FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10 ; rule 13]
1. TITLE OF THE INVENTION:
"Process for preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl] propionamide and novel intermediates thereof
2. APPLICANT:
a) NAME: USV LIMITED
b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
c) ADDRESS: B.S.D. Marg, Govandi, Mumbai400 088,
Maharashtra, India

3.
PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention

Technical field:
The present invention relates to process for preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl] propionamide (Ramelteon) of formula (I) in pure isomeric form and free from unwanted impurities. The present invention further relates to novel intermediates used for the preparation of Ramelteon (1) and process for

Background and prior art:
Ramelteon is an orally active hypnotic, chemically designated as (S)- N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide and containing one chiral center. (S)- Ramelteon is marketed by Takeda Pharmaceuticals under the brand name Rozerem ™. Ramelteon is a selective melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon is useful in treatment of insomnia characterized by difficulty with sleep onset, sleep-awake rhythm disorders, jet lag and seasonal melancholia. Ramelteon can be used in combination with at least one selected from Zolpidem, zopiclone, triazolam and brotizolam.
US6034239 (referred hereinafter as US '239) discloses synthesis of S-Ramelteon which comprises a) reacting 2,3-dihydrobenzofuran (2) with dimethylformamide (DMF) and phosphorous oxychloride to get 2,3-dihydrobenzofuran-5-carbaldehyde (3) which on reacting with triethyl phosphonoacetate in the presence of sodium hydride in tetrahydrofuran (THF) gives Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (4); b) hydrogenating the compound (4) using 5% palladium-carbon to get Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-propionate (5); c) brominating compound (5) with bromine in acetic acid to obtain Ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl)-propionate (6) which on further bromination with bromine in acetic acid in the presence of iron powder as a catalyst gives crude Ethyl 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionate (7); d)
2

hydrolyzing compound (7) by treating with aqueous sodium hydroxide in THF to give 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid (8); e) reacting the compound (8) with thionyl chloride and aluminum chloride to get crude 4,5-dibromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (9); f) dehalogenating compound (9) in acetic acid under hydrogen atmosphere using palladium-carbon to give crude 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (10) followed by reacting with diethyl cyanomethylphosphonate in presence of sodium hydride in THF to get crude (E)-(l,6,7,8-te1rahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (11) and hydrogenating the compound (11) in ammonia-ethanol solvent mixture using Raney cobalt to get (E)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine (12); g) treating compound (12) with saturated hydrogen chloride/ethanol solution to get the HCL salt followed by reduction of HC1 salt in the presence of hydrogen and [Ru2Cl4((R)-BINAP)2 (NEt3)] under 100 atmospheric pressure at 50° C for 20 hours to get (S)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethylamine hydrochloride (13) with optical purity of 88.8% ee; h) purifying compound (13) by recrystallization using mixture of methanol-acetone to obtain purity of 100%ee; i) reacting compound (13) with propionyl chloride in the presence of triethyl amine to give S-Ramelteon (1). The reaction is as represented in Scheme I below;


The main disadvantage of this process is that all the intermediates formed were purified by using column chromatography, which is expensive, time consuming and impractical at industrial scale. Another major disadvantage of this process is that chiral reduction of compound (12) to compound (13) involves the use of hydrogen gas under 100 atmospheric pressure at 50° C for 20 hours which is very hazardous operation at industrial scale as well as unproductive.
US '239 also discloses another process for synthesizing S-Ramelteon comprising hydrolysing Ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl) propionate (6) with aqueous sodium hydroxide in tetrahydrofuran (THF) to get Ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl) propionic acid (14) which on reacting with thionyl chloride and aluminum chloride gives crude 4-bromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one which is purified by column chromatography using hexane-ethyl acetate mixture as eluting solvent to get pure compound (15). The compound (15) is reacted with diethyl cyanomethylphosphonate in presence of sodium hydride in THF to obtain crude (E)-(4-bromo-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitriIe followed by purifying the obtained compound by column chromatography using hexane-ethyl acetate mixture as eluting solvent to get pure compound (16). The compound (16) thus obtained is hydrogenated in presence of Raney nickel in ammonia-ethanol solvent mixture followed by treatment using palladium-carbon to provide 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrobromide (17). The compound (17) is reacted with propionyl chloride in presence of aqueous sodium hydroxide to get N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]ruran-8-yl)ethyl]propionamide (racemic Ramelteon) (18) which on further purification by HPLC provides S-Ramelteon (1). The main disadvantage of this process is that the intermediates formed in the process were purified by using column chromatography which results in low yield of the compound (15), thus making the process expensive, time consuming and impractical at industrial scale.
The reaction is as represented by Scheme II below;
4


WO2008062468 discloses method for the preparation of chirally active indeno[5,4-b]furan derivatives, which includes separation of chirally pure intermediates and / or racemic Ramelteon in its pure isomeric form and free from other impurities, by the separation of isomers using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.
Hence there is a need for simple and commercially viable process for the preparation of (S)- Ramelteon without involving the hazardous operation as well as to eliminate /minimize the undesired impurities to get the pure desired product. Thus the present invention provides commercially viable process for preparation of (S)- Ramelteon with purity more than 99.8%.
Object of the invention:
An object of the present invention is to provide simple and industrially feasible process
for the preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide (Ramelteon) in high yield and high purity.
Another object of the present invention provides isolated impurity A i.e. N-[2-(3,5,6,7,-
tetrahydro-2H-indeno[5,6-b]furan-7-yl)ethyl]propionamide; impurity B i.e. (R)-N-[2-
(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide ; and impurity C i.e.
N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethyl]propionamide.
Another object of the present invention is to provide synthesizing and using the isolated
impurities i.e., Impurity A, Impurity B or Impurity C as a reference marker/standard.
5

Yet another object of the present invention is to provide crystalline forms of Ramelteon.
Another object of the present invention is to provide (S)-Ramelteon free from unwanted
impurities viz., Impurity A, Impurity B and Impurity C.
Another object of the present invention is to provide novel intermediate, (1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile and separation of the desired isomer,
(-)(l,6,7,8-tetrahydro-2H-indeno[5,4-b]fiiran-8-yl)acetonitrile using Novasep, which is a
key intermediate used for preparation of (S)-Ramelteon.
Further object of the invention is to provide process for recovery of novel intermediate
(-)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile from its unwanted (+)
isomer and further converting it to S-Ramelteon thus making the process cost effective.
Summary of the invention:
The present invention discloses process for preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (Ramelteon) (I) in high yield and purity comprising the steps of;
a) reacting 2,3-dihydrobenzofuran (2) with phosphorous oxychloride and dimethyl formamide to give 2,3-dihydrobenzofuran-5-carbaldehyde (3);
b) reacting the obtained compound (3) with triethyl phosphonoacetate in the presence of a base to obtain ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (4);
c) reducing the obtained compound (4) to give Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-propionate (5);
d) reacting the obtained compound (5) with bromine in the presence of a base to obtain Ethyl-3-(6,7-dibromo-2,3-dihydiobenzofuran-5-yl) propionate(7);
e) hydrolysing the obtained compound (7) to give 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid (8);
f) reacting the obtained compound (8) with thionyl chloride and aluminum chloride to give 4,5-dibromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one(9);
g) dehalogenating the compound (9) to give l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one(10);
h) combining the compound (10) with diethyl cyanomethylphosphonate in presence of a base to get (E)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (11);
6

i) reducing the compound (11) to obtain (l,6,7,8-tetrahydro-2H-indeno[5,4-
b]furan-8-yl)methylacetonitrile(19); j) separating the enantiomer from racemic compound (19) on chiral stationary phase
using chromatographic techniques to obtain (-) l,6,7,8-tetrahydro-2H-indeno[5,4-
b]furan-8-yl-methylacetonitrile(20); k) reducing compound (20) to get (-) 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine hydrohalide (22) and 1) combining the compound (22) with propionyl chloride to obtain (-) N-[2-(l,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (Ramelteon)(I).

According to another aspect of the present invention there is provided a novel intermediate, l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19) and process for preparation thereof.
According to another aspect of the present invention there are provided novel intermediates, (-) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (20) and (+) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (21) and converting (-) 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (20) into (S)- Ramelteon.
7

Another aspect of the present invention provides recovery of (-) l,6,7,8-tetrahydro-2H-
mdeno[5,4-b]furan-8-ylacetonitrile (20) from the unwanted isomer, (+) 1,6,7,8-
tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile(21).
According to another aspect of the present invention there is provided an isolated
impurity A i.e. N-[2-(3,5,6,7,-tetrahydro-2H-indeno[5,6-b]furan-7-yl)ethyl]propionamide;
impurity B i.e. (R)-N-[2-(I,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide; and impurity C i.e. N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-
b]furan-8-ylidene)ethyl]propionamide.
Another aspect of the present invention provides synthesizing and using Impurity A,
Impurity B and Impurity C as reference marker/standard.
Another aspect of the present invention provides analytical method for testing the
impurity profile of Ramelteon (1) using Impurity A, Impurity B and Impurity C as
reference marker/standard.
Brief description of the figures:
Fig.l is a characteristic X-ray Powder diffraction pattern of Ramelteon (I) obtained by
the process of the present invention.
Fig.2 is a characteristic X-ray Powder diffraction pattern of (-) l,6,7,8-tetrahydro-2H-
indeno[5,4-b]furan-8-ylacetonitrile (20).
Fig.3 is a characteristic X-ray Powder diffraction pattern of l,2,6,7-tetrahydro-8H-
indeno[5,4-b]furan-8-one (10).
Detailed description of the invention:
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 (Ramelteon) of formula (I) which comprises the steps of;
a) reacting 2,3-dihydrobenzofuran (2) with phosphorous oxychloride and an organic solvent to give 2,3-dfihydrobenzofuran-5-carbaldehyde (3);


b) reacting compound (3) with a wittig reagent in presence of base in an organic solvent to obtain Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (4);

(4) c) hydrogenating compound (4) in organic solvent using catalyst to give Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-propionate (5);

(5) d) brominatimg compound (5) using a brominating agent in the presence of organic solvent, and optionally in presence of base and catalyst to obtain Ethyl-3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionate (7);

(7) e) hydrolyzing compound (7) in presence of base and organic solvent to give 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid (8);

(8) f) cyclizing the compound (8) with lewis acid in organic solvent in presence of
halogenating agent to give 4,5-dibromo-l ,2,6,7-tetrahydro-8H-indeno[5,4-
b]furan-8-one (9);
9


g) dehalogenating compound (9) in presence of a base and an organic solvent using a catalyst under hydrogen atmosphere to give l,2,6,7-tetrahydro-8H-indeno[5,4-b]ruran-8-one(10);

h) reacting compound (10) with wittig reagent in presence of a base in an organic
solvent to get (E)-(l,6;7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
ylidene)acetonitrile (11);

i) hydrogenating compound (11) in organic solvent using a catalyst and base to obtain l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19);

j) separating isomers of racemic compound (19) on crural HPLC column to obtain (-) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (20) and (+) 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile;
10


k) hydrogenating compound (20) in organic solvent using a catalyst to get (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-y^ethylamine or salt thereof (22);

1) reacting compound (22) with propionyl chloride in an organic solvent in presence of base to obtain (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]ftiran-8-yl) ethyl] propionamide (Ramelteon) (1) and

S-Ramelteon (I) m) optionally purifying (S)- Ramelteon with organic solvent.
In step a) the Vilsmeier Haack formylation reaction is carried out at temperature between 15-85°C. The solvent used for extraction of the product may be selected from halogenated solvent, hydrocarbon or ester. Halogenated solvent may be selected from dichloromethane, chloroform or trichloroethane; hydrocarbon may be selected from hexane or toluene, ester may be selected from ethyl acetate, methyl acetate or isopropyl acetate.
In step b) the wittig reagent used is triethyl phosphonoacetate. The reaction is carried out at temperature between 15-85°C. The base may be selected from metal hydride or metal alkoxide; the metal hydride may be selected from sodium hydride or calcium hydride and metal alkoxide may be selected from sodium methoxide, sodium ethoxide, sodium tertiary butoxide or potassium tertiary butoxide. The organic solvent may be selected
11

from toluene, THF or 1,4-dioxane.
In step c) the hydrogenation reaction may be carried out at pressure between 0,5-10 kg/cm2 and temperature ranges between 20-50°C. The organic solvent used may be selected from acetic acid or alcohol such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol. The catalyst used may be selected from supported noble metal catalyst like palladium-charcoal, palladium-alumina or noble metal oxide like palladium oxide, palladium hydroxide or platimum oxide.
In step d) the brominating agent used may be selected from N-bromosuccinimide, hydrogen peroxide-HBr mixture, oxone-NaBr mixture, ferric chloride (anhydrous and hexahydrate)-liquid bromine mixture, preferably liquid bromine. The catalyst used is iron powder (about l0um particle size). The base used may be selected from sodium acetate or potassium acetate and the solvent may be selected from acetic acid or halogenated solvent. Halogenated solvent may be selected from dichloromethane, chloroform or trichloroethane.
In step e) the hydrolytic reaction is carried out at temperature ranges from 20-80°C. The base used may be selected from sodium carbonate, potassium carbonate, sodium or potassium bicarbonates, sodium hydroxide, potassium hydroxide, or lithium hydroxide. The organic solvent used may be selected from ethereal solvent, preferably THF or 1,4-dioxane.
In step f) the cyclization reaction is carried out by converting carboxylic acid to its acid halide derivative followed by treatment with Lewis acid. The halogenating agent used may be selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride. The organic solvent used may be selected from dichloromethane, chloroform or trichloroethane. The Lewis acid used may be selected from anhydrous aluminum chloride, anhydrous ferric chloride, anhydrous zinc chloride or polyphosphoric acid or boron trifluoride-diethyl etherate complex.
In step g) the dehalogenation reaction is carried out at pressure between 0.5-10 kg/cm2 and temperature ranges between 20-50°C. The organic solvent used may be selected from DMF, acetic acid, 1,4-dioxane, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol or mixture thereof. The catalyst used may be
12

selected from palladium-charcoal, palladium-alumina, palladium oxide or platimum oxide. The base used may be selected from sodium acetate or potassium acetate.
In step h) the wittig reagent is diethyl cyanomethylphosphonate. The wittig reaction is carried out at temperature between 15-85°. The base used may be selected from metal hydride or metal alkoxide. Metal hydride may be selected from sodium hydride or calcium hydride and metal alkoxide may be selected from sodium methoxide, sodium ethoxide, sodium tertiary butoxide or potassium tertiary butoxide. The organic solvent used may be selected from toluene, THF or 1,4-dioxane
In step i) the hydrogenation reaction may be carried out at pressure between 0.5-10 kg/cm2 and temperature between 20-50°C. The organic solvent used may be selected from DMF, acetic acid, 1,4-dioxane, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol, ethylene glycol or mixtures thereof. The catalyst used may be selected from supported noble metal catalysts like palladium-charcoal, palladium-alumina or noble metal oxides like palladium oxide or platimum oxide.
In step j) the chiral separation may be carried out on a column that is packed with a Chiral Stationary Phases (CSP) like Kromosil 10 μm -Cellucoat or any equivalent Daicel CSP.
In step k) the hydrogenation reaction is carried out at pressure between 0.5-10 kg/cm2 and temperature between 20-50°C. The organic solvent used may be selected from toluene, water, DMF, acetic acid, 1,4-dioxane, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol, ethylene glycol or mixtures thereof. The catalyst used may be selected from Raney nickel, supported noble metal catalysts like palladium-charcoal, palladium-alumina, or noble metal oxides like palladium oxide or platimum oxide. The base used may be selected from sodium carbonate, potassium carbonate, sodium or potassium bicarbonates, sodium hydroxide, potassium hydroxide or lithium hydroxide.
In step 1) the organic solvent used for acylation reaction may be selected from dimethylformamide (DMF), tetrahydroiiiran (THF), 1,4-dioxane, dimethyl ether or mixtures thereof. The base used may be selected from triethyl amine, pyridine, sodium carbonate, potassium carbonate, sodium or potassium bicarbonates, sodium hydroxide, potassium hydroxide or lithium hydroxide .
13

According to another embodiment of the present invention, the crude Ramelteon thus obtained is purified using an organic solvent or water or mixtures thereof. The organic solvent may be selected from ester such as methyl acetate, isopropyl acetate, ethyl acetate, preferably ethyl acetate. Organic solvent used in combination with water may be selected from methanol, ethanol, isopropyl alcohol, THF or acetonitrile. The process of the present invention provides Ramelteon of the formula (1) in high chiral purity (ee >99.8 %), chemical purity > 99.5% and polymorphic purity > 99%. The particle size distribution is as follows; d90 is less than 500 μ preferably less than 250 μ. more preferably less than 100μ and d50 is less than 250 μ. preferably less than 150 μ. more preferably less than 100μ,.
The highly crystalline Form of Ramelteon thus obtained is further micronized by conventional micronization techniques to have the particle size distribution, d90 is about 3-100μ preferably 3-60μ more preferably 3-30μ. The specific surface area of Ramelteon is atleast about 1 m2/g or more. The pure Ramelteon thus obtained has an X-ray powder diffraction pattern as shown in Fig. 1;

Pos [°2Th ]±
0.2°
7.74 Rel. Int. [%]
15.69
8.21 41.88
14.4 14.95
14.91 100
16.99 22.95
18.46 20.14
20.57 52.31
21.09 10.51
22.31 27.79
23.14 46.31
24.07 58.94
28.25 29.93 30.32 7.88 7.99 7.09
Another embodiment of the present invention provides a novel intermediate, 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19) and process for preparation thereof.
14

The process for preparation of novel intermediate, l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19) according to present invention comprises hydrogenating compound (11) in organic solvent using a catalyst to obtain l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19);

The pressure of the hydrogenation reaction may be between 0.5-10 kg/cm2; temperature may be between 20-50°C. Organic solvent used can be selected from dimethyformamide , acetic acid, 1,4-dioxane, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol, ethylene glycol or mixtures thereof. The catalyst used can be selected from supported noble metal catalysts like palladium-charcoal, palladium-alumina or noble metal oxides like palladium oxide or platimum oxide.
Another embodiment of the present invention provides novel intermediates, (-) 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (20) and (+) l,6)7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (21).
According to another embodiment there is also provided a process for preparation of (S)-2-(l,6?7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine or salts thereof which comprises the steps of;
a) separating isomers of racemic compound (19) on chiral HPLC column (Novasep) to obtain (-) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (20) and (+) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (21);

(20) [(-) isomer] (21) [(+) isomer]
b) hydrogenating compound (20) in organic solvent using a catalyst to get (S)- 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine or converting into salts thereof (22).
15


The chiral separation may be carried out on a column, that is packed with a CSP like Kromosil 10 μm -Cellucoat or any equivalent Daicel CSP; mobile phase may be either a single solvent or a mixture of solvents in different proportions selected from hydrocarbon like hexane and alcohol such as methanol, ethanol or isopropyl alcohol.
The conditions used for separating the desired compound (20) are as follows;
Column: Kromosil 10-Cellucoat 250*4.6 mm, 10 μm
Mobile phase: Hexane-ethanol (90:10% v/v)
Run time: 20 minutes
Flow rate: 1.0 ml/min
Specific optical rotation [ct]D20 = -136.07 (c 1.005, methanol)
The unwanted (+) isomer, compound (21) with specific optical rotation of [ot]D20 =
+136.07 (c 1.005, methanol) is used for recovering the compound (20).
The hydrogenation reaction may be carried out at pressure between 0.5-10 kg/cm2 and at temperature between 20-50°C. The organic solvent used is selected from toluene, water, dimethylformamide (DMF), acetic acid, 1,4-dioxane, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol, ethylene glycol or mixtures thereof. The catalyst used may be selected from Raney nickel, supported noble metal catalyst like palladium-charcoal, palladium-alumina, or noble metal oxide like palladium oxide or platimum oxide. The base used can be selected from sodium carbonate, potassium carbonate, sodium or potassium bicarbonates, sodium hydroxide, potassium hydroxide or lithium hydroxide.
The compound (20) thus obtained exhibits XRPD as shown in Fig 2 represented in below table.
Pos [2Theta]
± 0.2°) Rel. Int. [%]
16

4.64 2.87
11.5 87.62
13.47 7.71
13.99 38.19
15.99 13.55
17.72 38.24
18.85 48.89
21.89 26.19
22.26 74.47
24.88 100
26.41 16.99
26.71 35.56
According to another embodiment, the present invention provides process for preparation of (S)- Ramelteon which comprises;
a) reacting compound (22) with propionyl chloride in an organic solvent in presence
of base to obtain (S)-N-[2-(l,6,7,8-terrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide (Ramelteon) (1) and

S-Ramelteon (I) b) optionally purifying (S)-Ramelteon with organic solvent.
The organic solvent used for acylation reaction can be selected from DMF , tetrahydrofuran (THF), 1,4-dioxane, dimethyl ether (DME) or mixtures thereof. The base used may be organic or inorganic base. The organic base used can be triethyl amine or pyridine and the inorganic base may be selected from sodium carbonate, potassium carbonate, sodium or potassium bicarbonates, sodium hydroxide, potassium hydroxide or lithium hydroxide.
According to another embodiment, the present invention provides process for recovery of desired isomer (-)-l,6,7,8 tetrahydro-2H-indeno[5,4]furan-8-yl acetonitrile, a key intermediate for preparation of (S)- Ramelteon which comprises;
a) brominating (+) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yIacetonitriIe (21) to get the corresponding bromo (l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
17

yl)acetonitrile (23).
b) treating compound (23) with a base to get (E)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (11).
c) hydrogenating compound (11) to get racemic l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19).
d) separating isomers of racemic compound (19) on chiral HPLC (Novasep) to get (-)l,6,7,8-tetrahydro-2H-indeno[5,4-b]ruran-8-ylacetonitrile(20).

Another embodiment of the present invention provides process for preparation of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (10), an important intermediate used for preparation of (S)-Ramelteon, comprising the steps of;
a) reacting 6-bromodihydrobenzofuran (24) with phosphorous oxychloride in presence of DMF to form 6-bromo-5-carbaldehyde-2,3-dihydrobenzofuran (25);
b) reacting compound (25) with malonic acid in presence of base to form 3-(6-bromo-2,3-dihydrobenzofuran-5-yl)-2-propenoic acid (26).
c) cyclizing compound (26) using anhydrous aluminum chloride to form 5-bromo-l,2-dihydro-8H-indeno[5,4-b]furan-8-one (27).
d) hydrogenating compound (27) to form l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one(10).


The reaction is represented in below scheme;

The compound (10) obtained according to the invention exhibits an XRD pattern as shown in Fig 3.

Pos. [2Theta] Rei. Int. [%]
10.9803 100.00
12.7049 28.67
13.8354 39.68
16.7785 5.66
17.0730 21.87
18.1471 9.11
20,8162 15,34
21.9646 71.48
22.3570 25.83
23.4572 16.02
25.8944 18.37
26.6842 7.04
28.0339 3.43
28.6585 16.51
29.7134 39.34
30.3725 14.38
30.9406 13.91
32.2451 10.78
33.3665 17.47
34.4277 8.27
35.6671 22.55
37.3165 4.53
37.8042 6.93
38.6010 6.32
41.5831 4.43
41.9455 5.56
43.8894 7.14
45.0140 7.71
46.0241 6.55
46.5140 4.04
49.3131 0.27
19

Another embodiment of the present invention provides process for synthesizing ethyI-3-(6,7-dibromo-2,3-dihydroberizofuran-5-yl) propionoate (7) which comprises the steps of;
a) reacting 2,3-dihydrobenzofuran (2) with phosphorous oxychloride in presence of dimethyl formamide to give 2,3-dihydrobenzofuran-5-carbaldehyde (3);
b) reacting compound (3) with malonic acid in presence of base to obtain 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoic acid (28);
c) reducing compound (28) using catalyst to give 3-(2,3-dihydrobenzofuran-5-yI)-propionic acid (29);
d) brominating compound (29) using brominating agent to obtain 3-(7-bromo-2,3-dihydrobenzofuran-5-yl) propionic acid (30);
e) reacting compound (30) with thionyl chloride to form acid chloride and then treating it with alcohol to form alkyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl) propionoate (6);
f) brominating compound (6) using brominating agent to obtain Ethyl-3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionoate (7);
The base used may be selected from pyridine, piperidine or mixtures thereof. The brominating agent used is bromine. The alcohol used may be selected from methanol or ethanol.
The compound (7) obtained according to the present invention is further converted to (S)-Ramelteon as represented in Scheme III.


In yet another embodiment, the present invention provides isolated impurity A i.e. N-[2-(3,5,6,7,-tetrahydro-2H-indeno[5,6-b]furan-7-yl)ethyl]propionamide; impurity B i.e. (R)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide; and impurity C i.e. N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethyl]propionamide.

Another embodiment of the present invention provides synthesizing and using the impurity A, impurity B, and impurity C as reference standards to analytically quantify the purity of Ramelteon (1) and to set specific limits to the amount of other impurities formed during the synthesis of Ramelteon (1).
In a further embodiment, the invention is directed to analytical methods for testing the impurity profile of Ramelteon (1). These methods are also suitable for analyzing and assaying Ramelteon (1) and its impurities.
As used herein, the term "reference standard" refers to a compound that may be used both
for quantitative and qualitative analysis of an active pharmaceutical ingredient. For
example, the HPLC retention time of the compound allows a relative retention time to be
determined, thus making qualitative analysis possible. The concentration of the
compound in solution before injection into an HPLC (or GC) column allows the areas
under the HPLC (or GC) peaks to be compared, thus making quantitative analysis
possible.
The following examples illustrate the invention described above; however, they are not
intended to Jimit its extent in any manner.
Examples:
Example 1: Preparation of 2,3-dihydrobenzofuran-5-carbaldehyde (3): To a solution
of 2,3-dihydrobenzofuran (600.0 g, 4.99 moles) in N,N-dimethylformamide (804 g, 10.98
moles) was added drop-wise phosphorous oxychloride (1530 g, 9.96 moles) over a period
of 45 min maintaining the temperature of reaction mixture between 30-35°C. The mixture
21

was slowly heated to 70°C and stirred for 8 hr. The mixture was cooled to room temperature and poured into 8 lit of ice-cold water and stirred for 1 hr. The reaction mixture was saturated with sodium chloride and then the product was extracted with ethyl acetate (6L). The extract was washed with saturated aqueous solution of sodium bicarbonate (1.5 L) and concentrated under reduced pressure to obtain (725 g, 98%) of the title compound.
Example 2: Preparation of Ethyl -3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (4):
To an ice-cooled suspension of potassium t-butoxide (658 g, 5.88 moles) in toluene (6.24 lit) was added drop-wise triethyl phosphonoacetate (1318 g, 5.88 moles). 2,3-dihydrobenzofuran-5-carbaldehyde (725 g, 4.90 moles) was added drop-wise to the obtained reaction mixture followed by stirring at room temperature for 1 hour. Acetic acid (75 ml) and water (3.5 lit) were then added to the reaction mixture. The toluene layer was separated and washed with water (1.5 lit). Solvent was distilled out from the reaction mixture under reduced pressure to get the residue. To the obtained residue hexane (1 lit) was added and stirred to obtain crystals (1007 g, 94%) of the title compound.
Example 3: Preparation of Ethyl- 3-(2,3-dihydrobenzofuran-5-yl)-propionate (5):
To a solution of Ethyl -3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (800 g, 3.66 moles) in acetic acid (4.8 lit) was added 10 % palladium on activated carbon (80.0 g, 50 % hydrous) and the reaction mixture was stirred at 50°C for 4 hours under hydrogen atmosphere (5 kg/cm2 pressure). The catalyst was filtered off and the filtrate containing the title compound (783.5 g, 97%) was taken up as such (without isolating product) for further reaction.
Example 4: Preparation of Ethyl 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionate (7):
Sodium acetate (309.2 g, 3.76 moles) was added in a solution of Ethyl 3-(2,3-dihydrobenzofuran-5-yl)-2-propionate (783.5 g, 3.56 moles) obtained as per example 3 in acetic acid. The obtained solution was cooled to 17-18°C and to this, was added drop-wise 30% solution of bromine (3498 g, 21.85 moles) in acetic acid. The reaction mixture was stirred for 45 min and then added to a 15% aqueous solution of sodium sulfite (6054
22

g). The mixture was then stirred for 1 hour and the product was extracted with dichloromethane (5 lit). The extract was washed with water and then concentrated under reduced pressure to obtain 1145 g (yield: 85 %) of the title compound
Example 5:
Preparation of Ethyl 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yI) propionate (7): Sodium acetate (309.2 g, 3.76 moles) was added in a solution of Ethyl 3-(2,3-dihydrobenzofuran-5-yl)-2-propionate (783.5 g, 3.56 moles) obtained as per example 3 in acetic acid. The obtained solution was cooled to 17-18°C and to this, was added drop-wise 30% solution of bromine (3498 g, 21.85 moles) in acetic acid. The reaction mixture was stirred for 45 min and then added to a pre-cooled (10-15°C) 15% aqueous solution of sodium sulfite (6054 g). The reaction mixture was stirred for 1 hour and the crystals obtained were filtered and washed with water to obtain 1294 g (yield: 96 %) of the title compound.
Example 6:
Preparation of 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yI) propionic acid (8):
Ethyl 3-(6)7-dibromo-2,3-dihydrobenzofuran-5-yl) propionate (1250 g, 3.49 moles) was dissolved in tetrahydrofuran (1875 ml) and to this 11.5 % aqueous solution of sodium hydroxide (791g, 19.77 moles) was added and the reaction mixture was heated to reflux for 1 hour. After the completion of reaction, the reaction mixture was cooled to room temperature and poured into 6 lit of ice-cold water. The mixture was acidified with concentrated hydrochloric acid and stirred for 30 min. The product obtained was filtered and washed with water to neutral pH, followed by washing with diisopropyl ether (2.5 lit) to obtain (906.6 g, 78 %) of the title compound.
Example 7:
Preparation of 4,5-dibromo-l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (9):
To a solution of 3-(6,7-Dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid (890.0 g, 2.54 moles) in dichloromethane (3.11 lit) was added thionyl chloride (454.8 g, 3.63 moles) and N,N-dimethylformamide (3 ml). The reaction mixture was heated to reflux for 1 hour. The reaction mixture was then cooled to -5 to 0°C and aluminium chloride
23

(414.74 g, 3.85 moles) was added to it followed by stirring for 30 min. The reaction mixture was poured into pre-cooled methanol (17.80 lit) and stirred for 30 min. The product obtained was filtered, washed with water (4.5 lit) to neutralized pH followed by washing with methanol (4.5 lit.) to obtain 720 g (yield: 90 %) of the title compound.
Example 8:
Preparation of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (10):
To a suspension of 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (720 g, 2.15 moles) in methanol (6.60 lit.) and acetic acid (1.5 lit.) was added 10% palladium on activated carbon (150 g, 50% hydrous) followed by addition of sodium acetate (500 g, 6.09 moles). The reaction mixture was stirred at room temperature for 2 hours under hydrogen atmosphere (5 kg/cm2). After the completion of reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were collected by filtration, washed with water (3 lit.) and recrystallized with methanol-water (5:1) to obtain 318 g (83% yield) of the title compound.
Example 9:
Preparation of (E)-(l,6,7,8-tetrahydro-2H-indenol5,4-b]furan-8-yIidene)acetonitrile
(11):
To a solution of l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (300 g, 1.72 moles) and diethyl (cyanomethyl) phosphonate (365.8 g, 2.06 moles) in toluene (7.5 lit.) was added drop-wise 28% sodium methoxide in methanol (399 g, 2.06 moles). After stirring for 2 hours at room temperature, water (3 lit.) was added to the reaction mixture to separate the organic layer which was washed with water (1.2 lit.) and concentrated under reduced pressure. The obtained crystals were collected by filtration to obtain 300 g (yield: 88 %) of the title compound.
Example 10:
Preparation of l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19):
To a solution of (E)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (100 g, 0.5 moles) in acetic acid (1.5 lit.) was added 5% palladium on alumina (10 g). The reaction mixture was stirred at room temperature for 8 hours under hydrogen atmosphere
24

(2.5 kg/cm2). The catalyst was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in ethyl acetate (250 ml). The organic layer was washed with water (100 ml) followed by washing with saturated aqueous solution of sodium bicarbonate (250ml) and concentrated under reduced pressure to obtain (80 g, 79.2%) of the title compound.
Example 11:
Preparation of l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile (19)
To a solution of (E)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (100 g, 0.5 moles) in a mixture of 1,4-dioxane (2.0 lit.) and acetic acid (200 ml) was added 5% palladium on alumina (20 g). The reaction mixture was stirred at room temperature for 8 hours under hydrogen atmosphere (5.0 kg/cm2). The catalyst was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in ethyl acetate (250 ml). The organic layer was washed with water (100 ml) followed by washing with saturated aqueous solution of sodium bicarbonate (250ml) and concentrated under reduced pressure to obtain (91.2g, 90.0%) of the title compound.
Example 12:
Separation of (-) l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-y!acetonitrile (20) by
Novasep from racemic l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylacetonitrile
(19).
The conditions used for separating the desired compound are as follows;
Column: Kromosil 10-Cellucoat 250*4.6 mm, 10 μm
Mobile phase: Hexane-ethanol (90:10% v/v)
Run time: 20 minutes
Flow rate: l.0ml/min
Specific optical rotation [a]D20 = -136.07 (c 1.005, methanol)
The unwanted isomer, compound (21) with specific optical rotation of [a]D20 = +136.07
(c 1.005, methanol) was used for recovering the compound (20).
25

Example 13:
Preparation of (S) 2-(l,6,7,8-tetrahydro-2H-indeiio[5,4-b]furan-8-yl)ethylamine
hydrochloride (22):
To a solution of (-)-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile (15.0 g, 75 mmole) in toluene (250 ml) were added methanol (50 ml), 14.4% aqueous solution of sodium hydroxide (5.3 g) and Raney nickel (22 g). The reaction mixture was stirred at 35°C for 5 hours under hydrogen atmosphere (2 kg/cm2). The catalyst was filtered off and water (80 ml) and 1N-HC1 (75 ml) were added to the filtrate. The mixture was then stirred at 40°C for 30 min. The aqueous layer was separated and a saturated aqueous solution of sodium chloride (150 ml) was added to it. The precipitated crystals were collected by filtration to obtain (15.0 g, 83%) of the title Compound.
Example 14:
Preparation of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethyl]propionamide (Ramelteon):
To. a suspension of (S)-2-(l,637,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (15.0 g, 62.55 mmole) in tetrahydrofuran (40 ml) at 15°C was added drop-wise an aqueous solution of sodium hydroxide (7.1%,80 ml). Propionyl chloride (6.66 g, 72 mmoles) was added drop-wise to the obtained reaction mixture and the reaction mixture was stirred at room temperature for 30 min. After the completion of reaction water (120 ml) was added to it and crystals precipitated were collected by filtration to obtain 15.5 g (yield: 96 %) of the title compound.
Example 15:
Purification of (S)-Ramelteon (1):
Ramelteon (15.5 g) was added to 40 ml of ethanol and the suspension was heated to form
a clear solution. To this, water (80 ml) was added and the mixture was cooled to room
temperature. The crystals obtained were filtered to obtain 14.9 g (92% yield) of pure (S)-
Ramelteon.
Specific optical rotation [ct]D20 = - 57.8 (c 1.005, Chloroform).
26

Example 16:
Purification of Ramelteon (1):
Ramelteon (15.5 g) was added to 40 ml of ethyl acetate and the suspension was heated to get a clear solution. The obtained solution was then cooled to room temperature. The obtained crystals were filtered to get 14.9 g (92% yield) of pure (S)-Ramelteon. Specific optical rotation [a]D20 = - 57.8 (c 1.005, Chloroform).
Dated this the 15th day of September 2008

27