal salt, at a temperature in the range of from about 0°C to about 30°C to form novel intermediate diethyl(2-ethyl propionamide)phosphonate of formula (VII); and condensing the compound of formula (VII) with the compound l,2,6,7-tetrahydro-8H-indeno-[5,4- b]furan-8-one of formula (VI) in the presence of a base in a suitable solvent to yield compound of formula (III).

The present invention provides an alternate route for the synthesis of compound of formula (VII), which comprises reacting compound diethyl(2-ethylamino)phosphonate of formula (VIII) with propionyl halide or propionic anhydride in the presence of suitable solvent.

Ramelteon obtained by the processes of the present invention is substantially free of the dimeric impurities A, B and C.

Ramelteon obtained by the process of the present invention may be used for the treatment of insomnia. It may be combined with at least one pharmaceutically accepted excipient in the preparation of pharmaceutical composition. While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation. The invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner. It will be appreciated that the invention may be modified within the scope of the appended claims. Examples:- Example 1

Synthesis of (1, 6,7,8-Tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene) -acetonitrile

l,2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8-one (100 gm, 0.5747 mol ) and cyano acetic acid ( 75 gm, 0.8823 mol ) were added in piperidine (400 ml ) at ambient temperature. The reaction mass was heated to 100-110°C and then cooled to 55°C and the piperidine was removed under reduced pressure below 55°C. Water (500 ml) was added to the residue and extracted with dichloromethane (3 X 500 ml). Organic layer was washed with brine and distilled under reduced pressure below 50°C. The solid was stirred in heptane (500 ml), filtered, washed with heptane and dried under vacuum at 50-60°C to give 106 gms of the title compound.

Yield:- 93% Example 2

Synthesis of N-[2-(l„6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)e thyI] propionamide

To a stirred solution of (l,6,7,8-Tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)-aceton itrile (100 gm, 0.507 mol) in methanol (2000 ml), was added Nickel Chloride (1 gm) . The reaction mass was cooled to 0-5°C under inert atmosphere. Propionic anhydride (66 ml, 0.507 mol), followed by Sodium borohydride (19.2 gm, 0.507 mol) were added in lots over a period of 60 minutes maintaining the reaction temperature below 5°C and the addition continued till the completion of the reaction. Completion of reaction was monitored by TLC. 10% ice cold solution of ammonium chloride (500 ml) was added and methanol was removed under reduced pressure below 45°C. Water (500 ml) was added to the residue and the reaction mass was extracted with dichloromethane (3X 500 ml). The organic layer was washed with water, dried over sodium sulfate and distilled under reduced pressure. The residue was stirred in heptane (500 ml), filtered and dried under vacuum at 50-60°C to give 95 gms of the title compound.

Yield:- 73% Example 3

Preparation of N-[2-(l,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyI]- propionamide

To a stirred solution of (l,6,7,8-Tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)-aceton itrile (100 gm, 0.507 mol) in methanol (2000 ml) was added Nickel Chloride (1 gm) under inert atmosphere. Propionic anhydride (66 ml, 0.507 mol) followed by Sodium borohydride (19.2 gm, 0.507 mol) were added in lots over a period of 60 minutes maintaining the reaction temperature at 25-30°C and the addition continued till the completion of the reaction. Completion of reaction was monitored by TLC. 10% ice cold solution of ammonium chloride (500 ml) was added and methanol was removed under reduced pressure below 45°C. Water (500 ml) was added to the residue and the reaction mass was extracted with dichloromethane (3X 500 ml). The organic layer was washed with water, dried over sodium sulfate and distilled under reduced pressure. The residue was stirred in heptane (500 ml), filtered and dried under vacuum at 50-60°C to give 111 gms of the title compound.

Yield:- 84 %

Example 4

Preparation of N-[2-(l,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]- propionamide

To a stirred solution of N-[2-(l„6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)e thyl] propionamide (100 gm, 0.389 mol) in methanol (2000 ml), was charged 10% Pd/C catalyst (10 gm, 50% wet) at ambient temperature. Sodium Borohydride (40 gm, 1.050 mol) was added portion wise over a period of 3-4 hrs controlling the reaction mass temperature below 35°C. The reaction mass was then filtered through celite bed to separate Palladium catalyst and the filtrate was concentrated under vacuum to residue. Water (1000 ml) was added to the residue and the reaction mass was extracted with dichloromethane (3X 500 ml). The organic layer was washed with water, dried over sodium sulfate and distilled under reduced pressure. The residue was stirred in heptane (500 ml), filtered and dried under vacuum at 50- 60°C to give 99 gms of the title compound.

Yield:- 98.2% Example 5

Synthesis of ramelteon

Preparation 1

N-[2-(l,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethy l]-propionamide (2.0 gm) was dissolved in 50.0 ml (n-Hexane:IPA:DEA) (as used herein, "IPA" stands for isopropyl alcohol, and "DEA" stands for diethylamine)

and optically resolved by high performance column chromatography on CHTRAL PACK IA-3 using Mobile phase : n-Hexane:IPA:DEA Flow rate: 1.0ml/min UV:285 nm; at a column temperature of 25°C;sample concentartion: lmg/ml and, eluted with mobile phase. Both the enantiomers were collected separately and after evaporation of solvent under vacuum, enantiomerically pure ramelteon (I) was obtained. Preparation 2- using Supercritical Fluid Chromatography (SFC)

N-[2-(l ₅ 6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]-pr opionamide (2.0 gm) was dissolved in 50.0 ml (n-Hexane:Ethanol:DEA) and optically resolved by Supercritical Fluid Chromatography (SFC) on CHIRAL PACK AD-H using a mobile phase : C02/(Methanol/ Diethylamine[DEA]) and eluted with mobile phase. Both the enantiomers were collected separately and after evaporation of solvent under vacuum, enantiomerically pure S- ramelteon of Formula (I) and R-ramelteon were obtained with isomeric purity>99%.

Example 6

Synthesis of Diethyl(2-ethyl propionamide)phosphonate

To a stirred solution of diethylcynomethylphosphonate (100 gm, 0.5649 mol) in methanol (1000 ml) was added Nickel Chloride (1 gm) at ambient temperature, under inert atmosphere. Propionic anhydride (74ml, 0.507mol) and Sodium borohydride (21.37 gm, 0.5649 mol) were then added in small portions over a period of 60 min maintaining the reaction temperature between 25-30°C. 10% ice cold solution of ammonium Chloride (500 ml) was added and the methanol was removed under reduced pressure below 45°C. Water (500 ml) was added to the residue and the reaction mass was extracted with dichloromethane (3X 500 ml). The organic layers were combined together, washed with water, dried over sodium sulfate and distilled under reduced pressure. The residue was stirred in heptane (500 ml), filtered and dried under vacuum at 50-60°C to give 88 gm of the title compound.

Yield:- 66.5%

Example 7

Synthesis of N-[2-(l„6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene) ethyl] pro ionamide

To a stirred solution of 1, 2,6,7-Tetrahydro-8H-indeno-[5,4-b]furan-8-one (100 gm, 0.5747 mol)and Diethyl(2-ethyl propionamide)phosphonate ( 204 gm, 0.8620 mol ) in toluene (1000 ml) at ambient temperature under inert atmosphere, were charged solution of sodium methoxide ( 62 gm, 1.1494 mol ) in methanol ( 100 ml). The reaction mass was heated to 50-60°C for 4-5 hrs, cooled to 40-50°C and toluene was removed under reduced pressure. Water (500 ml) was added to the residue and extracted with dichloromethane (3 X 500 ml). The organic layer was washed with brine and distilled of under reduced pressure below 50°C. The residue was stirred in heptane (500 ml) for 2 hrs at ambient temperature, filtered, washed with heptane (2 X 50 ml) and dried under vacuum at 50-60°C to give 85 gms of the title compound.

Yield: - 57.5%

Example 8

Synthesis of (2-Propionylamino-ethyl)-phosphonic acid diethyl ester

To a stirred solution of (2-Amino-ethyl)-phosphonic acid diethyl ester (100 gm, 0.552 mol), in dichloromethane (1000 ml) at ambient temperature under inert atmosphere was charged triethylamine (130 ml). The reaction mass was cooled to 0°C and propionic anhydride (115 ml, 0.828 mol) was added portion wise over a period of 60 minutes maintaining the temperature of the reaction mass below 10°C. The reaction mass was then gradually warmed to 25-30°C. The reaction was monitored by Thin Layer Chromatography. The reaction mass was then cooled to 10°C and water (2000 ml) was added. The organic layer was separated, washed with water and concentrated under reduced pressure to obtain the desired product. Yield:- 75%,

HPLC Purity > 98 %

Example 9

N-[2-(l -Tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]-propionamide

(")

To a stirred solution of (l,6,7,8-Tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)-aceton itrile (100 gm, 0.507 mol) in methanol (2000 ml) was added Nickel Chloride (1 gm) under inert atmosphere. Propionic anhydride (66 ml, 0.507 mol) followed by Sodium borohydride (19.2 gm, 0.507 mol) were added in lots over a period of 60 minutes maintaining the reaction temperature at 15-25°C and the addition continued till the completion of the reaction. Completion of reaction was monitored by TLC. 10% ice cold solution of ammonium chloride (500 ml) was added and methanol was removed under reduced pressure below 45°C. Water (500 ml) was added to the residue and the reaction mass was extracted with dichloromethane (3X 500 ml). The organic layer was washed with water, dried over sodium sulfate and distilled under reduced pressure to obtain the residue containing mixture of Compound II & Compound III.

The residue was further dissolved in methanol and treated with 10% palladium on Carbon catalyst (5gm). The resulting mixture was hydrogenated at 30 psi (0.2 MPa) Hydrogen pressure, filtered through celite and the clear filtrate concentrated under reduced pressure to obtain the residue. The residue was then triturated in Heptane (500 ml), filtered and dried under vacuum at 50-60°C to give the desired product.

Yield : 95 gm

HPLC Purity : 99%+