WO2009106966A1

WO2009106966A1 - Process for preparing ramelteon.

Info

Publication number: WO2009106966A1
Application number: PCT/IB2009/000362
Authority: WO
Inventors: Pelayo Camps Garcia; Ester Masllorens Llinas
Original assignee: Medichem SA
Current assignee: Medichem SA
Priority date: 2008-02-28
Filing date: 2009-02-27
Publication date: 2009-09-03
Anticipated expiration: 2010-08-28

Abstract

The invention relates to an improved process for preparing indane derivatives including, for example, ramelteon. The invention provides a process for preparing ramelteon from a compound of formula (II), wherein the process comprises successive reduction reactions and converting a compound of formula (IV) to ramelteon: The invention further relates to an improved process for converting a compound of formula (IV) to ramelteon.

Description

PROCESS FOR PREPARING INDANE DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application Nos. 61/032,364, filed on February 28, 2008; 61/037,855, filed on March 19, 2008; and 61/099,722, filed on September 24, 2008, all of which are incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Ramelteon is an active pharmaceutical substance with an empirical formula of C₁₆H₂]NO₂ and a molecular weight of 259.344. Ramelteon is the international common accepted name for (5)-N-[2-(l,6,7,8-tetrahydro-2H-indeno-[5,4-ό]furan-8- yl)ethyl]propionamide, which is represented by a compound of 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 other compounds are disclosed in U.S. Patent No. 6,034,239 ("the '239 patent") which is incorporated herein by reference. The '239 patent discloses synthetic strategies for the preparation of ramelteon, one of which is illustrated herein at Scheme 1. [0005] In particular, Example 19 of the '239 patent describes a direct preparation of ramelteon by reacting enantiomerically pure compound (IV) hydrochloride with propionyl chloride in the presence of triethylamine as a base, and in the presence of Ny/V-dimethylformamide as a solvent. Further, the '239 patent describes the preparation of compound (IV) from compound (II) via two consecutive hydrogenation reactions (see reference Examples 27 and 20 of the '239 patent, in that order). Scheme 1

enantioselective double bond reduction

H₂, Ru₂CI₄KR)-BINAP]₂Et₃N

(IV) • HCI

(II)

ramelteon, (I)

[0006] The synthetic route described in Scheme 1 is not suitable for industrial implementation since the preparation of intermediate compound (IV) involves two consecutive hydrogenation reactions, that is, the process requires large amounts of hydrogen gas, the handling of which 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, special care must be taken in accordance with safety operating conditions to reduce the risk of accidents.

[0007] Another disadvantage to the synthesis depicted in Scheme 1 is that the propionylation of compound (IV) hydrochloride is carried out in MjV-dimethylformamide (DMF) as a solvent. According to International Conference on Harmonisation (ICH) Guidelines, DMF is listed as a Class 2 solvent, that is, "a solvent to be limited" due to significant toxicities. Therefore, DMF is an undesired solvent for reactions on an industrial scale.

[0008] Thus, there is a need for an improved process for preparing ramelteon, which is suitable for industrial implementation and/or avoids one or more of the disadvantages discussed above.

BRIEF SUMMARY OF THE INVENTION

[0009] The invention provides an improved process for preparing indane derivatives. [0010] In an embodiment, the present invention provides a process for preparing ramelteon from l,2,6,7-tetrahydro-8H-indeno[5,4-ό]furan-8-ylideneacetonitrile of formula (II), wherein a compound of formula (II), or a solvate or salt thereof, is converted to (8S)- l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8-ylacetonitrile of formula (III), or a solvate or salt thereof, which is converted to 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8- yl]ethanamine of formula (IV), or a solvate or salt thereof, which is converted to ramelteon. [0011] In another embodiment, the present invention provides an improved process for preparing ramelteon from a compound of formula (IV).

DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention provides improved processes for preparing indane derivatives, for example, ramelteon. Processes in accordance with the invention reduce or avoid the use of extensive amounts of hazardous hydrogen gas, which makes for safer operating conditions. In addition, the processes of the invention are cost-effective and suitable for industrial implementation.

[0013] In accordance with an embodiment, the present invention provides a process for preparing ramelteon comprising the steps of: i) converting a compound of formula (II), or a solvate thereof, into a compound of formula (III), or a solvate thereof, by an enantioselective conjugate reduction reaction; ii) converting a compound of formula (III), or a solvate thereof, into a compound of formula (IV), or a salt or solvate thereof, by a nitrile reduction reaction; and iii) converting a compound of formula (IV), or a salt or solvate thereof, into ramelteon. [0014] By conducting an enantioselective conjugate reduction of a compound of formula (II) or a solvate thereof, then reducing the nitrile moiety of a compound of formula (III) or a solvate thereof, to form a compound of formula (IV) or a salt or solvate thereof, which is converted into ramelteon, the present invention provides a process for preparing ramelteon which has industrial advantages, e.g., reducing or avoiding the use of extensive amounts of hydrogen gas and increased safety.

[0015] In an embodiment, the present invention provides a process for preparing ramelteon as depicted in Scheme 2.

Scheme 2

(H) (III) (IV) ramelteon [0016] In accordance with an embodiment, the conversion of a compound of formula (II) to a compound of formula (III) comprises an enantioselective conjugate reduction reaction.

Typically, the enantioselective conjugate reduction reaction employs a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand. Applicants have surprisingly discovered that using a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand in step i) above leads to an efficient and highly enantioselective conjugate reduction of compound (II), or a solvate thereof.

[0017] In accordance with embodiments of the invention, the enantionselective conjugate reduction reaction is conducted in a suitable solvent, e.g., a hydrocarbon solvent. Illustrative hydrocarbon solvents are aromatic solvents, e.g., toluene. In keeping with the invention, the enantioselective conjugate reduction reaction is conducted at a suitable temperature, e.g., from about 0 °C to about room temperature.

[0018] In accordance with an embodiment of the invention, the enantioselective conjugate reduction reaction of step i) comprises contacting compound of formula (II), or a solvate thereof, with a reducing agent, in the presence of a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand, and in the presence of a solvent.

[0019] In preferred embodiments, the catalyst comprising copper of step i) is prepared from copper (II) acetate as the catalytic precursor.

[0020] In preferred embodiments, the chiral ferrocenyl-based biphosphine ligand of step i) is (S)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ligand (i.e., generally referred as the Josiphos ligand), or a derivative thereof. The Josiphos ligand is preferably prepared using (S)-I -[(R)-2-

(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct as the ligand precursor.

[0021] In preferred embodiments, the reducing agent of step i) is a siloxane compound, more preferably the reducing agent of step i) is polymethylhydrosiloxane.

[0022] In accordance with an embodiment of the invention, the conversion of a compound of formula (III) to a compound of formula (IV) comprises a nitrile reduction reaction. Typically, the nitrile reduction reaction of step ii) comprises contacting a compound of formula (III), or a solvate thereof, with either (a) hydrogen and a metal catalyst or (b) another reducing agent.

[0023] As used herein, the term "contacting" refers to reacting one or more substances under suitable conditions to achieve the desired result. For example, a compound of formula (III), or a solvate or salt thereof, is reacted with a suitable amount of a reducing agent in a suitable reaction vessel at a suitable temperature in a suitable solvent for a suitable period of time under suitable other conditions to form a compound of formula (IV).

[0024] In accordance with an embodiment of the invention, the nitrile reduction reaction is conducted in a suitable solvent, e.g., polar aprotic solvents. An illustrative polar aprotic solvent is THF. In keeping with the invention, the nitrile reduction reaction is conducted at a suitable temperature, e.g., from about 0 °C to about 40 °C.

[0025] In a preferred embodiment, the reducing agent of step ii) (a) is lithium aluminium hydride.

[0026] In certain embodiments, the metal catalyst of step ii) (b) is a palladium, platinum or nickel catalyst, more preferably a nickel catalyst, and even more preferably is Raney nickel.

[0027] In accordance with an embodiment of the invention, the conversion of a compound of formula (IV), or a salt or solvate thereof, to ramelteon in step iii) comprises a propionylation reaction wherein a compound of formula (IV), or a salt or solvate thereof, is contacted with a propionylating agent. In preferred embodiments, the propionylating agent of step iii) is propionyl chloride or propionic anhydride.

[0028] In preferred embodiments, the salt or solvate of a compound of formula (IV) of step iii) is any suitable organic or inorganic salt of compound (IV). More preferably, the compound of (IV), or a salt or solvate thereof, of step iii) is a hydrogen halide salt of compound (IV), most preferably the compound of (IV), or a salt or solvate thereof, of step iii) is the hydrogen chloride salt of compound (IV).

[0029] In accordance with an embodiment of the invention, the propionylation reaction of a compound of formula (IV), or a salt or solvate thereof, of step iii) is preferably carried out in the presence of a base such as sodium hydrogen carbonate or sodium hydroxide.

[0030] In accordance with an embodiment of the invention, the propionylation reaction of a compound of formula (IV), or a salt or solvate thereof, of step iii) is preferably carried out in the presence of a solvent comprising tetrahydrofuran, water, or mixtures thereof. More preferably, the solvent of step iii) of the process of the invention is water.

[0031] In an embodiment, the reaction medium or solvent is free or substantially free of class II solvents, e.g., DMF.

[0032] In some embodiments, the present invention provides a process for preparing ramelteon, said process comprising contacting a salt of compound of formula (IV) with propionic anhydride as a propionylating agent, in the presence of a base, and in the presence of water as a solvent.

[0033] To date, applicants are not aware of a publication describing the propionylation of the hydrochloride salt of compound of formula (IV) using an aqueous solvent. This propionylation reaction has only been described using organic solvents such as DMF. This is due to the instability in water of propionylating agents such as propionyl chloride, which hydrolyze rapidly.

[0034] Applicants have surprisingly discovered that the propionylation of the hydrochloride salt of compound of formula (IV) can be carried out efficiently in the presence of water when propionic anhydride is used as a propionylating agent. Water is an inexpensive, safe and non-toxic solvent, which is abundant in nature. Accordingly, the use of water as a solvent is desirable for a green chemical process. Thus, the process for preparing ramelteon from the hydrochloride salt of a compound of formula (IV) avoids the use of organic solvents and is cost-effective and suitable for industrial implementation.

[0035] Further, the use of water as a solvent in the process of the invention above entails a number of advantages which additionally increase the efficiency of the reaction. For example, the hydrochloride salt of compound of formula (IV), that is, the starting material for the reaction, is highly soluble in water and the ramelteon product is insoluble in water, and thus precipitates as the reaction proceeds.

[0036] In accordance with an embodiment of the invention, the salt of compound of formula (IV) can be any suitable organic or inorganic salt of compound of formula (IV).

Preferably, the salt of compound of formula (IV) is a hydrogen halide salt of compound of formula (IV). More preferably, the salt of compound of formula (IV) is the hydrogen chloride salt of compound of formula (IV).

[0037] The base used in the propionylation reaction of the invention can be any base suitable to liberate the compound from the salt, e.g., sodium hydrogen carbonate or sodium hydroxide. The base should be used in amounts sufficient to liberate the compound of formula (IV) from the corresponding salt, as well as to permit the reaction to proceed efficiently.

[0038] In keeping with embodiments of the invention, the ramelteon obtained according to the processes of the invention has a high chemical and enantiomeric purity profile.

[0039] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES HPLC Method 1

[0040] The chromatographic separation was conducted at 40 ⁰C using a Chiralpak^® IB, 5 μm, 250 x 4.6 mm I.D. column. The mobile phase was prepared by mixing 950 mL of M-hexane with 40 mL of 2-propanol, 10 mL of ethanol, 4 mL of trifluoroacetic and 2 mL of triethylamine.

[0041] The chromatograph was equipped with a UV detector monitoring 225 nm and the flow rate was 1.2 mL per minute. Samples were prepared at a concentration of 2.5 mg/mL of mobile phase and 10 μL of sample were injected onto the column.

HPLC Method 2

[0042] The chromatographic separations were conducted at 40 ⁰C using a Chiralpak AD-H, 5 μm, 250 x 4.6 mm I.D. column. The mobile phase was prepared by mixing 950 mL of H-hexane with 40 mL of 2-propanol, 10 mL of ethanol, 4 mL of trifluoroacetic and 2 mL of triethylamine.

[0043] The chromatograph was equipped with a UV detector monitoring 225 nm and the flow rate was 1.2 mL per minute. Samples were prepared at a concentration of 1 mg/mL in a 1:1 mixture of H-hexane and 2-propanol and 10 μL of sample were injected onto the column.

Example 1

[0044] This example illustrates a process for preparing (8iS)-l,6,7,8-tetrahydro-2H- indeno[5,4-6]furan-8-ylacetonitrile (compound of formula III) via enantioselective reduction of l,2,6,7-tetrahydro-8H-indeno[5,4-6]furan-8-ylideneacetonitrile (compound of formula II) in accordance with an embodiment of the invention. [0045] Copper (II) acetate (10.6 mg), 35.4 mg of (S)-(+)-l-[(R)-2- (diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct, 0.48 mL of polymethylhydrogen siloxane and 2 mL of toluene were loaded into a reaction flask. The suspension was cooled to 0-5 ⁰C. Added to the suspension were: 393.9 mg of compound (II), 0.76 mL of tert-butanol and 2 mL of toluene. After addition, the suspension was allowed to warm to room temperature (about 20 ⁰C) over a period of approximately two hours and allowed to stand overnight. To the reaction mixture was added: 10 mL of water, 40 mL of diethyl ether, and 4.8 mL of aqueous 2.5 M NaOH. The resulting mixture was vigorously stirred for 30 minutes and let to decant. After separating the phases, the aqueous phase was extracted again with 40 mL of diethyl ether for 10 minutes. The combined organic phases were washed with 20 mL of saturated solution of NaCl, dried over Na₂SO₄, concentrated in vacuum and finally the solvent was removed with ethyl acetate to yield a residue weighing 1.0 g. Analysis of the residue using HPLC showed a main peak with a 89.1 area percentage at 7.057 minutes, a second peak with a 7.8 area percentage at 7.992 minutes and a third peak with a 3.1 area percentage at 10.525 minutes. This last peak was also observed at the same retention time and with a similar area percentage in the starting compound of formula (II) used in this example.

Example 2

[0046] This example illustrates a process for preparing 2-[(8S)-1 ,6,7,8-tetrahydro-2H- indeno[5,4-ό]furan-8-yl]ethanamine (compound of formula IV) via nitrile reduction of (8S)- l,6,7,8-tetrahydro-2H-indeno[5,4-ό]furan-8-ylacetonitrile (compound of formula III) in accordance with an embodiment of the invention.

[0047] In a 25 mL reaction flask, was added 152 mg of Lithium Aluminum Hydride (supplied by Sigma Aldrich) and 6.10 mL of dry tetrahydrofuran. After cooling the mixture to 5 ⁰C, a solution of 800 mg of compound of formula (III) (as obtained in Example 1) in 5 mL of tetrahydrofuran was added over a period of 20 minutes. The reaction mixture was warmed to room temperature (about 20 ⁰C) over a period of approximately 1 hour and maintained at room temperature for 2.5 hours. The reaction mixture was then heated to 40 ⁰C and maintained at this temperature for 2.5 hours and then cooled. Direct In Process Control of the reaction mass using the same HPLC method of Example 1 (that uses a chiral column) showed a main peak with a 89.1 area percentage at 21.717 minutes. Other peaks present were: 11.9% at 6.848 min.; 1.3% at 7.468 min.; 1.2% at 7.887 min.; 6.1% at 17.980 min.; 1.2 % at 20.233 min.; 6.5% at 23.764 min.; 3.1% at 30.357 min.

[0048] The retention time of the main peak of the reaction mass obtained in Example 2 coincides with the retention time of one of the two peaks observed for a sample of racemic compound of formula (IV).

Example 3

[0049] This example illustrates a process for preparing 2-[(8S)- 1 ,6,7,8-tetrahydro-2H- indeno[5,4-ό]furan-8-yl]ethanamine hydrochloride (compound IVΗC1) in accordance with an embodiment of the invention. [0050] Step A) enantioselective reduction of compound of formula (II): [0051] Copper (II) acetate (160 mg), 530 mg of (S)-(+)-l-[(Λ)-2- (diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct, 14 mL of polymethylhydrogen siloxane and 50 mL of toluene under a nitrogen atmosphere were loaded into a reaction flask. The suspension was cooled to 0-5 ⁰C and 1O g of compound of formula (II), 20 mL of tert-butanol and 40 mL of toluene were added.

[0052] The reaction mass was stirred for one hour at 0-5 ⁰C and then heated to 20 ⁰C. The reaction mixture was maintained at this temperature for 3 hours. Toluene was then removed under vacuum, 100 mL of water were added and the vacuum distillation was continued until complete removal of toluene.

[0053] The mixture was cooled to 20 ⁰C, 150 mL of 10% NaOH solution were added and the mixture was stirred at 20-25 ⁰C for 3 hours. Toleune (150 mL) was then added and the mixture was stirred for an additional 2 hours. The suspension was filtered and the collected cake was washed with 50 mL of water. The filtrate was poured into a separating funnel and allowed to separate. The aqueous phase was discarded and the organic phase was kept. [0054] The cake was then suspended in 150 mL of toluene and stirred for 2 hours, filtered and the collected cake was washed with 50 mL of water. This process of washing with toluene and water was repeated two times. The filtrates resulting from these washings were poured into a separating funnel and allowed to separate. The aqueous phase was discarded and the toluene phase was combined with the previously obtained toluene phase and washed with saturated brine (2x200 mL). The organic phase was distilled under vacuum to a volume of approximately 150 mL.

[0055] Step B) nitrile reduction of compound of formula (III):

[0056] The 150 mL of solution containing the compound of formula (III) were charged into a 500 mL autoclave, together with 40 mL of methanol, 4 g of 15% NaOH solution and 1O g of Nickel Raney catalyst. The autoclave was purged with nitrogen and then hydrogen was introduced. The reaction mass was heated to 35-40 ⁰C and the pressure adjusted to 0.5 MPa with hydrogen and, after the pressure had dropped, more hydrogen was loaded to recuperate the initial pressure of 0.5 MPa. After the hydrogen consumption ended (about 90 min.), the reaction mixture was stirred for 2 additional hours. The reaction mixture was filtered to remove the catalyst, which was also washed with 80 mL of water. After combining the filtrate and the aqueous washings, 50 mL of IN HCl solution was charged and the mixture stirred at 40 ⁰C for 30 min. After separating the aqueous phase which contained compound (IV) HCl, the organic phase was stirred with 300 mL of brine for 4 hours. The two aqueous phases (i.e., the first aqueous phase and the brine) were combined, cooled to 5 ⁰C, and the solid was filtered and dried to obtain 6 g of solid. The solid was treated with 60 mL of methanol at reflux temperature for 30 minutes, and filtered while hot to remove insolubles. The filter was washed with 10 mL of methanol and the methanolic solution was cooled until the solid crystallized (at about 30 ⁰C). Then, 180 mL of acetone were charged at room temperature and the mixture was cooled to 0 ⁰C and filtered. The solid was washed with some acetone and after drying 5.5 g of solid corresponding to compound (IV)-HCl were obtained.

[0057] Analysis (HPLC method 1): 99.99% area % (retention time 25.14 min.), 0.01% area % (retention time 28.28 min.); Purity = 99.99%; e.e. = 99.98%.

Example 4

[0058] This example illustrates a process for preparing (S,R)-N-[2-(l ,6,7,8-tetrahydro- 2H-indeno-[5,4-6]furan-8-yl)ethyl]propionamide (i.e., racemic ramelteon) in accordance with an embodiment of the invention.

[0059] 5.00 g of 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-ό]furan-8-yl)ethanamine hydrochloride (racemic compound IV-ΗC1) and 30 mL of water were loaded into a reaction flask. The orange solution was cooled to 5-10 ⁰C and 4.0 mL of propionic anhydride was added followed by solid sodium bicarbonate (3-4 g) until there was no further effervescence (the pΗ of the mixture was about 5.5). The suspension was maintained at a temperature of 5-10 ⁰C for 1 hour. The precipitate product was filtered, washed with water (2x3 mL), and dried in a vacuum desiccator to yield a solid corresponding to (S,R)-N-[2-(l, 6,7,8-tetrahydro- 2H-indeno-[5,4-6]furan-8-yl)ethyl]propionamide (yield: 4.63 g, 86%). [0060] Analysis (ΗPLC method 1): 48.93% area % (retention time 12.64 min. corresponding to (5)-ramelteon); 48.83% area % (retention time 13.90 min. corresponding to (Λ)-ramelteon).

Example 5

[0061] This example illustrates a process for preparing (5',/?)-N-[2-(l ,6,7,8-tetrahydro- 2H-indeno-[5,4-6]furan-8-yl_>)ethyl]propionamide (i.e. racemic ramelteon) in accordance with an embodiment of the invention.

[0062] 2.00 g of 2-(l,6,7,8-tetrahyΛo-2H-indeno[5,4-ό]furan-8-yl)ethanamine hydrochloride (racemic compound IV-ΗC1) and 4 mL of tetrahydrofuran were loaded into a reaction flask. The suspension was cooled to 5-10 ⁰C and 8.54 g of 10% NaOH solution was added while maintaining the temperature below 5-10 ⁰C (pH 13.0-13.5). The suspension was maintained at this temperature for 30 minutes and then 0.94 mL of propionyl chloride was added dropwise. Once the addition was complete, the pH (5.5-6.0) was adjusted to pH 12-13 using 10% NaOH solution. The reaction mixture was allowed to warm to room temperature (about 20-25 ⁰C) over a period of approximately Ih and it was maintained at this temperature for one hour. Water (15-20 mL) was then added dropwise until a suspension was observed. The suspension was kept at this temperature for 30 minutes. The precipitate product was filtered, washed with water (2x1 mL), and dried in a vacuum desiccator to yield a solid corresponding to (S,R)-N-[2-(\ ,6,7,8-tetrahydro-2H-indeno-[5,4-ό]furan-8- yl)ethyl]propionamide (yield; 1.62 g, 75%).

[0063] Analysis (ΗPLC method 1): 48.60% area % (retention time 12.68 min. corresponding to (iS)-ramelteon); 48.42% area % (retention time 13.93 min. corresponding to (i?)-ramelteon).

Example 6

[0064] This example illustrates a process for recrystallizing (S,R)-N-[2-(l, 6,7,8- tetrahydro-2H-indeno-[5,4-ό]fura«-8-yl)ethyl]propionamide (i.e., racemic ramelteon) in accordance with an embodiment of the invention.

[0065] 1.00 g of (5^r,Λ)-N-[2-(i,6,7,8-tetrahydro-2H-indeno-[5,4-6]furan-8- yl)ethyl]propionamide and 23 g of EtOΗ/water (1 :2) solution were loaded into a reaction flask. The suspension was heated to reflux for a period of 15 minutes. The solution was cooled to room temperature over a period of Ih and maintained at 20-25 ⁰C for one hour. The precipitate product was filtered, washed with a solution of EtOΗ/water (2x1 mL) and dried in a vacuum desiccator to yield a solid corresponding to (5,i?)-N-[2-(l,6,7,8-tetrahydro-2H- indeno-[5,4-6]furan-8-yl)ethyl]propionamide (yield; 0.76 g, 76%). [0066] Analysis (ΗPLC method 1): 49.29% area % (retention time 12.68 min. corresponding to (S)-ramelteon), 49.30% area % (retention time 13.93 min. corresponding to (i?)-ramelteon).

Example 7

[0067] This example illustrates a process for preparing (S)-N-[2-(\ ,6,7,8-tetrahydro-2H- indeno-[5,4-ό]furan-8-yl)emyl]propionamide (i.e., ramelteon) in accordance with an embodiment of the invention. [0068] 25.0 g (0.104 mol) of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8- yl)ethanamine hydrochloride (compound IVΗC1) and 375 mL of water were loaded into a reaction flask. The brownish solution was cooled to 10-15 ⁰C and 20.98 g (0.156 mol) of 97% propionic anhydride was added followed by 50% sodium hydroxide solution (22.77 g, 0.285 mol). The pΗ was 6.0-6.5. During the addition, a precipitate was quickly formed. Once the addition was complete, the suspension was heated to 20-25 ⁰C for 2 hours. Then, the suspension was heated to 60±5 ⁰C and maintained at this temperature for 1 hour. The suspension was then cooled to 40±2 ⁰C. The precipitate product was filtered at 40±2 ⁰C, and washed with water (2x20 mL). 69.84 g of wet solid were obtained and charged with 375 mL of water into a reaction flask. The suspension was heated to 60±5 ⁰C and maintained at this temperature for 1 hour. Finally, the suspension was cooled to 40±2 ⁰C. The precipitate product was filtered at 40±2 ⁰C, and washed with water (2x20 mL). 49.90 g of wet solid were obtained and charged with 375 mL of water into a reaction flask. The suspension was heated to 60±5 ⁰C and maintained at this temperature for 1 hour. Finally, the suspension was cooled to 40±2 ⁰C. The precipitate product was filtered at 40±2 ⁰C, washed with water (2x20 mL). 47.41 g of wet solid were obtained and charged with 109 mL of acetone into a reaction flask. The solution was filtered at 20-25 ⁰C through a filter to remove insolubles and the filter was washed with 5.0 mL of acetone. The stirred solution was heated to reflux. Water (217 mL) was then added over the solution of ramelteon in acetone. The solution was cooled to 20-25 ⁰C and stirred at this temperature for at least 2 hours. A white suspension was formed when the temperature arrived to 35 ⁰C. The suspension was filtered and the collected white solid was washed with water (2x20 mL) to give 37.29 g of wet product. The wet product was dried under vacuum at 60 ⁰C to constant weight, to give 19.84 g of white solid (yield: 73%). [0069] Analysis (ΗPLC method 2): 100.00% area % (retention time 14.07 min. corresponding to (5)-ramelteon); (i?)-ramelteon: not detected (retention time 19.62 min.). Purity: 99.76%; ee.: > 99.96% (based on a Limit of Quantification for (i?)-ramelteon of 0.02% when using ΗPLC method 2).

[0070] 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.

[0071] 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 process for preparing ramelteon of formula (I):

said process comprising: i) converting l,2,6,7-tetrahydro-8H-indeno[5,4-6]furan-8- ylideneacetonitrile of formula (II), or a solvate thereof:

into (8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-6]furan-8-ylacetonitrile of formula (III), or a solvate thereof:

by an enantioselective conjugate reduction reaction; ii) converting the compound of formula (III), or a solvate thereof, into 2-

[(8iS)-l,6,7,8-tetrahydro-2H-indeno[5,4-Zj]furan-8-yl]ethanamine of formula (IV), or a salt or solvate thereof:

by a nitrile reduction reaction; and iii) converting the compound of formula (IV), or a salt or solvate thereof, into ramelteon.

2. The process of claim 1, wherein the enantioselective conjugate reduction reaction of step i) employs a catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand.

3. The process of claim 2, wherein the enantioselective conjugate reduction reaction of step i) comprises contacting the compound of formula (II), or a solvate thereof, with a reducing agent, and the catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand in the presence of a solvent.

4. The process of claim 3, wherein the catalyst comprising copper and a chiral ferrocenyl-based biphosphine ligand is prepared from copper (II) acetate as the catalytic precursor.

5. The process of claim 3 or 4, wherein the reducing agent is a siloxane compound.

6. The process of claim 5, wherein the siloxane compound is polymethylhydrosiloxane.

7. The process of any one of claims 1 to 6, wherein the nitrile reduction reaction of step ii) comprises contacting a compound of formula (III), or a solvate thereof, with either (a) hydrogen and a metal catalyst or (b) another reducing agent.

8. The process of claim 7, wherein the another reducing agent is lithium aluminium hydride.

9. The process of claim 7, wherein the metal catalyst is a palladium, platinum or nickel catalyst.

10. The process of claim 9, wherein the metal catalyst is a nickel catalyst.

11. The process of claim 10, wherein the nickel catalyst is Raney nickel.

12. The process of any one of claims 1 to 11, wherein step iii) comprises contacting the compound of formula (IV), or a salt or solvate thereof, with a propionylating agent.

13. The process of claim 12, wherein the propionylating agent is propionyl chloride or propionic anhydride.

14. The process of claim 12, wherein the contacting the compound of formula (IV), or a salt or solvate thereof, with the propionylating agent is carried out in the presence of a base.

15. The process of claim 12, wherein the contacting the compound of formula (IV), or a salt or solvate thereof, with the propionylating agent is carried out in the presence of water as a solvent.

16. A process for preparing ramelteon of formula (I):

said process comprising contacting a compound of formula (IV) or a salt thereof:

with propionic anhydride in the presence of a base and in the presence of water as a solvent.

17. The process of claim 16, wherein the salt of compound of formula (IV) is an organic or inorganic salt of compound of formula (IV).

18. The process of claim 16, wherein the salt of compound of formula (IV) is a hydrogen halide salt of compound of formula (IV).

19. The process of claim 18, wherein the hydrogen halide salt of compound of formula (IV) is the hydrogen chloride salt of compound of formula (IV).

20. The process of any one of claims 16 to 19, wherein the base is sodium hydrogen carbonate or sodium hydroxide.