PROCESS OF MAKING RAMELTEON AND RELATED SUBSTANCES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of United States Provisional Patent Application No. 61/029,51 1 , filed February 18, 2008, the disclosure of which is hereby incorporated herein by reference.

TECHNICAL FIELD

The present patent application relates to a process for the preparation of compounds of Formula I, purified compounds of Formula I, pharmaceutical compositions containing a therapeutically effective amount of compounds of Formula I and/or pharmaceutically acceptable salt(s) of any of the foregoing. BACKGROUND OF THE INVENTION U.S. Patent No. 6,034,239 appears to describe the compounds of formula

Wherein R ¹ represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group; R ² represents a hydrogen atom or an optionally substituted hydrocarbon group; R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; X represents CHR ⁴ , NR ⁴ , O or S in which R ⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group; Y represents C, CH or N, provided that when X is CH ₂ , Y is C or CH; "^ represents a single bond or a double bond; ring A represents an optionally substituted, 5- to 7-membered oxygen-containing heterocyclic ring; ring B represents an optionally substituted benzene ring; and m represents an integer of 1 to 4, or a salt thereof.

The compound (S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8- yl)ethyl] propionamide is also described in this patent. The proprietary name for this compound is Ramelteon and is structurally represented by the Formula.

Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset and is marketed as ROZEREM ™ in US. Ramelteon, the S-enantiomer has 500-fold greater potency for binding of the MT1 receptor than its R- enantiomer. U.S. Patent No. 6,034,239 describes compounds of Formula I, process for its preparation and methods of its use related to sleep disorders. International Publication No. WO 2006/030739A1 and Drugs of the Future, Vol. 28, No.10, 2003 describes the processes for the preparation of compound of Formula I, which are incorporated herein as reference. There is a continuing need to develop an improved process for producing compounds of Formula I in safer and less expensive ways suitable for commercial manufacturing and use.

SUMMARY OF THE INVENTION Optical purity, also referred to herein as stereogenic purity, both meaning a single absolute confirmation at all chiral atoms, can be of importance in the field of pharmaceuticals and the enantiomers / diastereomers of a drug substance may sometimes exhibit vastly different properties such as solubility, potency and toxicity. Therefore, for chiral drug substances (substances including at least one chiral atom), it is required by many regulatory authorities that products be as pure (in terms of stereogenic or optical isomers) as possible. Therefore, there is a need to obtain the desired enantiomer of compounds of Formula I with high enantiomeric purity.

The present patent application provides a process for the preparation of pure compounds of the Formula I,

Formula I wherein " ¹ ^ represents a single bond or a double bond. R represents ethyl, vinyl or ethynyl. The process includes one or more of the following steps:

a) treating an amine of the Formula IV

Formula IV with a chiral resolving agent to afford the salt of Formula MIA;

Formula III A

wherein X is the chiral resolving agent, which is, preferably, a chiral acid suitable for resolving the amine of the Formula (IV);

b) optionally generating a chiral amine compound of Formula III from compound of Formula IHA;

c) converting chiral amine of the Formula III and/or salt compound of Formula IHA to an isocyanate of Formula II; and

Formula Il

d) reacting isocyanate of Formula Il with a Grignard or R-Mg-X reagent to afford compound of the Formula I.

Formula I wherein "^* represents a single bond or a double bond; R represents ethyl, vinyl or ethynyl; X is a halogen or "halo" such as, without limitation, F, Cl, Br and I. In a preferred embodiment, this process results in a stereogenic or optically pure compound of Formula I wherein it is essentially pure, substantially pure or pure in terms of being free of other stereogenic or optical isomers.

These steps individually, and in any combination, as well as the compositions that result from such steps are considered to be part of the invention as well. In particular, the invention includes a process for the preparation of compound of Formula I, comprising: reacting isocyanate of Formula Il

Formula Il

with a compound having the formula R-Mg-X to afford compound of the Formula I

wherein ^í11 ^ represents a single bond or a double bond; R represents ethyl, vinyl or ethynyl; X is a halogen. The process may, in addition or instead comprise the step of converting a compound of Formula MIA

Formula III A wherein X is the chiral resolving agent, preferably, and/or a compound of Formula III

to an isocyanate of Formula II.

The process may, in addition or instead comprise the step of treating an amine compound of Formula IV

Formula IV with a chiral resolving agent to afford the salt of Formula IMA;

Formula III A

wherein X is the chiral resolving agent for resolving the amine of the Formula (IV).

The process may, in addition or instead comprise the step of generating an amine compound of Formula III from a compound of Formula IHA;

Formula III. The process may, in addition or instead comprise the steps of treating an amine compound of Formula IV

Formula IV with a chiral resolving agent to afford the salt of Formula IHA;

Formula III A

wherein X is the chiral resolving acid suitable for resolving the amine of the Formula (IV); a) optionally generating an amine compound of Formula III from a compound of Formula IHA;

b) converting an amine compound of Formula III and/or salt compound of Formula MIA to an isocyanate of Formula Il

Formula II.

If desired, the compound of Formula I wherein R is unsaturated and/or "^ represents a double bond, may be further reduced to obtain the corresponding saturated compound.

In another aspect, the process relates to a purification process of the compound of Formula I, which process includes the step of recrystallizing or slurrying the compounds of Formula I from a suitable solvent(s) to afford the desired pure compound of Formula I. Purity may also include essentially pure, substantially pure and/or pure in terms of impurities other than of the stereogenic or optical isomers. Thus, in a particularly preferred embodiment, the compound of Formula I is both optically or stereogenically pure and pure with regard to other contaminants, reactants, reaction byproducts and the like. And, the purity, in terms of stereogenic or optical purity and freedom from other contaminants may be different. For example only, a product could be essentially pure in terms of

contaminants and substantially pure in terms of other optical or stereogenic species. Preferably, however, they are both "pure" as defined herein.

In another aspect, the present patent application relates to a pharmaceutical composition that includes a compound of Formula I or its pharmaceutically acceptable salt obtained by the process described herein and at least one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25 ⁰ C and normal pressure unless otherwise designated. All temperatures are in Degrees Celsius unless specified otherwise. The present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" and "include" are also to be construed as open ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given technique used to measure a value.

When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of stereoisomers and/or optical isomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. Note that stereoisomers, stereogenic isomers and optical isomers are used interchangeably, understanding that compounds might have one or more chiral centers and therefore be stereogenic and yet not bend polarized light so as not to truly be optical isomers. "Substantially" pure

means, the same as "pure" except that the lower limit is about 95% pure or more, both in terms of stereogenic purity and purity from byproducts and the like. "Essentially" pure means the same as "substantially" pure except that the lower limit is about 90% pure or more. The present patent application relates to a process for the synthesis of compound of Formula I, which process includes one or more of the following steps: a) treating racemic amine of the Formula IV

Formula IV

with a chiral resolving agent to afford the diastereomeric salt of Formula IHA;

Formula III A

wherein X is the chiral resolving agent, preferably, chiral acid suitable for resolving the amine of the Formula (IV); b) optionally generating a chiral amine compound of Formula III from compound of Formula HIA;

c) converting chiral atom-containing amine of the Formula III or from compound of Formula IIIA (a salt) to an isocyanate of Formula Il (which intermediate may or may not be isolated); and

Formula Il d) reacting isocyanate of Formula Il with a Grignard or R-Mg-X reagent to afford compound of the Formula I.

Formula I wherein ""^ ¹¹ represents a single bond or a double bond; R represents ethyl, vinyl or ethynyl; X is a halogen or "halo" such as, without limitation, F, Cl, Br and I.

If desired, the compound of Formula I wherein R is unsaturated and/or "= represents a double bond, may be reduced to obtain the corresponding saturated compound. Each step is separately contemplated.

The process of resolution in step (a) includes preparation of a solution of racemic amine of the Formula IV followed by treatment with a chiral resolving agent in presence of a solvent to form a salt of compound of Formula MIA.

The solution of racemic amine of the Formula IV may be prepared by dissolving racemic amine of the Formula IV prepared using any of the processes described in the art, such as dissolving in a solvent, or such a solution may be obtained directly from a reaction in which racemic amine of the Formula IV is formed. Note that "racemic" used in this context is used loosely to cover any combination of optical or stereogenic isomers with a purity (in terms of other stereogenic isomers) of less than about 90% of any one species including true racemic (50:50) mixtures.

The chiral resolving agents that may be utilized for this step include, but are not limited to, pyroglutamic acid, tartaric acid, mandelic acid, di-p-toluyl tartaric acid, debenzoyl tartraric acid, camphor sulfonic acid, α-methoxy-α- (trifluoromethyl)phenylacetic acid (also known as Mosher's acid), naproxen and the like. Other suitable chiral acid resolving agents may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention.

The solvents that may be utilized for this step include, but are not limited to, alcoholic solvents such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethylmethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutyl ether, tetrahydrofuran and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane; nitrile solvents such as acetonitrile and propionitrile; dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF) and N, N- dimethylacetamide; or water or mixtures thereof.

For the complete conversion of the compound of Formula IV to the compound of Formula MIA, the temperatures may range from about 0 ⁰ C to reflux temperature of the solvent used. The reaction time may range from about 30 minutes to about 30 hours, or longer, depending on the conditions chosen.

The obtained salt of compound of Formula IMA (which are generally optically enriched as a single enantiomer) may be isolated by techniques, such as centrifugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids. Optionally, the solvent from the reaction mass may be removed completely or partially by distillation techniques such as atmospheric distillation, distillation under vacuum or evaporation before isolation. The salt of compound of Formula IHA thus obtained may be further purified to remove impurities, reaction byproducts, and the like by slurrying or crystallizing from a suitable solvent. The solvents mentioned above may be used for this purification step.

The process for the generation of chiral amine of the Formula III as in step

(b) involves preparing a solution or slurry of the salt of the Formula (IIIA) followed by adjusting the pH of the solution to a basic value. Either the wet solid or a dry solid of compound of Formula IHA may be used for preparation of the solution or slurry of the salt.

The solvents that may be utilized for this step include, but are not limited to, alcoholic solvents such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethylmethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutyl ether, tetrahydrofuran and 1 ,4-dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane; nitrile solvents such as acetonitrile and propionitrile; dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF) and N, N- dimethylacetamide; or water or mixtures thereof. The preferred solvent is water.

Bases that are useful in this step include, but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, and alkoxides, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, and the like or their aqueous solutions; and organic bases such as, for example, tertiary amines, e.g., N ₁ N- diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, 1,4- diazabicyclo[2.2.2]-octane, N-methyl morpholine, diisopropyl ethyl amine, pyridine, and the like.

The pH of the reaction mass may range from about 7 to about 14. The temperatures for this step may range from about 10 ⁰ C to about 60 ⁰ C.

After the completion of reaction, an organic solvent which is insoluble in water may be added and stirred for sufficient time and then the organic layer containing the free base may be separated. This layer may be progressed to further processing directly or it may be concentrated to form a residue. The residue thus obtained may be further purified to remove impurities, reaction byproducts, and the like by slurrying or crystallizing from a solvent.

The product of Formula III obtained from this reaction may be used in the next reaction step, without isolation from the reaction mixture or in the form of a crude product. If desired, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified to remove impurities, reaction byproducts, and the like by means of separation, for example, recrystallization, distillation, chromatography and slurrying in a solvent. The solvents described above may be used for this purification step.

The reagents that are used for the reaction of compound of Formula IHA and/or compound of Formula III in step (c) include, but are not limited to, phosgene, diphosgene, triphosgene, and ditertiary butyl tricarbonate. 0.8-1.2 moles of this reagent may be used for every mole of the compound of Formula MIA or compound of Formula III.

The solvent that may be used in this step include, but are not limited to, chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1 ,1 ,1 ,-trichloroethane, trichloroethylene etc. or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene, etc. or aprotic solvents including Dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidine and acetonitrile.

The reaction may be conducted in presence of a base. Bases that are useful in the reaction include, but are not limited to, inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, carboxylates, and alkoxides, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium acetate, sodium methoxide, and the like or their aqueous solutions; and organic bases such as, for example, tertiary amines, e.g., N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4- ethylmorpholine, 1 ,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, diisopropyl ethyl amine, pyridine, and the like. The base is used in an amount of approximately 1 to 10 moles, or approximately 1 to 5 moles, per mole of the compound of Formula NIA or compound of Formula III. For the complete conversion of the compound of Formula III and/or compound of Formula NIA to the compound of Formula II, the temperatures may range from about 10 ⁰ C to about 50°C or from about 25 to about 30 ⁰ C and the reaction time may range from about 30 minutes to about 5 hours or longer.

Water may be added after the completion of the reaction and layers may be separated if required water immiscible solvent may be added before the separation of layers.

The compound may be isolated by removal of the solvent. The solvent may be removed using any suitable methods such as evaporation, atmospheric distillation, or distillation under vacuum.

The product of Formula Il obtained from this reaction may be used in the next reaction step, without isolation from the reaction mixture or in the form of a crude product. If desired, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified to remove impurities, reaction byproducts, and the like by means of separation, for example, recrystallization, distillation and chromatography.

Suitable temperature for addition of Grignard reagent in step (d) may range from about -10 ⁰ C to about 30 ⁰ C, or from about -1O ⁰ C to about 0°C as increase in the temperature may lead to the formation of side products and process related impurities.

The Grignard reagent that may be used in this step include, ethyl magnesium halide, vinyl magnesium halide or ethynyl magnesium halide. Ethyl magnesium halide and vinyl magnesium halides are commercially available. Ethynyl magnesium halide may be prepared according to the procedures disclosed in the Journal, Molecules, 2002, 7, 341-352 or any other methods known in the art.

Suitable organic solvents that may be used in step (d) include, but are not limited to, ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutyl ether and tetrahydrofuran; hydrocarbons solvents, for example, toluene, xylene, n-hexane, n-heptane, and cyclohexane; and mixtures thereof.

If desired, the compound of Formula I wherein R is unsaturated and/or "^* ¹ represents a double bond, may be reduced to obtain the corresponding saturated compound. Compound of Formula (I) having """^ represents a single bond or R represents ethyl may be produced by catalytically reducing compound of Formula I wherein R is unsaturated and/or ^ ⁸ "=" represents a double bond in a hydrogen atmosphere in the presence of various catalysts. The catalysts to be used for the reduction include, for example, platinum oxide, platinum on activated carbon,

palladium on activated carbon, palladium on barium sulfate, raney-nickel, copper- chromium oxide, rhodium, cobalt, ruthenium, etc. The amount of the catalyst to be used may be approximately 5 to 1000% by weight, preferably approximately 5 to 300% by weight relative to compound of Formula I. The reaction is advantageously conducted in a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; ethers such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, and1 ,4-dioxane; hydrocarbons solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; .amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; organic acids such as formic acid, acetic acid, etc.; water, etc., or a suitable mixture of these solvents are preferable. The reaction time varies, depending on the activity of the catalyst and the amount thereof used. In general, it is 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0 to 12O ⁰ C, preferably 20 to 8O ⁰ C. The pressure for the reaction is generally 1 to 100 atmospheres. Additives (promoters) that enhance the activity of the catalyst used can be added to the reaction system. Acidic additives advantageously usable for this purpose include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, etc.; organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Basic additives are also advantageously usable and include, for example, sodium hydroxide, potassium hydroxide, ammonia, sodium acetate, triethyl phosphonium acetate etc. The compound of Formula I obtained may be easily purified by means recrystallization or chromatography.

Also provided is a process for purification of compounds of Formula I, which involves recrystallization or slurrying the crude compound of the Formula I from a solvent(s) to afford compound of Formula I having desired purity. This purity may be essentially pure, substantially pure or pure in terms of optical or

stereogenic purity and/or essentially pure, substantially pure or pure in terms of impurities, byproducts, contaminants and the like.

The solvents that may be utilized for the purification of compounds of

Formula I either by recrystallization or by slurrying include but are not limited to methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethylmethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethylether, di- isopropylether, methyltertiarybutyl ether, tetrahydrofuran and 1 ,4-dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane and n- hexane; nitrile solvents such as acetonitrile and propionitrile; DMSO, DMF and N,

N-dimethylacetamide; water or mixtures thereof.

The temperatures that may be utilized for forming a slurry or a solution for recrystallization range from about 10 ⁰ C to about reflux temperature of the solvent used. The concentration of the compound of Formula I in the solvent may range from about 10% to about 80% or more. The solution may be prepared at an elevated temperature if desired to achieve a higher solute concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the compound of Formula I is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature for dissolution will allow the precipitation from solutions with higher concentrations of compound of Formula I, resulting in better economies of manufacture.

Optionally solvent from the solution may be removed completed or partially using techniques such as atmospheric distillation, distillation under vacuum, evaporation etc. Other solvent(s) or the same solvent may be added to the remaining reaction mass before its isolation. The solvents listed above may be used for this step. Optionally the reaction mass may be cooled before the isolation of the product.

Crystal formation from the solution may be promoted by cooling the solution. A seeding sample may be added to isolate the desired polymorphic form during the recrystallization step.

Isolation of the product thus obtained includes collection of the material with or without cooling below the operating temperature by any techniques such as filtration by gravity or suction, centrifugation, and the like and optional washing with the solvent.

The solid material obtained by any of the techniques described above may be further dried. Drying may be suitably carried out by any known methods such as tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out under reduced pressures and at temperatures. The temperature may range from about ambient temperature to about 100 ⁰ C for a time period that produces the desired result.

The compounds of Formula I prepared as described herein is essentially pure meaning no more than about 10% of the R-isomer. In another embodiment, it is substantially pure meaning no more than about 5% of the R-isomer. In still another embodiment, the compound of Formula I is pure meaning no more than about 1% of the R-isomer as an impurity.

Typically the compound of Formula I may also be prepared with the process described in the present patent application with high stereogenic purity such as at least 99.0 wt%, or at least 99.5 wt %, or at least 99.9 wt %. Correspondingly, the level of isomeric impurity may be less than about 1 wt %, 0.5 wt %, or 0.1 wt % as determined by chiral high performance liquid chromatography (CHPLC). In yet another embodiment, the present application provides substantially pure compounds of Formula I. As used herein "pure" refers to chemical purity. This includes essentially pure meaning no more than about 10% by weight of impurities, byproducts, contaminants and the like, substantially pure meaning no more than about 5% of such impurities and pure meaning no more than about 1 % of such impurities. Compounds of Formula I of the present application may also contain less than about 0.5% of total impurities, or more preferably less than about 0.1 % of total impurities. These impurities can be characterized by high performance liquid chromatography ("HPLC").

The present invention also includes compounds II, III, HIA and IV individually, preferably in isolated and at least essentially pure form. Typically, compound of Formula I obtained by the process of the present invention has a average particle size of about 250 microns, often less than about 200 microns as measured by sieve analysis by weight. The desired particle size may be obtained directly from the process or may be obtained by using the techniques known to the person skilled in the art such as milling, grinding, spray drying etc.

The starting material amine of Formula IV may be prepared by any known process or by the following process.

(i) reacting a compound of Formula XIII with N,N-dimethylformamide (DMF) and phosphorous oxychloride (POCI ₃ ) to afford compound of Formula XII;

Formula XIII Formula XII

(ii) reacting compound of Formula XII with malonic acid to afford compound of

Formula Xl;

Formula Xl (iii) reacting compound of Formula Xl with ethanol and thionyl chloride to afford a compound of Formula X;

Formula X (iv) reducing compound of Formula X with a reducing agent in an organic solvent to afford compound of Formula IX;

Formula IX (v) brominating compound of Formula IX, followed by hydrolysis to afford compound of Formula VIII;

Formula VIII (vi)cyclizing compound of Formula VIII to afford compound of Formula VII;

Formula VII (vii) debrominating compound of Formula VII with a metal catalyst to afford compound of Formula Vl;

Formula Vl (viii) reacting compound of Formula Vl with diethylcyanomethyl phosphonate in presence of a base to afford compound of Formula V;

Formula V

(ix) reducing compound of Formula V using a reducing agent to afford racemic compound of Formula IV;

Formula IV wherein "^ represents a single bond or a double bond;

Each step is separately contemplated.

The temperature for addition of phosphorous oxychloride in step (i) may range from about 0 ⁰ C to about 50°C or from about 25 ⁰ C to about 30 ⁰ C. The solvents which may be used in step (a) include but are not limited to; aprotic polar solvents such as N,N-dimethylformamide (DMF), Dimethylsulfoxide (DMSO), N ₁ N- dimethylacetamide (DMA) and the like; or mixtures thereof in various proportions.

For complete conversion of the compound of Formula XIII to the compound of Formula XII, temperatures may range from about 10 ⁰ C to about 100°C. The reaction time may range from about 30 minutes to about 10 hours or longer.

Compound (Xl) of step (ii) can be produced from compound (XII) and malonic acid through the Knoevenagel condensation thereof in the presence of a base. One mole of compound (XII) is reacted with approximately 1.0 to 5.0 moles, preferably approximately 1.0 to 2.0 moles of malonic acid. The base includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, piperidine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. The base is used in an amount of approximately 0.1 to 10.0 moles, preferably approximately 0.1 to 5.0 moles per mole of compound (XII). The reaction is advantageously conducted in a solvent inert thereto. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.; amides such as N,N-dimethylformamide, N, N- dimethylacetamide, etc.; organic acids such as formic acid, acetic acid, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, etc., or a suitable mixture of these solvents are preferable. The reaction time varies, depending on the reagents and solvents used, and are generally 30 minutes to 24 hours, preferably 30 minutes to 8 hours. The reaction temperature is generally 0 to 15O ⁰ C, preferably 0 to 130 ⁰ C. The product (Xl) can be used in the next reaction step, while it is in the reaction

mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography. Suitable temperature for addition of thionyl chloride in step (iii) can range from about O ⁰ C to about 80 ⁰ C, or about 15°C to about 80 ⁰ C. Suitably addition of thionyl chloride is carried out slowly to control the exothermicity of the reaction.

Suitable solvents cum reagents that may be utilized for this step include alcohol solvents such as methanol, ethanol, isopropanol etc, preferably ethanol. Compound of formula (IX) as in step (iv) may be produced by catalytically reducing compound (X) in a hydrogen atmosphere in the presence of various catalysts. The catalysts to be used for the reduction include, for example, platinum oxide, platinum on activated carbon, palladium on activated carbon, palladium on barium sulfate, raney-nickel, copper-chromium oxide, rhodium, cobalt, ruthenium, etc. The amount of the catalyst to be used may be approximately 5 to 1000% by weight, preferably approximately 5 to 300% by weight relative to compound (X). The reaction is advantageously conducted in a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; ethers such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, and1 ,4-dioxane; hydrocarbons solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; .amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; organic acids such as formic acid, acetic acid, etc.; water, etc., or a suitable mixture of these solvents are preferable. The reaction time varies, depending on the activity of the catalyst and the amount thereof used. In general, it is 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0 to 12O ⁰ C, preferably 20 to 8O ⁰ C. The pressure for the reaction is generally 1 to 100 atmospheres. Additives (promoters) that enhance the activity of the catalyst used can be added to the reaction system. Acidic additives advantageously usable for this purpose include, for example,

inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, etc.; organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Basic additives are also advantageously usable and include, for example, sodium hydroxide, potassium hydroxide, ammonia, sodium acetate, triethyl phosphonium acetate etc. The product (IX) can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography.

Suitable temperature for addition of bromine in step (v) may range from about O ⁰ C to about 3O ⁰ C, or from about 10 ⁰ C to about 30°C as an increase in the temperature may lead to the formation of side products and process related impurities.

Examples of organic solvents that may be used in step (v) include, but are not limited to, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and 2-butanone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and tertiary butyl acetate; nitriles such as acetonitrile, and propionitrile; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; organic acids such as acetic acid, formic acid etc; and mixtures thereof or their combinations in various proportions. Suitable bases such as sodium acetate optionally may be added in this step. Aqueous sodium sulfite solution may be added to the reaction mass after the completion of bromination reaction for hydrolysis purpose. The reaction mass may be heated to about 100 ⁰ C and maintained for sufficient time to complete the reaction. The hydrolysis time may range from 30 minutes to 10 hours or longer. The separated solid may be isolated by the techniques known in the art or the methods described in the instant patent application.

The hydrolysis step may also be carried out in presence of inorganic basic compound such as calcium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate and the like may be used for this step. Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid

and the like may also be used for this hydrolysis step. Any other methods that accomplish the hydrolysis without affecting the product molecule may also be used.

The base or acid that is used in this reaction may be used in amounts ranging from approximately 1 to 10 moles, or approximately 1 to 5 moles, per mole of compound of Formula VIM.

The reaction may be carried out from about room temperature to about the reflux temperature of the solvent used.

The reaction may be carried out for any desired time periods to achieve the desired product yield and purity. The reaction time typically varies from about 30 minutes to 10 hours, or longer.

The cyclization as in step (vi) may be conducted in the presence of a Lewis acid after compound (VIII) is allowed to react with a halogenating agent such as thionyl chloride, thionyl bromide, etc.; phosphoryl halides such as phosphoryl chloride, phosphoryl bromide, etc.; phosphorus halides such as phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide, etc.; oxalyl halides such as oxalyl chloride, etc.; phosgene, etc. The halogenating agent is used in an amount of approximately 1.0 to 30 moles, preferably approximately 1.0 to 10 moles per mol of compound (VIII). The reaction is advantageously conducted in either the absence of a solvent or the presence of a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; ethers such as tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, etc.; amides such as N,N-dimethylformamide, N.N-dimethylacetamide, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1 ,2- dichloroethane, o-dichlorobenzene, etc., or a suitable mixture of these solvents are preferable. The reaction time is generally 10 minutes to 12 hours, preferably 10 minutes to 5 hours. The reaction temperature is generally -10 to 200 ⁰ C, preferably -10 to 12O ⁰ C. The product can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified by means of separation, for example, recrystallization, distillation and chromatography. The Lewis acid to be used in the next cyclization includes,

for example, anhydrous aluminium chloride, anhydrous zinc chloride, anhydrous iron chloride, etc. The Lewis acid is used in an amount of approximately 0.1 to 20 moles, preferably approximately 0.2 to 5.0 moles per mol of compound (VIII). The reaction is advantageously conducted in either the absence of a solvent or the presence of a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, aromatic hydrocarbons such as benzene, toluene, etc.; halogenated hydrocarbons such as monochlorobenzene, o-dichlorobenzene, 1 ,2,4-trichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; or a suitable mixture of these solvents are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally -20 to 200 ⁰ C, preferably -5 to 12O ⁰ C. The product (VII) produced by the above-mentioned cyclization can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography. Compound of formula (Vl) as in step (vii) may be produced by catalytically reducing compound (VII) in a hydrogen atmosphere in the presence of various catalysts. The catalysts to be used for the reduction include, for example, platinum oxide, platinum on activated carbon, palladium on activated carbon, palladium on barium sulfate, raney-nickel, copper-chromium oxide, rhodium, cobalt, ruthenium, etc. The amount of the catalyst to be used may be approximately 5 to 1000% by weight, preferably approximately 5 to 300% by weight relative to compound (VII). The reaction is advantageously conducted in a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; ethers such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether,

tetrahydrofuran, and1 ,4-dioxane; hydrocarbons solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; .amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; organic acids such as formic acid, acetic acid, etc.; water, etc., or a suitable mixture of these solvents are preferable. The reaction time varies, depending on the activity of the catalyst and the amount thereof used. In general, it is 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0 to 12O ⁰ C, preferably 20 to 8O ⁰ C. The pressure for the reaction is generally 1 to 100 atmospheres. Additives (promoters) that enhance the activity of the catalyst used can be added to the reaction system. Acidic additives advantageously usable for this purpose include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, etc.; organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Basic additives are also advantageously usable and include, for example, sodium hydroxide, potassium hydroxide, ammonia, sodium acetate, triethyl phosphonium acetate etc. The product (Vl) can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography.

Compound of formula (V) as in step (viii) may be produced by reacting a phosphonate-carbanion, which is produced by the treatment of a dialkyl cyanomethylphosphonate with a base, with compound (Vl). This is obtained as a single E-form or Z-form configurational isomer or as a mixture of such E- and Z- isomers. The dialkyl cyanomethylphosphonate includes, for example, diethyl cyanomethylphosphonate, etc. The dialkyl cyanomethylphosphonate is used in an amount of approximately 1.0 to 3.0 mols, preferably approximately 1.0 to 1.5 mols per mol of compound (Vl). The base includes, for example, alkali metal hydrides such as sodium hydride, potassium hydride, etc., metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. The base is used in an amount of approximately 1.0 to 5.0 moles, preferably

approximately 1.0 to 1.5 moles per mol of compound Vl. The reaction is advantageously conducted in a solvent inert thereto. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform; ethers, such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, and 1 ,4-dioxane; hydrocarbons solvents, such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; amides such as N ₁ N- dimethylformamide, N,N-dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc., or a suitable mixture of these solvents are preferable. The reaction time is generally 1 hour to 50 hours, preferably 1 hour to 10 hours. The reaction temperature is generally -78 to 200 ⁰ C, preferably 0 to 15O ⁰ C. The mixture of isomers of compound (V) can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography.

Compound of formula (IV) as in step (ix) may be produced by catalytically reducing compound (V) in a hydrogen atmosphere in the presence of various catalysts. The catalysts to be used for the reduction include, for example, platinum oxide, platinum on activated carbon, palladium on activated carbon, palladium on barium sulfate, raney-nickel, copper-chromium oxide, rhodium, cobalt, ruthenium, etc. The amount of the catalyst to be used may be approximately 5 to 1000% by weight, preferably approximately 5 to 300% by weight relative to compound (V). The reaction is advantageously conducted in a solvent inert to the reaction. While, as the solvent, any one can be used so far as the reaction advances therein, for example, alcohols such as methanol, ethanol, propanol, etc.; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; ethers such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, and 1 ,4-dioxane; hydrocarbons solvents such as toluene, xylene,

n-hexane, n-heptane, and cyclohexane; .amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; organic acids such as formic acid, acetic acid, etc.; water, etc., or a suitable mixture of these solvents are preferable. The reaction time varies, depending on the activity of the catalyst and the amount thereof used. In general, it is 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0 to 120 ⁰ C, preferably 20 to 80 ⁰ C. The pressure for the reaction is generally 1 to 100 atmospheres. Additives (promoters) that enhance the activity of the catalyst used can be added to the reaction system. Acidic additives advantageously usable for this purpose include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, etc.; organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Basic additives are also advantageously usable and include, for example, sodium hydroxide, potassium hydroxide, ammonia, sodium acetate, triethyl phosphonium acetate etc. The product (IV) can be used in the next reaction step, while it is in the reaction mixture or in the form of a crude product. If desired, however, it may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in terms of impurities, byproducts, contaminants, and the like by means of separation, for example, recrystallization, distillation and chromatography. The present invention also relates to the individual compounds of Formulas V-XII which may be used in the production of the compound of Formula I and others as well.

Also provided are pharmaceutical compositions containing a therapeutically effective amount of pure compound of Formula I or a pharmaceutically acceptable salt thereof, containing less than about 1.0%, and more preferably 0.1% or less of any individual impurity, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical composition comprising compounds of Formula I or its pharmaceutically acceptable salt along with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms including, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms including but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations including but not limited to solutions, dispersions, and freeze dried compositions.

The above-prepared formulations may be in the form of immediate release, delayed release or modified release. Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations. Modified release compositions may include hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. The compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. The compositions of the present patent application may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present patent application include, but are not limited to: diluents for example starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders for example acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants for example starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants for example stearic acid, magnesium stearate, zinc stearate and the like; glidants for example colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. The compounds of Formula I may be used in an effective amount which is an amount necessary to obtain a measurable therapeutic response, even if this does not result in a cure, treatment or lessening of symptoms. Generally, however, the amount ranges from 0.01 micrograms to 2 grams per dose, more preferably 1 milligram to about 100 milligrams, more preferably 5 milligrams to

about 10 milligrams per dose. This can be taken in a single dose or divided doses (multiple dosage forms to deliver a dose).

Having described the invention with reference to certain embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further illustrated by reference to the following examples describing in detail certain specific embodiments and aspects of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES

EXAMPLE 1 : Preparation of 2, 3- DIHYDROBENZOFURAN -5- CARBALDEHYDE (FORMULA XII, wherein ^í1 ^ represents a single bond)

400 g of 2,3-dihydro benzofuran of Formula XIII (wherein =* represents a single bond) and 566 ml of dimethyl formamide (DMF) were charged into a clean and dry 4 neck round bottom flask followed by stirring for about 5 minutes. 544 ml of phosphorous oxy chloride was slowly added through a dropper for 65 minutes at 3O ⁰ C. The reaction solution was heated to 95-98°C followed by stirring for 4 hours for the completion of the reaction. The reaction mass was then cooled to 10 ⁰ C and quenched into ice slowly followed by stirring for 20-30 minutes. 1300 ml of caustic lye was added to the solution at 25 - 35 ⁰ C to adjust the pH of the reaction mass to neutral. The reaction mass was extracted with dichloromethane (3X1000 ml) and separated the organic layer and aqueous layer. The combined organic layer was washed with brine solution (2000 ml). The resultant organic layer was distilled completely below 6O ⁰ C to afford 497 g of the title compound. EXAMPLE 2: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoic acid (FORMULA Xl, wherein ^^^ represents a single bond)

202 g of 2, 3- dihydrobenzofuran -5- carbaldehyde of Formula XII (wherein ¹ ^" represents a single bond), 400 ml of pyridine, 17.4 g of piperidine and 197.18 g of malonic acid were charged into a clean and dry 4 neck round bottom flask followed by stirring given. The reaction mass was heated to 120 ⁰ C and stirred for about 6 hours up to completion of the reaction. The reaction mass was cooled to 26 ⁰ C and quenched into ice slowly (2000 g). The resultant reaction solution was extracted with ethyl acetate (3x800 ml) and the organic and the aqueous layer were separated. The combined organic layer was washed with water (5 X

1000ml) brine solution (2 X 750 ml). The resultant organic layer was distilled completely below 5O ⁰ C under vacuum. Diisopropyl ether 600 ml was added to the obtained crude followed by stirring for 30 minutes at 26 ⁰ C. The separated solid was filtered and washed with 100 ml diisopropyl ether solvent. The obtained solid was dried under vacuum at 58 ⁰ C to afford 175.4 g of the title compound. EXAMPLE 3: Preparation of ethyl-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (FORMULA X, wherein """^ represents a single bond)

220 g of 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoic acid of Formula Xl (wherein "^* represents a single bond), and 1100 ml of ethanol were charged into a clean and dry 4 neck round bottom flask followed and stirring given at 26 ⁰ C. Thionyl chloride 200 ml was added slowly through dropper for 15 minutes between 26-73 ⁰ C. The reaction mass was heated to reflux and then maintained for 25 minutes and then cooled to 6O ⁰ C. The solvent was distilled completely under vacuum and added the water (500 ml) and ethyl acetate (500 ml) and stirred for 10 minutes. Organic and aqueous layers were separated. The organic layer was washed with brine solution (2 X 800 ml) and water (500 ml) and dried over sodium sulphate. The resultant organic layer was distilled completely below 5O ⁰ C under vacuum to afford 200 g of the title compound. EXAMPLE 4: Alteranate process for the preparation of ethyl-3-(2,3- dihydrobenzofuran-5-yl)-2-propenoate (FORMULA X, wherein ""^ represents a single bond)

100 g of 2, 3- dihydrobenzofuran -5- carbaldehyde of Formula XII (wherein '^"^ represents a single bond), 1000 ml of toluene were charged into a clean and dry 4 neck round bottom flask and stirring given. The reaction mass was cooled to O ⁰ C and added triethyl phosphonium acetate followed by liquid sodium methoxide solution (assay 31.5%) slowly at 0-10 ⁰ C. The temperature of the reaction mass was raised to 26 ⁰ C and maintained between 26 - 3O ⁰ C for 15 minutes and added water (500 ml) and ethyl acetate (1500 ml) and separated the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate (1500 ml). The combined organic layer was washed with water (2 X 100 ml). The resultant organic layer was distilled completely below 5O ⁰ C under vacuum to afford 146.2 g of the title compound.

EXAMPLE 5: Preparation of ethyl-3-(2,3-dihydrobenzofuran-5-yl)-2-propionate (FORMULA IX, wherein ^= represents a single bond)

47 g of ethyl-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate of Formula X (wherein ¹ ^*** represents a single bond), methanol (800 ml) and raney-nickel (9.4 g) were charged into an autoclave. The reaction mixture was maintained at about 0-10 kg/cm ² hydrogen pressures at about 5O ⁰ C. After the completion of the reaction (for about 4 hours), the reaction mixture was cooled to 26 ⁰ C, filtered and washed with 50 ml of methanol. The resultant filtrate was distilled off completely at below 5O ⁰ C under a vacuum to afford 47 g of crude form of the title compound. EXAMPLE 6: Preparation of 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl)propionic acid (FORMULA VIII, wherein " ¹ ^ represents a single bond) 172.5 g of ethyl-3-(2,3-dihydrobenzofuran-5-yl)-2-propionate of Formula IX

(wherein = represents a single bond), acetic acid 1380 ml and sodium acetate 64.2 g were charged into an clean and dry 4 neck round bottom and cooling given to the reaction mass. 222.5 ml of bromine was slowly added through a dropper at below 20 ⁰ C for about 2 hours. Reaction mass was maintained at 22-28 ⁰ C for about 12 hours. Sodium sulphite solution (296.2 g sodium sulphite dissolved in 2070 ml of cold water) was added slowly followed by addition of 431.2 ml of acetonitrile. The reaction mass was heated to about 96-97 ⁰ C and stirred for about 2 hours. The reaction mass was cooled to about 25 ⁰ C and stirred for about 1 hour. The separated solid was filtered and washed with 400 ml of water. The obtained solid was dried under vacuum at about 65 ⁰ C till a constant weight to afford 220.3 g of the title compound.

EXAMPLE 7: Preparation of 4,5-dibromo-1 ,2,6,7-tetrahydro-8H-indeno[5,4- b]furan-8-one (FORMULA VII, wherein """^ represents a single bond)

250 g of 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl)propionic acid of Formula VIII (wherein ⁸ ^ represents a single bond), 875 ml of 1 ,2- dichlorobenzene and 0.7 ml of dimethyl formamide were charged into an clean and dry 4 neck round bottom flask and stirring given. 87.5 ml of thionyl chloride was slowly added through a dropper at 28 ⁰ C. The reaction mass was heated to about 50-60 ⁰ C and stirred for about 2 hours to complete of the reaction. The reaction mass was cooled to about O ⁰ C and 104.25 g aluminum chloride was added to the reaction mixture followed by stirring at -5 to 5°C for about 60 minutes. The resultant reaction mass was quenched into methanol 3750 ml and then charged 500 ml of cold water followed by stirring for about 30 minutes. The separated solid was filtered and slurry washed with 1700 ml of saturated sodium

bicarbonate (pH : 7.5), filtered and washed with 300 ml of water and 700 ml of methanol. The wet compound was dried at 54°C to a constant weight to afford the 200.8 g of title compound.

EXAMPLE 8: Preparation of 1 ,2,6,7-tetrahydro-8H-indano[5,4-b]furan-8-one (FORMULA Vl, wherein ^ii: ^^ represents a single bond)

70 g of 4,5-dibromo-1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of Formula VII (wherein ^=" represents a single bond ) was charged into an autoclave-containing methanol (1600 ml) and sodium acetate (44 g). 8.75 g of 10% palladium carbon was charged and the resultant reaction mixture was maintained at about 3.0-3.7 kg/cm ² hydrogen pressures at about 42 ⁰ C. After the completion of the reaction the reaction mixture was filtered through celite followed by washing the celite with 500 ml of methanol. The resultant filtrate was distilled off completely at below 64 ^Oo C under vacuum to afford crude. The obtained crude was cooled to 26 ⁰ C and 700 ml of water was added followed by stirring for solid separation. The separated solid was filtered and washed with 200 ml of water. The obtained solid was dried under vacuum at 5O ⁰ C to a constant weight to afford 33 g of the title compound.

EXAMPLE 9; Alternate process for the preparation of 1 ,2,6,7-tetrahydro-8H- indano[5,4-b]furan-8-one (FORMULA Vl, wherein ¹ ^* represents a single bond) 70 g of 4,5-dibromo-1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of

Formula VII (wherein "^^ represents a single bond), methanol (1600 ml) and sodium acetate (44 g) and 28 g of raney chloride were charged into an autoclave and the resultant reaction mixture was maintained at about 10 kg/cm ² hydrogen pressures at 5O ⁰ C. After the completion of the reaction the reaction mixture was filtered through celite followed by washing the celite with (50 ml) of methanol. The resultant filtrate was distilled off completely at below 5O ⁰ C under vacuum. The obtained crude was cooled to 26 ⁰ C and water was added followed by stirring for solid separation. The separated solid was filtered and washed with water. The obtained solid was dried under vacuum at 7O ⁰ C to a constant weight to afford 30.0 g of the title compound.

EXAMPLE 10: Preparation of 2-(1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)acetonitrile (FORMULA V, wherein "**** represents a single bond)

53 g of 1 ,2,6,7-tetrahydro-8H-indano[5,4-b]furan-8-one of Formula Vl (wherein """^ represents a single bond), and toluene 1325 ml were charged into

an clean and dry 4 neck round bottom flask followed by stirring and cooling given. To the above solution 89.1 g of diethylcyanomethyl propionate was slowly added at 5 ⁰ C and then 73.1 g of sodium methoxide was slowly added to the reaction mass at about 10-12 ⁰ C. The resultant reaction mixture was stirred at 25 ⁰ C till the completion of the reaction. The resultant reaction mass was quenched by addition of 530 ml of water followed by stirring for about 10 minutes. Organic and aqueous layers were separated. The aqueous layer was extracted with toluene 100 ml. Combined both the organic layers and completely distilled under vacuum at below 60 ⁰ C to obtain the residue. 265 ml of water was added to the residue followed by stirring for 30 minutes. The separated solid was filtered and washed with water. The obtained solid was dried under vacuum at 50 ⁰ C to a constant weight to afford 58 g of the title compound.

EXAMPLE 11 : Preparation of racemic 2-(1 , 6,7,8,- tetrahydro-2H-indeno[5,4-b] furan-8-yl) ethyl amine (FORMULA IV, wherein " ⁸ ^ represents a single bond) 27gm of 2-(1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitri le of Formula V (wherein ^^^^ represents a single bond), Aqueous Ammonia (373.6 ml) and 27 g of raney nickel and ethanol (1188 ml) were charged into an autoclave and the resultant reaction mixture was maintained at about 5.0 kg/cm ² hydrogen pressures at about 30-38 ⁰ C for about 5- 6 hours. 10%Pd/C (50% wet) (5.4gm) was added and the resultant reaction mixture was maintained at about 5.0 kg/cm ² hydrogen pressures at about 35-38 ⁰ C for about 2-3 hrs. After the completion of the reaction, the reaction mixture was filtered through celite followed by washing the celite with 50 ml of methanol. The resultant filtrate was distilled off completely at about 5O ⁰ C under vacuum. Two lots of (each 100 ml) were added to the reaction mass and distilled the solvent once again to afford 27.2 g of crude from of the title compound.

EXAMPLE 12: Alternate process for the preparation of racemic 2-(1 , 6,7,8,- tetrahydro-2H-indeno[5,4-b] furan-8-yl) ethyl amine (FORMULA IV, wherein "^ represents a single bond) 3 gm of 2-(1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitri le of Formula V (wherein ¹ ^ represents a single bond), ethanol (163 ml), Aqueous Ammonia (37 ml) and 3 g of raney nickel were charged into an autoclave and the resultant reaction mixture was maintained at about 20.0 kg/cm ² hydrogen pressures at 5O ⁰ C for about 3-4 hrs. After the completion of the reaction, the

reaction mixture was filtered through celite followed by washing the celite with 50 ml of toluene. The resultant filtrate was distilled off completely at about 50-56 ⁰ C under vacuum. Two lots of (each 50 ml) were added to the reaction mass and distilled the solvent once again to afford 3 g of crude from of the title compound. EXAMPLE 13: Preparation of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8- yl)ethyl amine additional salt of pyroglutamic acid (FORMULA III, wherein ^iiaasi: represents a single bond)

1150 ml of isopropyl alcohol and 27 g of racemic 2-(1 ,6,7,8,- tetrahydro-2H- indeno[5,4-b] furan-8-yl) ethyl amine of Formula IV wherein ^ ⁵ = represents a single bond) and 17.2 g of D-pyroglutamic acid were charged into a clean and dry round bottom and stirred at about 26°C for 24 hours. The solid obtained was filtered and dried under vacuum at about 54°C to a constant weight to afford 12.8 g of the title compound. The mother liquor was distilled to half of its volume under vacuum and the obtained solid was filtered and dried to a constant weight to obtain a second crop of 14.8 g of the title compound. Purity by chiral HPLC: 76.7%.

EXAMPLE 14: Purification of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8- yl)ethyl amine additional salt of pyroglutamic acid (FORMULA IHA, wherein *^í represents a single bond) 14.2 g of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl amine additional salt of pyroglutamic acid of Formula IMA (wherein ""^ represents a single bond ) was charged into a clean dry round bottom flask containing 142 ml of ethanol and the stirring and heating given. The reaction mass was heated to about 7O ⁰ C to get complete dissolution. The reaction mass was cooled to 26 ⁰ C and stirred for about 4-5 hours for solid separation. The separated solid was filtered and washed with ethanol. The obtained solid was dried at 7O ⁰ C to a constant weight to afford 4.5 g of the title compound.

The mother liquor was distilled to half of its volume under vacuum and the obtained solid was filtered and dried to a constant weight to obtain a second crop of 4.0 g of the title compound.

By repeating the same procedure as in second crop, 1.0 g of 3 ^rd crop obtained. Purity by chiral HPLC: 91.85%.

EXAMPLE 15: Preparation of (S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan- 8-yl)ethyl] propionamide (FORMULA I, wherein "= represents a single bond and R represents ethyl)

6 g of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl amine additional salt of pyroglutamic acid of Formula IMA wherein ^< ^^ represents a single bond), 5.1 g of triphosgene and 200 ml of dichloromethane, were charged into an clean and dry 4 neck round bottom flask followed by stirring given. Sodium carbonate solution (3.816 g of sodium carbonate in 200 ml of water) was slowly added to the reaction mass at 26 ⁰ C and stirred at the same temperature for the completion of the reaction. The organic and the aqueous layer were separated and the organic layer was dried with sodium sulphate. The solvents completely distilled off under vacuum to obtain crude of formula Il (wherein ^=" represents a single bond).

The obtained crude was charged in to a clean and dry 4 necks round bottom flask containing 150 ml of toluene followed by stirring given. The reaction solution was cooled to about -5 ⁰ C. 100 ml of ethyl magnesium bromide was slowly added through a dropper at about -5 ⁰ C followed by stirring the reaction mass at the same temperature for the completion of the reaction. The resultant reaction mass was quenched by addition of 200 ml 10% acetic acid solution. Organic and aqueous layers were separated. The separated organic layer was distilled off completely under vacuum to obtain crude. Di-isopropyl ether (50.0 ml) was added to the crude followed by stirring for about 10-15 minutes for solid separation. The separated solid was filtered and the solid obtained was dried at about 50-54-5 ⁰ C under vacuum to a constant weight to afford 2.5 g of the title compound.

Purity by chiral HPLC: 95.91 %.

EXAMPLE 16: Alternate process for the preparation of (S)-N-[2-(1 ,6,7,8- tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl] propionamide (FORMULA I, wherein ^iaa!S " represents a single bond and R represents ethyl) 7 g of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl amine additional salt of pyroglutamic acid of Formula IHA (wherein ^= represents a single bond), 6.0 g of triphosgene and 400 ml of dichloromethane, were charged into an clean and dry 4 neck round bottom flask followed by stirring given. Sodium carbonate solution (4.45 g of sodium carbonate and 400 ml of water) was slowly

added to the reaction mass at 26 ⁰ C and the reaction mass was maintained at the same temperature till the completion of the reaction. The organic and the aqueous layer were separated and the organic layer was dried with sodium sulphate. The resultant organic solvent was distilled off completely under vacuum to obtain crude of formula Il (wherein "^ represents a single bond).

The obtained crude was charged in to a clean and dry 4 necks round bottom flask containing 100 ml of toluene followed by stirring given. The reaction solution was cooled to about O ⁰ C. 70 ml of ethyl magnesium bromide was slowly added through a dropper at about O ⁰ C followed by stirring the stirring the reaction mass at the same temperature for the completion of the reaction. The resultant reaction mass was quenched by addition of 20% acetic acid solution followed by stirring for about 15-20 minutes and organic and aqueous layers were separated. The obtained aqueous layer was extracted with ethyl acetate and separated the organic and aqueous layer. The separated organic layers were combined and washed with water. The obtained neat organic layer was distilled off completely under vacuum, followed by addition of n-hexane. The obtained solid was filtered and dried at 70 ⁰ C to a constant weight to afford 4.5 g of the title compound. EXAMPLE 17: Purification of (S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan- 8-yl)ethyl] propionamide (FORMULA I, wherein ^í *^ represents a single bond and R represents ethyl)

4 g of (S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl] propionamide crude of Formula I (wherein "^ represents a single bond and R represents ethyl) was charged into a clean and dry 4neck round bottom flask containing 200 ml of ethyl acetate and then stirring and heating given to get a clear solution at about 4O ⁰ C. Activated charcoal (0.4 g) was charged followed by stirring for 10 minutes. The reaction mixture was filtered through celite and the celite was washed with 10 ml of ethyl acetate. The resultant filtrate was distilled off completely at below 5O ⁰ C under a vacuum to produce a white solid. Diisopropyl ether (50 ml) was charged to the crude followed by stirring for about 30 minutes at about 10-26 ⁰ C. The separated solid was filtered and the solid obtained was dried at 54 ⁰ C to a constant weight under vacuum to afford 1.8 g of the title compound. Purity by chiral HPLC: 99.9%.

EXAMPLE 18: Alterante process for the purification of (S)-N-[2-(1 ,6,7,8- tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl] propionamide (FORMULA I, wherein =" represents a single bond and R represents ethyl)

4.9 g of (S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl] propionamide crude of Formula I (wherein ^í **^ represents a single bond and R represents ethyl) was charged into a clean and dry 4 neck round bottom flask containing a 11.2 g ethanol and water mixture (10:1 ratio) and stirring given to get a clear solution. The reaction solution was treated with carbon (0.049 g) and filtered through celite and the celite was washed with 4.6 g of ethanol and water mixture (10:1 ratio). The obtained clear solution was charged into a fresh dry round bottom flask. 37.5 ml of water was added to the above reaction solution at 26 ⁰ C and then the reaction mass was cooled to 10 ⁰ C and stirred for about 1-2 hours and filtered the separated solid. The solid was dried at 7O ⁰ C under vacuum to afford 4.3 g of the title compound.