WO2009093133A1

WO2009093133A1 - Method for determining the enantiomeric purity of indane derivatives

Info

Publication number: WO2009093133A1
Application number: PCT/IB2009/000115
Authority: WO
Inventors: Maria Carmen Burgarolas Montero; Pelayo Camps Garcia; Jordi Bosch I Llado; Antonio Camacho Carrasco
Original assignee: Medichem, S.A.
Priority date: 2008-01-25
Filing date: 2009-01-23
Publication date: 2009-07-30

Abstract

The invention relates to an improved process for preparing (8iS)-2-(l,6,7,8-tetrahydro- 2H-indeno[5,4-b]furan-8-yl)ethanamine of formula (S)-(III), or a salt or solvate thereof, and to the use thereof for preparing ramelteon. The present invention further relates to ramelteon polymorphic Form I and processes therefor. The present invention further provides a method for differentiating and quantifying the enatiomers, thereby determining the enantiomeric purity, of a compound of formula (III) or ramelteon.

Description

METHOD FOR DETERMINING THE ENANTIOMERIC PURITY OF INDANE

DERIVATIVES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 61/023,603, filed January 25, 2008, which is incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Ramelteon is an active pharmaceutical substance with an empirical formula of Ci₆H_2INO₂ and a molecular weight of 259.344 g/mol. Ramelteon is the international common accepted name for (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-&]furan-8- yl)ethyl]propionamide, which is represented by Formula I:

[0003] Ramelteon is a commercially marketed pharmaceutically active substance known to be useful for treating or preventing sleep disorders. Ramelteon is a melatonin agonist that selectively binds to the melatonin receptors in the suprachiasmatic nucleus. In the United States, ramelteon is marketed under the name Rozerem™ for the treatment of insomnia. [0004] Ramelteon and similar compounds are disclosed in U.S. Patent No. 6,034,239 ("the '239 patent"), which is incorporated herein by reference. [0005] Synthetic strategies for the preparation of ramelteon are reported in the '239 patent. One procedure disclosed in the '239 patent uses an enantiomerically pure compound of formula (S)-(III) as an intermediate compound. In particular, Example 19 of the '239 patent describes a direct preparation of ramelteon by reacting enantiomerically pure (S)-(III) with propionyl chloride. Furthermore, the '239 patent describes the preparation of a compound of formula (S)-(III) from a compound of formula (II) via two consecutive hydrogenation reactions (see Examples 27 and 20). The process disclosed in the '239 patent is depicted herein at Scheme 1.

[0006] Examples 11 and 19 of the '239 patent disclose the isolation of ramelteon after crystallization from ethyl acetate. However, the '239 patent does not disclose a polymorphic form of ramelteon.

(II) (S)-(III)

CICOEt HCOEt

ramelteon, (I)

Scheme 1

[0007] The synthetic route described in Scheme 1 is not suitable for industrial implementation since the preparation of compound (S)-(III) involves two consecutive hydrogenation reactions, that is, the process requires large amounts of hydrogen gas. The handling of hydrogen gas presents several drawbacks. For example, hydrogen gas is highly flammable and when mixed with oxygen across a wide range of proportions, explodes upon ignition. Thus, according to safety operative conditions, special care must be taken to reduce the risk of accidents.

[0008] Another disadvantage to the synthesis depicted in Scheme 1 is that the preparation of compound (S)-(III) involves an asymmetrical reduction reaction which requires the use of an expensive ruthenium-based, asymmetrical reduction catalyst which is difficult to prepare and is not cost-effective when used on an industrial scale.

[0009] Also, since the eutomer of ramelteon is the (S)-enantiomer, there exists a need to develop a reliable and reproducible method for differentiating and quantifying the (R)- and

(S)-enantiomers of ramelteon and its intermediate compound (III), thereby determining their enantiomeric purity.

[0010] Thus, there is a need for an improved process for the preparation of ramelteon which is suitable for industrial implementation and which avoids the disadvantages discussed above. BRIEF SUMMARY OF THE INVENTION

[0011] The present invention provides an improved process for preparing a compound of formula (S)-(III), which is a useful intermediate compound for the synthesis of ramelteon of formula (I).

[0012] The present invention also provides an improved synthesis of ramelteon.

[0013] The present invention further provides ramelteon polymorphic Form I and processes therefor.

[0014] The present invention further provides a method for determining the enantiomeric purity of compound of formula (I) or (III).

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 illustrates a X-ray powder diffraction (XRD) of ramelteon Form I prepared in accordance with the invention.

[0016] Figure 2 illustrates an infrared (IR) spectrum of ramelteon Form I prepared in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention provides a process for preparing (8S)-2-(l,6,7,8-tetrahydro- 2H-indeno[5,4-Z>]furan-8-yl)ethanamine of formula (.S)-(III):

[0018] In some embodiments, the present invention provides salts or solvates of a compound of formula (S)-(III). In preferred embodiments, the present invention provides (S)-(III) hydrochloride or (S)-(III) tartrate prepared according to processes of the invention. [0019] In keeping with the invention, a compound of formula (S)-(III), or a salt or solvate thereof, is prepared from a compound of formula (III):

or a salt or solvate thereof. [0020] A compound of formula (S)-(III), or a salt or solvate thereof, is a useful intermediate compound for the synthesis of (S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4- ό]furan-8-yl)ethyl]propionamide (i.e., ramelteon) of formula (I):

[0021] In keeping with the invention, processes of the invention reduce the use of extensive amounts of hazardous hydrogen gas, which makes for safer operating conditions. In addition, processes in accordance with the invention are cost-effective and suitable for industrial implementation.

[0022] In an embodiment, the present invention provides a process for preparing a compound of formula (S)-(III), or a salt or solvate thereof, comprising reacting a compound of formula (II), or a salt or solvate thereof:

with a reducing agent to form a compound of formula (III), or a salt or solvate thereof, reacting the compound of formula (III), or a salt or solvate thereof, with a chiral resolving agent to form a compound of formula (S)-(III).

[0023] As illustrated above, some embodiments of the invention comprise the use of a reducing agent. In preferred embodiments, the reducing agent comprises a mixture of hydrogen gas and Raney-Nickel.

[0024] In keeping with the invention, some embodiments of the invention comprise a chiral resolution of enantiomers. For example, in some embodiments, a compound of formula (III) or a salt or solvate thereof, is resolved into (R)- and (S)-enantiomers. In a preferred embodiment, the (S)-enantiomer of a compound of formula (III), that is, a compound of formula (S)-(III), or a salt or solvate thereof, is obtained. Illustrative chiral resolution methods include, for example, the use of chiral resolving agents to form diasteromeric complexes and chiral chromatography.

[0025] In some embodiments, the chiral resolution comprises the use of chiral resolving agents, for example, optically active carboxylic acids. For example, in an embodiment, the present invention provides a process for preparing a compound of formula (S)-(III) or a salt or solvate thereof, comprising resolving a compound of formula (III), or a salt or solvate, thereof into enantiomers by treating a compound of formula (III), or a salt or solvate thereof, with an optically active carboxylic acid. Illustrative preferred, optically active carboxylic acids include camphosulfonic acid, tartaric acid, di-O,O'-p-toluyl-tartaric acid, and O,O'-dibenzoyl-tartaric acid. Most preferably, the optically active carboxylic acid is D-tartaric acid.

[0026] Further, in some embodiments, the chiral resolution comprises reacting in a first solvent, a compound of formula (III) with an optically active carboxylic acid, which acts as a chiral resolving agent, to form a diastereoisomeric mixture comprising the carboxylate salt of the (S)-enantiomer of a compound of formula (III) and the carboxylate salt of the (7?)-enantiomer of compound of formula (III). Preferably, the carboxylate salt of the (S)-enantiomer of a compound of formula (III) is isolated from the mixture and crystallized from a second solvent. In some embodiments, the crystallized carboxylate salt of the (S)-enantiomer of a compound of formula (III) is converted into a compound of formula (S)-(III), or a salt or solvate thereof.

[0027] The first solvent and the second solvent are the same or different, and preferably comprise an alcohol, water, or mixtures thereof. Preferably, first and second solvent are a mixture of isopropanol and water.

[0028] In some embodiments, processes for preparing a compound of formula (S)-(III) in accordance with the invention comprise precipitating the carboxylate salt of the (S)-enantiomer of the compound of formula (III) from a diastereoisomeric mixture, and filtering the mixture, to obtain the carboxylate salt of the (S)-enantiomer of compound of formula (III).

[0029] In other embodiments, processes for preparing a compound of formula (S)-(III) in accordance with the invention comprise precipitating the carboxylate salt of the (Λ)-enantiomer of the compound of formula (III) from a diastereoisomeric mixture, and removing the precipitate from the mixture, to obtain a filtrate comprising the carboxylate salt of the (S)-enantiomer of compound of formula (III).

[0030] In other embodiments, processes for preparing a compound of formula (S)-(III) in accordance with the invention comprise converting the carboxylate salt of the (S)-enantiomer of a compound of formula (III) into a compound of formula (S)-(III) or a salt or solvate thereof of by treating the carboxylate salt of the (S)-enantiomer of a compound of formula (III) with a base. In some embodiments, the carboxylate salt of the (S)-enantiomer of a compound of formula (III) is converted into a salt.

[0031] Illustrative preferred bases include, for example, sodium hydroxide and sodium methoxide.

[0032] In some embodiments, the chiral resolution step comprises resolving a compound into enantiomers by means of chiral chromatography column capable of separating enantiomers of a compound. For example, in some embodiments a compound of formula

(III) is separated into (R)- and (S)-enantiomers.

[0033] In a preferred embodiment, the chiral chromatography column comprises a derivatized cellulose as a chiral stationary phase. More preferably, the derivatized cellulose is tm(3,5-dimethylphenylcarbamate).

[0034] In preferred embodiments, the chromatographic conditions for the chiral chromatography are normal-phase conditions.

[0035] In some embodiments, the present invention provides ramelteon prepared using a compound of formula (S)-(III), which has been prepared according to processes of the invention. For example, in some embodiments, processes of the invention further comprise converting a compound of formula (S)-(III), or a salt or solvate thereof, into ramelteon of formula (I), for example, by converting the amino group of compound of (S)-(III) to a propionamide group. In preferred embodiments, a compound of formula (S)-(III) is reacted with propionyl chloride.

[0036] In some embodiments, ramelteon prepared in accordance with the present invention is crystallized. In preferred embodiments, ramelteon prepared according to the invention is crystallized from a mixture of ethanol and water.

[0037] Ramelteon prepared according to the invention has a high chemical purity and stereochemical purity. For example, ramelteon prepared according to processes of the invention typically has a chemical purity greater than about 98.5% as measured by HPLC, preferably greater than about 99%, more preferably 99.5%, and most preferably greater than about 99.8%, as measured by HPLC.

[0038] Further, ramelteon prepared in accordance with the invention has a high enantiomeric purity. Preferably, ramelteon prepared according to processes of the invention has an enantiomeric purity greater than about 99.5% as measured by HPLC.

[0039] In keeping with another aspect of the invention, the Applicants have surprisingly discovered that ramelteon prepared according to processes of the invention is polymorphic Form I (referred to herein as ramelteon Form I). In an embodiment, ramelteon Form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 14.7, 20.4, 23.0, and 24.0 ± 0.2 degrees 2Θ. In another embodiment, ramelteon Form I of the present invention is characterized as having an X-ray powder diffraction pattern comprising peaks at about 7.6, 8.0, 14.7, 16.8, 20.4, 22.1, 23.0, and 24.0 ± 0.2 degrees 2Θ. In yet another embodiment, ramelteon Form I of the present invention is characterized as having an X-ray powder diffraction pattern comprising peaks at about 7.6, 8.0, 14.2, 14.7, 15.2, 16.8, 18.3, 19.2, 20.4, 20.9, 22.1, 23.0, and 24.0 ± 0.2 degrees 2Θ. X-ray powder diffraction data of ramelteon Form I is summarized in Table 1.

2Θ d-spacings

7.6 11.6

8.0 11.0

14.2 6.2

14.7 6.0

15.2 5.8

16.8 5.3

18.3 4.85 19.2 4.63

20.4 4.35

20.9 4.24 22.1 4.01 23.0 3.87 24.0 3.71

Table 1

[0040] Another aspect of the present invention is to provide a process for preparing ramelteon Form I, said process comprising dissolving ramelteon in a solvent, to form a solution, allowing ramelteon to precipitate from said solution to form a suspension, and removing the solvent from said suspension, to provide ramelteon Form I.

[0041] In a preferred embodiment, the solvent is selected from the group consisting of acetone, methanol, ethanol, 2-propanol, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, water, and mixtures thereof.

[0042] Ramelteon can be dissolved at room temperature or at reflux temperature, as desired.

[0043] Solvent removal can be carried out, for example, by evaporating the solvent or by filtration, as desired. In preferred embodiments, the solvent is removed by filtering the suspension. [0044] In an embodiment, the invention provides a process for preparing ramelteon Form

I, said process comprising forming a suspension of ramelteon in water, and removing the water from said suspension, to give ramelteon Form I.

[0045] The ramelteon used for preparing ramelteon Form I can be ramelteon obtained by a known method. In preferred embodiments, the ramelteon used for preparing ramelteon

Form I is ramelteon obtained according to the process of the invention.

[0046] In a preferred embodiment of the invention, the ramelteon obtained after crystallizing in a mixture of ethanol and water corresponds to ramelteon Form I.

[0047] In some embodiments, the present invention provides formulations comprising ramelteon Form I obtained according to the processes of the invention.

[0048] In other embodiments, the present invention provides a method for determining the enantiomeric purity of a compound of formula (I) or (III), said method comprising (i) preparing a sample comprising a compound of formula (I) or (III); (ii) introducing the sample to a chiral high performance liquid chromatography column capable of separating enantiomers of the compound of formula (I) or (HI); (iii) eluting the sample from the column with a mobile phase using suitable chromatographic conditions; (iv) identifying the respective retention times of the enantiomers of compound of formula (I) or (III); (v) and comparing the areas of the peaks associated with the retention times of enantiomers of compound of formula (I) or (III), thereby quantifying the enantiomers, and thereby determining the enantiomeric purity of a compound of formula (I) or (III).

[0049] In a preferred embodiment, the invention provides a method for differentiating and quantifying the enantiomers of a compound of formula (I) or (III), and thus provides a method for determining the enantiomeric purity of the enantiomers of a compound of formula

(I) or (III). Differentiation and quantification of enantiomers, and thus determination of enantiomeric purity, is performed using high performance liquid chromatography (HPLC) under suitable chromatographic conditions.

[0050] Columns used in accordance with the invention are capable of separating enantiomeric mixtures, for example, an enantiomeric mixture of compounds of formula (III), an enantiomeric mixture of compounds of formula (I), and the like. In preferred embodiments, columns used in the invention have a chiral stationary phase (CSP). Typically, the CSP comprises polysaccharides which have been immobilized or coated onto silica.

Suitable polysaccharides include, for example, amylose compounds and cellulose compounds, including mixtures thereof, which have been derivatized to modify the polysaccharide structure. Illustrative amylose compounds and cellulose compounds include, for example, alkyl-substituted arylcarbamate derivatives of amylose and alkyl-substituted arylcarbamate derivatives of cellulose. Preferably, the polysaccharide derivative is tris-3,5- dimethylphenylcarbamate cellulose or trw-3,5-dimethylphenylcarbamate amylose.

[0051] The suitable chromatographic conditions preferably are normal-phase conditions.

As known to the skilled artisan, normal-phase conditions generally refer to conditions in which the stationary phase is more polar than the mobile phase.

[0052] In accordance with the invention, the mobile phase comprises at least one solvent selected from the group consisting of non-polar solvents, polar aprotic solvents, polar protic solvents, and mixtures thereof. In a preferred embodiment, the mobile phase comprises at least one solvent selected from the group consisting of w-hexane, isopropanol, ethanol, and mixtures thereof.

[0053] In accordance with the invention, the mobile phase can comprise at least one additive. Typically, additives are acidic compounds, basic compounds, or buffers, depending on the chromatographic conditions which are utilized. In a preferred embodiment, the additive comprises at least one of trifluoroacetic acid, triethylamine, and mixtures thereof.

[0054] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0055] The following general experimental conditions were used.

[0056] For X-ray Powder Diffraction studies, the samples were mounted as flat layers in a glass sample-holder and analyzed by the Θ-2Θ technique to get their X-ray diffraction intensity profile and to determine the position of the Bragg peaks in the range 4-50° of 2Θ, which are characteristic of a specific crystalline phase. The position of the Bragg peaks is directly related with the cell parameters of the crystal. CuKa radiation (wavelength:

1.541838 A) was used in the experiments performed in a Siemens D5000 equipment.

Calibrations were periodically done using silicon and quartz as references.

[0057] For infrared spectroscopy, Fourier transform IR spectra were acquired on a Perkin

Elmer 100 FT-IR spectrometer, and polymorph was characterized in potassium bromide discs.

[0058] For HPLC chromatography, two HPLC methods were used.

[0059] Chromatographic separations using HPLC method 1 were carried out using a

Chiralpak^® IB, 5 μm, 250 x 4.6 mm LD. column; at 40 ⁰C. The mobile phase was prepared by mixing 950 mL of n-hexane with 40 mL of 2-propanol, 10 mL of ethanol, 4 mL of trifluoroacetic and 2 mL of triethylamine.

[0060] Under the conditions of HPLC method 1 , the retention time of (2E)- 1 ,2,6,7- tetrahydro-8H-indeno[5,4-ό]furan-8-ylideneacetonitrile is approximately 7 minutes, 20 minutes for 2-[(SS)-1, 6,7,8-tetrahydro-2H-indeno[5,4-ό]furan-8-yl]ethanamine, 21 minutes for 2-[(8i?)-l,6,7,8-tetrahydro-2H-indeno[5,4-ό]furan-8-yl]ethanamine, 13 minutes for (S)- ramelteon and 15 minutes for (i?)-ramelteon.

[0061] Alternatively, chromatographic separations using ΗPLC method 2 were carried out using a Chiralpak^® AD-Η, 5 μm, 250 x 4.6 mm LD. column; at 40 ⁰C. The mobile phase was prepared by mixing 950 mL of rø-hexane with 40 mL of 2-propanol, 10 mL of ethanol,

4 mL of trifluoroacetic and 2 mL of triethylamine.

[0062] Under the ΗPLC method 2 conditions, the retention time for (5)-ramelteon is

14 minutes, and for (iJ)-ramelteon the retention time is 20 minutes.

[0063] Under both ΗPLC methods, the chromatograph was equipped with a detector monitoring 225 nm and the flow rate was 1.2 mL per minute. Samples were prepared by dissolving a sufficient amount of sample to obtain 1 mg/mL in a 1 :1 mixture of n-hexane and

2-propanol. Ten microliters were injected.

Example 1: Preparation of 2-(l,6,7,8-tetrahydro-2//-indeno [5,4-6] furan-8- yl)ethanamine hydrochloride (i.e., compound of formula (III) hydrochloride).

[0064] This example illustrates a process for preparing the hydrochloride salt of a compound of formula (III) in accordance with an embodiment of the invention. [0065] In a 2 L autoclave reactor was added 76 g (0.385 moles, 1.0 molar equivalent) of (2E)-l,2,6,7-tetrahydro-8H-indeno[5,4-ό]furan-8-ylideneacetonitrile (compound of formula II), 1250 mL of toluene, 250 mL of methanol, 26.3 g of NaOH 14.4% solution and 75 g of Raney Nickel catalyst. Hydrogen was introduced, the pressure was raised to 0.5 Mpa and the temperature was raised to 40 ⁰C. When the pressure was stable, the reaction mixture was left to react for 1 hour at 40 ⁰C, after which time the catalyst was filtered off. To the obtained filtrate was added 400 mL of deionised water and 375 mL of 1 N HCl. The reaction mixture was stirred at 40 ⁰C for 30 minutes and the aqueous phase was separated. To the organic phase was added 400 mL of saturated NaCl solution and the mixture was stirred at 20-25 ⁰C for 4 hours, cooled to 0-5 ⁰C and filtered. The obtained solid was dried under vacuum to obtain 70.1 g of compound of formula III hydrochloride, (yield: 75.89%; HPLC (area%): 99.5 %; HPLC (area % S/R): 49.56% / 49.95%.

Example 2: Preparation of 2-[(8S)-l,6,7,8-tetrahydro-2i/-indeno[5,4-£]furan-8- yljethanamine hydrochloride (i.e., compound of formula (S)-(III) hydrochloride).

[0066] This example illustrates a process for preparing the hydrochloride salt of a compound of formula (S)-(III) in accordance with an embodiment of the invention.

A) Preparation of the D-tartrate salt of compound of formula (S)-(IH):

[0067] In a 500 mL round bottom flask was added 30 g of compound of formula (III) hydrochloride (2-(l ,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8-yl)ethanamine hydrochloride, 0.125 moles, 1.0 molar equivalent) and 250 mL of methanol. The mixture was stirred until a clear or nearly clear solution was obtained. To this solution was added a mixture of 6.9 g of sodium methoxide (0.128 moles, 1.021 molar equivalent) and 100 mL of methanol. [0068] The resulting suspension was stirred for 1 hour, after which time the solvent was removed by distillation initially at atmospheric pressure, then under vacuum. To the residue was added 100 g of isopropanol, the suspension was stirred for 30 min, filtered and the obtained cake was washed with 50 mL of isopropanol. An isopropanol solution of compound of formula (III) was obtained.

[0069] In a 1 L round bottom flask was added 23 g (0.153 moles, 1.225 molar equivalent) of D-tartaric acid and 145 g of water. The mixture was stirred to obtain a clear or nearly clear solution. To the solution was added 285 g of isopropanol and the mixture was stirred for 15 minutes. The isopropanol solution of compound of formula (III) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred for 2.5 hours at 27-28 ⁰C (room temperature).

[0070] The resulting suspension was filtered, and the cake was washed with isopropanol. The obtained solid, i.e. D-tartrate salt of compound of formula (S)-(III), was used in step B), and the filtration mother liquor was used in step D).

B) Crystallization of the D-tartrate salt of compound of formula (S)-(III):

[0071] In a 500 mL round bottom flask was added the solid of step A) and 260 g 75% isopropanol solution (3:1 isopropanohwater). The reaction mixture was stirred at 55-60 ⁰C for two hours and slowly cooled to room temperature. The reaction mixture was stirred for 30 min at 20-25 ⁰C and filtered. The obtained cake was washed with isopropanol. [0072] The solid was analyzed by HPLC and if the (S/R) correlation was higher than 85/15, the solid was used for the next step C). If not, another crystallization under the same conditions was conducted.

[0073] After drying, 15.5 g of solid, i.e., tartrate salt of (5)-enantiomer of compound (III), was obtained (yield: 35.05% in reference to 30 g of compound of formula (III) hydrochloride). The filtration mother liquor was used for step D).

C) Preparation of compound of formula (S)-(IH^") hydrochloride:

[0074] In a 500 mL round bottom flask was added the solid of step B) and 100 mL of water. Sodium hydroxide (50 mL of a 30% solution) was added, and the reaction mixture was stirred for 30 min. Toluene (150 mL) was added, and the two phases were separated. The aqueous phase was extracted with toluene (2x100 mL). The combined organic phases were washed with saturated NaCl solution.

[0075] To the toluene phase was added 60 mL of 2.5 N HCl. The mixture was stirred for 30 min. The solvent was distilled to dryness in vacuum. To the obtained residue was added 35 g of methanol. The resulting suspension was heated until dissolution and then cooled. Upon cooling, a precipitate formed which was filtered and re-dissolved in acetone (80 g) with heating. The acetone solution was cooled to room temperature, then to 0-5 ⁰C, filtered, and the obtained cake was washed with cold acetone. A white solid (5.5 g) was obtained after drying (yield 52.30% from the tartrate salt, 18.33% from 30 g of initial compound (III)). [0076] The filtration and washing solutions were distilled in vacuum to dryness. 10 g of methanol and 25 g of acetone were added to the residues for recrystallization to obtain 1.5 g of solid, i.e., compound of formula (S)-(IH) hydrochloride. Total amount of solid 7 g (yield: 66.54%; global yield: 23.33% from 30 g of compound of formula III hydrochloride). The filtrate was concentrated to get 1.5 g of a residue that was recycled for step A). [0077] Analyses of the final product: HPLC (area %): 100 %; HPLC (area % S/R): 100 % / not detected.

D) Recycle of compound of formula (III) hydrochloride:

[0078] The filtrates of steps A) and B) were concentrated. To the residue was added

60 mL of 30% NaOH solution. The mixture was stirred for 30 minutes and toluene (200 mL) was added to extract the product. The aqueous phase was extracted with toluene (2x150 mL). The combined toluene phases were washed with 200 mL of saturated NaCl solution. A mixture of 100 mL of water and 20 mL of concentrated HCl was added to the toluene phase, the mixture was stirred for 30 min, the toluene was distilled in vacuum, and 200 mL of saturated NaCl solution was charged. The reaction mixture was cooled to room temperature and filtered. 18 g of recycled compound (III) hydrochloride was obtained after drying.

Example 3: Preparation of l-p/O-M^S-tetrahydro-liy-indenoIS^-^furan-S- yl]ethanamine hydrochloride (i.e., (/?)-compound of formula (III) hydrochloride).

[0079] This example illustrates a process for preparing the hydrochloride salt of a compound of formula (i?)-(III) in accordance with an embodiment of the invention.

[0080] The compound of formula (III) hydrochloride obtained in step D) of Example 2 was chirally resolved as described in Example 2, steps A), B), and C), using L-tartaric acid instead of D-tartaric acid.

[0081] Step B) afforded 12.5 g of the tartrate salt of the (i?)-enantiomer of compound (III) having a (R/S) correlation higher than 85/15.

[0082] After step C), 6.0 g of (i?)-enantiomer of compound (III) hydrochloride and 1.0 g of compound (III) hydrochloride was obtained.

[0083] After step D), 8.5 g of recycled compound (III) hydrochloride was obtained.

Example 4: Preparation of ramelteon.

[0084] This example illustrates a process for preparing ramelteon in accordance with an embodiment of the invention.

[0085] In a 500 mL round bottom flask was added 12 g (0.050 moles, 1.0 molar equivalent) of compound of formula (S)-(III) hydrochloride and 40 g of THF. The reaction mixture was cooled to 10 ⁰C and added dropwise to 68 g of 7.1% NaOH solution at 10 ⁰C. The reaction mixture was stirred for 30 min and a solution of 6 g (0.065 moles, 1.3 molar equivalent) of propionyl chloride dissolved in 20 g THF was added slowly at 10 ⁰C. After addition was complete, the temperature was raised to 20-25 ⁰C and the mixture was stirred for 1 hour. Water (300 mL) was added and the mixture was stirred for 30 min and filtered. The isolated solid was washed with water. 1O g of ramelteon was obtained after drying. HPLC (area %): 98.5 %. [0086] The above product was crystallized from 230 g ethanol/water (1 :2) to obtain 9.5 g of a white solid (yield: 73.18%).

[0087] The following analyses of the dry solid were made: HPLC (area %): 99.8 %; HPLC (area % S/R): 100 % / not detected; m.p.: 113.2-114.1 ⁰C; X-Ray diffraction: The X-Ray diffractogram was substantially identical to the XRD shown in Figure 1 ; IR: The IR spectrum was substantially identical to the IR shown in Figure 2.

Example 5: Preparation of 2-[(8S)-l,6,7,8-tetrahydro-2//-indeno[5,4-6]furan-8- yl]ethanamine D-tartrate salt (Le., D- tart rate salt of compound (S)-(III)).

[0088] This example illustrates a process for preparing the D-tartrate salt of compound (iS)-(III) in accordance with an embodiment of the invention.

A) Preparation of the D-tartrate salt of compound of formula (S)-(HI):

[0089] In a 100 mL round bottom flask was added 3 g of compound III hydrochloride (2- (l,6,7,8-tetrahydro-2H-indeno[5,4-ό]furan-8-yl)ethanamine hydrochloride, 0.013 moles, 1.0 molar equivalent) and 26 mL of methanol. The mixture was stirred until a clear or nearly clear solution was obtained. To this solution was added a mixture of 0.69 g of sodium methoxide (0.013 moles, 1.021 molar equivalent) and 11 mL of methanol. [0090] The resulting suspension was stirred for 1 hour, the solvent was distilled off under vacuum to remove the methanol. Residual methanol was displaced by azeotropic distillation with isopropanol (10 mL). To the residue was added 12.7 mL of isopropanol. The suspension was stirred for 10 min and filtered. The cake was washed with 5 mL of isopropanol. An isopropanol solution of compound III was obtained. [0091] In a 100 mL round bottom flask was added 1.52 g (0.010 moles, 0.81 molar equivalent) of D-tartaric acid, 14.5 g of water and 36 mL of isopropanol. The mixture was stirred for 15 minutes, then heated to 55-60 ⁰C. The isopropanol solution of compound of formula (III) was added dropwise over a period of about 30 min at 55-60 ⁰C. After addition, the reaction mixture was stirred for 2 hours at 55-60 ⁰C, cooled to 25-30 ⁰C over a period of about 5 hours, and then filtered at 26 ⁰C. The cake was washed with 25 mL of isopropanol. The filtrate mother liquor could be recycled.

[0092] After drying, the obtained 2.37 g of solid, i.e., D-tartrate salt of compound of formula (S)-(III) (yield: 53.62%), was used for the following step B). [0093] ΗPLC (area %): 100 %; ΗPLC (area % S/R): 66.69 % / 33.31 %. B) Crystallization of the D-tartrate salt of compound of formula CSVflH):

[0094] In a 100 mL round bottom flask were charged the solid of step A), 40.6 mL of isopropanol, and 10.7 mL of water. The reaction mixture was stirred at 55-60 ⁰C for about two hours and then cooled to room temperature over a period of about 4 hours. Stirring was continued for 45-30 min at 25-30 ⁰C, and then the reaction mixture was filtered at 26 ⁰C. The obtained cake was washed with isopropanol. The filtrate mother liquor could be recycled. [0095] After drying, 1.32 g of D-tartrate salt of compound (S)-(III) was obtained (yield: 55.70%; global yield: 29.86% in reference to 30 g of compound of formula III hydrochloride). [0096] HPLC (area %): 100 %; HPLC (area % S/R): 89.53 % / 10.47 %.

Examples 6-14: Preparation of ramelteon Form I.

[0097] These examples illustrate a process for preparing ramelteon Form I in accordance with embodiments of the invention.

[0098] Samples of ramelteon were dissolved in the solvent as indicated in Table 2, either at room temperature or at reflux, and were filtered to remove insolubles. The solution was left to precipitate over 48 hours, and the precipitated ramelteon was removed either via slow evaporation of the solvent at room temperature or via filtration of the suspension. The obtained solids were analyzed by XRD. The different solvents tested and the results are summarized in Table 2.

Example Solvent XRD

6 Acetone Form I

7 Methanol Form I

8 Ethanol Form I

9 2-propanol Form I

10 Chloroform Form I

11 Dichloromethane Form I

12 Acetonitrile Form I

13 Tetrahydrofuran Form I

14 Water Form I

Table 2 Example 15: Preparation of ramelteon Form I.

[0099] This example illustrates a process for preparing ramelteon Form I in accordance with an embodiment of the invention.

[0100] A sample of ramelteon (41 mg) was suspended in 1.5 mL of water at room temperature. The suspension was stirred at room temperature for 3 hours, and the suspension was filtered to obtain ramelteon (37 mg). The obtained solid was analysed by XRD. [0101] The obtained solid was analysed by XRD: the X-Ray diffractogram was substantially identical to the XRD shown in Figure 1.

[0102] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0103] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A method for determining the enantiomeric purity of a compound of formula (I) or (III), said method comprising:

(i) preparing a sample comprising a compound of formula (I) or (III);

(ii) introducing the sample to a chiral high performance liquid chromatography column capable of separating enantiomers of the compound of formula (I) or of the compound of formula (III);

(iii) eluting the sample from the column with a mobile phase;

(iv) identifying the respective times of retention of the enantiomers of the compound of formula (I) or the compound of formula (III); and

(v) comparing the areas of the peaks associated with the retention times of the enantiomers of a compound of formula (I) or the enantiomers of a compound of formula (III), quantifying the enantiomers, and determining the enantiomeric purity of a compound of formula (I) or (III).

2. The method of claim 1, wherein the chiral chromatography column comprises at least one polysaccharide as a stationary phase.

3. The method of claim 2, wherein the polysaccharide is selected from the group consisting of an amylose compound, a cellulose compound, and mixtures thereof.

4. The method of claim 3, wherein the polysaccharide is cellulose tris(3,5- dimethylphenylcarbamate) or tm-3,5-dimethylphenylcarbamate amylose.

5. The method of claim 1, wherein the mobile phase comprises at least one solvent selected from the group consisting of non-polar solvents, polar aprotic solvents, polar protic solvents, and mixtures thereof.

6. The method of claim 5, wherein the solvent is selected from the group consisting of «-hexane, isopropanol, ethanol, and mixtures thereof.

7. The method of claim 5, wherein the mobile phase further comprises at least one of trifluoroacetic acid, triethylamine, or mixtures thereof.

8. Compound of Formula (S)-(III) or salt thereof having less than about 0.5% by percentage area HPLC of (8Z?)-2-(l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8-yl)ethanamine, compound of formula (ZJ)-(III), as determined by the method of claim 1.

9. Ramelteon of Formula (I), (5)-ramelteon, or salt thereof having less than about 0.5% by percentage area ΗPLC of (i?)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4- ό]furan-8-yl)ethyl]propionamide, (i?)-ramelteon, as determined by the method of claim 1.