Field of the Invention:
The present invention relates to an improved process for the preparation of (S)-N-[2-l)6,7,8-tetrahydro-2H-indeno-[534-b]furan-8-yl)ethyl]propionamide compound of formula-1, ^presented by the following structural formula:
C2H5COHNH2CH2Cv H / \Q
Formula-1 background of the Invention:
Ramelteon is a selective melatonin receptor agonist that has demonstrated efficacy in le treatment of insomnia characterized by difficulty with sleep onset. Approximately one in iree American adults complains of some type of insomnia and 20 million Americans suffer om chronic insomnia. It is characterized by difficulty falling asleep, difficulty staying sleep, or poor quality sleep, leading to impairment of next day functioning. Insomnia has een linked to a variety of health problems, including obesity, diabetes, hypertension, heart isease, and depression. Ramelteon is the first and only prescription sleep medication that has !iown no evidence of abuse and dependence, and as a result, has not been designated as a ontrolled substance by the DEA. Its approval also allows physicians to prescribe Ramelteon >r long-term use in adults. Ramelteon provides a unique therapeutic mechanism of action for lerapy of insomnia and represents a new treatment option. However, clinical comparisons nth other hypnotic agents are not available and will be needed to better differentiate these roducts.
Ramelteon is the active ingredient in ROZEREM, and is approved by the United tates Food and Drug Administration for the treatment of insomnia characterized by difficulty Ath sleep onset.
Ramelteon is approved for the treatment of insomnia characterized by difficulty with leep onset and is marketed as ROZEREM (TM) in US. Ramelteon, the S-enantiomer has 00-fold greater potency for binding of the MTl receptor than its R- enantiomer.

US Patent No. 6,034,239 describes compounds of Formula-1, process for its preparation and methods of its use related to sleep disorders.
Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of (S)-2-( 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetamide compound of formula-4.
The second aspect of the present invention is to provide a process for the preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5J4-b]furan-8-yl)ethyl]propionamide compound of formula-1.
Detailed Description of Invention:
The present process provides an improved process for the preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1.
The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate.and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-Diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium diiso porpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-colIidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane,

cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene. glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl methyl ether, 1,2-
> dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichJoroethane and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl
) isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, 1, 2-ethoxyethanol, diethylene glycol, diethylene glycol mono ethyl ether, cyclohexanol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the term "suitable hydrochloric acid source" used in the present invention is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl, preferably ethanol-HCl.
) The first aspect of the present invention provides an improved process for the
preparation of (S)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetamide compound of formula-4, comprising of:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound
of formula-2 with a suitable alkylating agent in a suitable base in a suitable solvent to
i provide alkyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound
of general formula-3,
b) reacting the compound of general formula-3 with formamide in presence of suitable
base in a suitable solvent to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-
carboxamide compound of formula-4.
)
Wherein, in step-a) the suitable alkylating agent is selected from dimethyl sulfate, diethyl
sulfate, methyl iodide, ethyl iodide, alkyl tosylate, trimethyl phosphate, dimethyl carbonate;
A

in step-a) and b) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of (S)-2-(l,6,7J8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetamide compound of formula-4, comprising of:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in a mixture of water and methanol to provide methyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of formula-3a,
b) reacting the compound of formula-3a with formamide in presence of sodium methoxide in dimethyl formamide to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4.
The process for the preparation of compound of formula-4 described in the prior art involve the reaction of compound of formula-2 with thionyl chloride to provide acid chloride compound of formula-2 with low yield and purity which is further reacted with ammonia to provide compound of formula-4 with low yield and purity.
The reaction is very sensitive, requires longer reaction time period and provides less stable acid chloride intermediate with low yield and purity as well as some quantity of unreacted starting material is left over as impurity. Further, utilizing such a low quality compound in the next stage will results in the unnecessary side reactions and thereby provides compound of formula-4 with very low yield and purity. Moreover thionyl chloride is highly hazardous, toxic, corrosive, a potential lachrymator and also difficult to handle on commercial scale and finally making the process not suitable for industrial scale-up.
Thus, there is a need in the art to develop an efficient, eco-friendly and safe synthetic route which overcomes the limitations in the processes disclosed in the prior art.

The present inventors developed simple, improved process for the preparation of compound of formula-4, by reacting compound of formula-2 with a suitable alkylating agent to provide alkyl esters of compound of formula-2 with good yield and purity. Alkyl ester of compound of formula-2 reacting with suitable amidating agent such as formamide to provide compound of formula-4 with high yield and purity.
The present invention involves the usage of non-hazardous reagents and easy to handle. The present invention also involves the reduction of reaction time period, cost, increased yield and purity of the compound of formula-4 as well as final compound of formula-1 and making the process commercially viable, environmentally friendly and suitable for large- scale preparation.
Further, the compound of formula-4 obtained according to the present invention is useful in the preparation of compound of formula-1.
The second aspect of the present invention provides a process for the preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyI]propionamide compound of formula-1, comprising of the following steps:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with a suitable alkylating agent in a suitable base in a suitable solvent to provide alkyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of general formula-3,
b) reacting the compound of general formula-3 with formamide in the presence of suitable base in a suitable solvent to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4,
c) reacting the compound of formula-4 with trifluoro acetic anhydride in a suitable base in a suitable solvent to provide (S)-2-(2,6,7)8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) acetonitrile compound of formula-5,
d) reducing the compound of formula-5 with Raney nickel in methanolic ammonia in a suitable solvent to provide (S)-2-(2)6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) ethanamine compound of formula-6,

e) treating the compound of formula-6 with a suitable hydrochloric acid source in a suitable solvent to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) ethanamine hydrochloride salt compound of formula-6a,
f) optionally, purifying the compound of formula-6a using a suitable solvent,
g) reacting the compound of formula-6a with propionyl chloride in presence of a suitable base in a suitable solvent to provide (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) ethyljpropionamide compound of formula-1,
h) optionally purifying the compound of formula-1 using suitable solvent to provide pure (S)-N-[2-(l)6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1.
Wherein, in step-a) the suitable alkylating agent is same as defined in step-a) of the first
aspect of the present invention;
in step-a), b), c) and g) the suitable base is selected from organic or inorganic base;
in step-e) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry
HC1, ethyl acetate-HCl, IPA-HC1, ethanoI-HCl, methanol-HCl;
in step-a) to h) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone
solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic
solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of (S)-N-[2-(l ,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1, comprising of the following steps:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in a mixture of water and methanol to provide methyl (S)-2,6;7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of formula-3a,
b) reacting the compound of formula-3a with formamide in presence of sodium methoxide in dimethyl formamide to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4,
c) reacting the compound of formula-4 with trifluoro acetic anhydride in aqueous
7

sodium carbonate in tetrahydrofuran to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno [5,4-b]furan-8-yl)acetonitrile compound of formula-5,
d) reducing the compound of formula-5 with Raney nickel in methanolic ammonia in methanol to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) ethanamine compound of formula-6,
e) treating the compound of formula-6 with ethyl acetate-hydrochloride in acetonitrile to provide (S)-2-(2,6J7J8-tetrahydro-lH-indeno[5)4-b]furan-8-yl)ethanamine hydrochloride salt compound of formula-6a,
f) purifying the compound of formula-6a using acetonitrile,
g) reacting the compound of formula-6a with propionyl chloride in presence of sodium carbonate in a mixture of water and ethyl acetate to provide (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1,
h) purifying the compound of formula-1 using ethyl acetate to provide pure (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1.
The starting material (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 used in the present invention can be prepared from the process known in the art.
The (S)-N-[2-(l,6J7)8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide ;ompound of formula-1 obtained according to the present invention is having purity greater :han 99.8 % as measured by HPLC.
(S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5)4-b]furan-8-yl)ethyl]propionamide ;ompound of formula-1 obtained according to the present invention is having particle size iistribution D90 less than 150 um, preferably less than 100 urn, more preferably less than 50 im.
Further, the compound of formula-1 obtained according to the present invention Slaving the Acetamide impurity, Amine impurity, Acetyl impurity, Acetonitrile impurity, Methyl ester impurity, R-isomer impurity less than 0.1%; preferably less than 0.06%; more

p
(S)-N-[2-Cl,6)7>8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
The process of the present invention can be represented schematically as follows:

o
H
rormuia-o * w* ■■.—-i
R = C|-C6 straight chain or branched alkyl FormuIa-3a = Methyl Formula-6a = Hydrochloride salt
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention. Examples
Example-l: Preparation of Methyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8- \ carboxylate: (Formula-3)
A mixture of water (62.5 ml), (SJ^^J.S-tetrahydro-lH-indeno^^-bJfuran-S-carboxylic acid (50.0 gms), methanol (62.5 ml), dimethyl sulfate (75.0 gms) and sodium bicarbonate were heated to 40-45°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture at 25-30°C and

stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Example-2: Preparation of (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide: (Formula-4)
Dimethyl formamide (250 ml) was added to the compound obtained in example-1 at 25-30°C and stirred for 10 minutes at the same temperature. Formamide (55.0 gms) was added to the reaction mixture at 25-30°C Cooled the reaction mixture to 0-5°C. Sodium methoxide solution was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated sojid, washed with water and dried to get the title compound. Yield: 46.7 gms; MR: 217°C-220°C.
Example-3: Preparation of (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yI) acetonitrile: (FormuIa-5)
Tetrahydrofuran (500 ml) was added to (S)-2,6)7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide (100 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Trifluoro acetic anhydride (290 gms) was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 3 hours at the same temperature. Distilled off the solvent completely under vacuum. Aqueous sodium carbonate solution was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Example-4: Preparation of (S)-2-(2,6,7,8-tetrahydro-lH-indeno[S,4-b]furan-8-yl) ethanamine hydrochloride salt: (Formula-6a)
Methanolic ammonia (500 ml) was added to (S)-2-(2,6,7J8-tetrahydro-lH-indeno[5,4-b]furan-8-yl)acetonitrile compound of formula-5 obtained in example-3 at 25-30°C in an autoclave. Methanol (50 ml), Raney nickel (60.0 gms) and methanolic ammonia (500 ml) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. 3-4 kg/cm hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 3 at the same temperature. Filtered the reaction mixture through hy-flow bed and washed

the bed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol was added to the obtained compound and distilled off completely and then co-distilled with cyclohexane. To the obtained compound, acetonitrile (300 ml) was added at 25-30°C. Cooled the reaction mixture to 0-5°C Ethyl acetate-HCl (250 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature.. Filtered the precipitated solid and washed with acetonitrile. To the obtained compound, acetonitrile (400 ml) was added at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 93.94 gms; M.R: 244°C-250°C.
Exampe-5: Preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) ethyljpropionamide: (Formula-1)
A mixture of ethyl acetate (1000 ml) and (S)-2-(2,6,7,8-Tetrahydro-lH-indeno[5,4-b]furan-8-yl) ethanamine hydrochloride salt (100 gms) were added to a precooled aqueous sodium carbonate solution (178 gms of sodium carbonate in 600 ml water) at 0-5°C and stirred for 15 minutes at the same temperature. Propionyl chloride (78 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 5-10°C. Water was slowly added to the reaction mixture at 5-10°C and stirred for 10 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer twice with ethyl acetate. Combined the organic layer and aqueous sodium bicarbonate was added at 25-30°C and stirred for 10 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the organic layer with water. Combined organic layers and filtered through filter paper and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with cyclohexane. To the obtained compound, ethyl acetate (500 ml) was added at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C

and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
Yield: 89.73 gms; M.R: 110°C-120°C; Purity by HPLC: 99.91%; Acetamide Impurity: Not detected; Amine Impurity: Not detected; Acetyl Impurity: 0.04%; Acetonitrile Impurity: Not detected; Methyl ester Impurity: Not detected; R-isomer Impurity: Not detected; HIUI: 0.05%. Particle Size Distribution (PSD): D(0.1) is 1.78 urn; D(0.5) is 5.13 urn; D(0.9) is 16.6 um;D[4.3] is 10.3 am.
Example-6: Preparation of methyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate: (Formula-3)
Water (12.5 Its) was added to (S)-2,6J,8-tetrahydro-lH-indeno[5Ab]furan-8-carboxylic acid (10.0 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Methanol (12.5 Its) followed by dimethyl sulfate (15.0 kgs) and sodium bicarbonate (11.6 kgs) were added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture at 25-30°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Example-7: Preparation of (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide: (FormuIa-4)
Dimethyl formamide (50 Its) was added to the compound obtained in example-6 at 25-30°C under nitrogen and stirred for 10 minutes at the same temperature. Formamide (11.0 kgs) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C. Sodium methoxide solution was slowly added to the reaction mixture at 0-5°C. Raised the temperature of. the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 9.3 kgs.

Example-8: Preparation of (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-bJfuran-8-yi) acetonitrile: (Formula-5)
Tetrahydrofuran (40 Its) was added to (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide (8.0 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Trifluoro acetic anhydride (23.3 kgs) was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 3 hours at the same temperature. Distilled off the solvent completely under vacuum. Aqueous sodium carbonate solution (4.0 kgs of sodium carbonate in 40 Its of water) was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Example-9: Preparation of (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5t4-b]furan-8-yI) ethanamine hydrochloride salt: (FormuIa-6a)
Methanolic ammonia solution (50 kgs of ammonia in 88 Its of methanol) was added to (S)-2-(2)6,7J8-tetrahydro-lH-indeno[5,4-b]furan-8-yl)acetonitriIe compound of formula-5 obtained in example-8 at 25-30°C in an autoclave. Methanol (40 Its), Raney nickel (4.8 kgs) and methanolic ammonia solution was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. 3-4 kg/cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 3 at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol was added to the obtained compound and distilled off completely and then co-distilled with cyclohexane. To the obtained compound, acetonitrile (24.0 Its) was added at 25-30°C. Cooled the reaction mixture to 0-5°C. Ethyl acetate-HCl (20.0 Its) was slowly added to the reaction mixture at 0-5°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid and washed with acetonitrile. To the obtained compound, acetonitrile (32.0 Its) was added at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 7.5 kgs.

Exampe-10: Preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yI) ethyljpropionamide: (Formuta-1)
A mixture of ethyl acetate (60 Its) and (S)-2-(2)6)7,8-Tetrahydro-lH-indeno[5,4-b] furan-8-yl)ethanamine hydrochloride salt (6.0 kgs) were added to a pre-cooled aqueous sodium carbonate solution (10.7 kgs of sodium carbonate in 36.0 Its of water) at 0-5°C and stirred for 15 minutes at the same temperature. Propionyl chloride (4.7 kgs) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 5-10°C. Water was slowly added to the reaction mixture at 5-10°C and stirred for 10 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer twice with ethyl acetate. Combined the organic layer and aqueous sodium bicarbonate was added at 25-30°C and stirred for 10 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the organic layer with water. Combined the organic layers and filtered through filter paper and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with cyclohexane. To the obtained compound, ethyl acetate (30 Its) was added at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 5.4 kgs.

We Claim:
1. An improved process for the preparation of (S)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]
furan-8-yl)acetamide compound of formula-4, comprising of:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formuIa-2 with a suitable alkylating agent in a suitable base in a suitable solvent to provide alkyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of general formuIa-3,
b) reacting the compound of general formuIa-3 with formamide in presence of suitable base in a suitable solvent to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide compound of formula-4.
2. The process according to claim-1, wherein, in step-a) the suitable alkylating agent is
selected from dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl iodide, alkyl tosylate,
trimethyl phosphate, dimethyl carbonate;
in step-a) and b) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
3. An improved process for the preparation of (S)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]
furan-8-yl)acetamide compound of formula-4, comprising of:
a) Reacting (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in a mixture of water and methanol to provide methyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of formula-3a,
b) reacting the compound of formula-3a with formamide in presence of sodium methoxide in dimethyl formamide to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4.
4. A process for the preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)
ethyl]propionamide compound of formula-1, comprising of the following steps:

a) Reacting (S)-2,6,7,8-tetrahydro-.lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with a suitable alkylating agent in a suitable base in a suitable solvent to provide alkyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of general formula-3,
b) reacting the compound of general formula-3 with formamide in the presence of suitable base in a suitable solvent to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4,
c) reacting the compound of formula-4 with trifluoro acetic anhydride in a suitable base in a suitable solvent to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) acetonitrile compound of formula-5,
d) reducing the compound of formula-5 with Raney nickel in methanolic ammonia in a suitable solvent to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]fliran-8-yl) ethanamine compound of formula-6,
e) treating the compound of formula-6 with a suitable hydrochloric acid source in a suitable solvent to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl) ethanamine hydrochloride salt compound of formuIa-6a,
f) optionally, purifying the compound of formula-6a using a suitable solvent,
g) reacting the compound of formula-6a with propionyl chloride in presence of suitable base in a suitable solvent to provide (S)-N-[2-(l,6,7J8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) ethyl]propionamide compound of formula-1,
h) optionally purifying the compound of formula-1 using suitable solvent to provide pure (S)-N-[2-(l56,7J8-tetrahydro-2H-indeno-[5)4-b]furan-8-yl)ethyl]propionamide compound of formula-1.
5. The process according to claim-4, wherein, in step-a) the suitable alkylating agent is selected from dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl iodide, alkyl tosylate, trimethyl phosphate, dimethyl carbonate;
in step-a), b), c) and g) the suitable base is selected from organic or inorganic base; in step-e) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCI, methanol-HCl;

in step-a) to h) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
6. A process for the preparation of (S)-N-[2-(l,6)7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) ethyl]propionamide compound of formula-1, comprising of the following steps:
a) Reacting (S)-2J6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in a mixture of water and methanol to provide methyl (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxylate compound of formula-3a,
b) reacting the compound of formula-3a with formamide in presence of sodium methoxide in dimethyl formamide to provide (S)-2,6,7,8-tetrahydro-lH-indeno[5,4-b] furan-8-carboxamide compound of formula-4,
c) reacting the compound of formula-4 with trifluoro acetic anhydride in aqueous sodium carbonate in tetrahydrofuran to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno [5,4-b]furan-8-yl)acetonitrile compound of formula-5,
d) reducing the compound of formula-5 with Raney nickel in methanolic ammonia in methanol to provide (S)-2-(2,6,7,8-tetrahydro-lH-indeno[5,4-b]furan-8-yl)ethanamine compound of formula-6,
e) treating the compound of formula-6 with ethyl acetate-hydrochloride in acetonitrile to provide (S)-2-(2,6)7)8-tetrahydro-lH-indeno[5,4-b]furan-8-yl)ethanamine hydrochloride salt compound of formula-6a,
f) purifying the compound of formula-6a using acetonitrile,
g) reacting the compound of formula-6a with propionyl chloride in presence of sodium carbonate in a mixture of water and ethyl acetate to provide (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5)4-b]furan-8-yl)ethyl]propionamide compound of formula-1,
h) purifying the compound of formula-1 using ethyl acetate to provide pure (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1.

7. (S)-N-[2-(l,6,738-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide compound of formula-1 obtained according to the preceding claims having purity greater than 99.8 % by HPLC.
8. (S)-N-[2-(lJ6,7)8-tetrahydro-2H-indeno-[5>4-b]furan-8-yl)ethyl]propionamide compound of formula-1 obtained according to the preceding claims having particle size distribution D90 less than 150 um, preferably less than 100 um, more preferably less than 50 ym.
9. (S)-N-[2-(l ^^.S-tetrahydro^H-indeno-fS^-bJfuran-S-ylJethylJpropionamide compound of formula-1 obtained according to the preceding claims having the Acetamide impurity, Amine impurity, Acetyl impurity, Acetonitrile impurity, Methyl ester impurity, R-isomer impurity less than 0.1%; preferably less than 0.06%; more preferably less than 0.02% by HPLC.
10. An improved process for the preparation of (S)-2-( 1,6,7,8-tetrahydro-2H-indeno[5,4-b]
furan-8-yl)acetamide compound of formula-4, comprising of reacting the compound of
general formula-3 with formamide in presence of suitable base in a suitable solvent to
provide (S)-2,6,7J8-tetrahydro-lH-indeno[5,4-b]furan-8-carboxamide compound of
formula-4.