Process for the preparation of ramelteon WO 2010103553 A1

RAMELTEON


Industriale Chimica S.R.L.

http://www.google.im/patents/WO2010103553A1?cl=en

Ramelteon, having the structural formula (I) illustrated below,

⁽U is a product known in literature and was described for the first time, with relative synthesis, in the patent EP 885210 B1 to Takeda Chem. Ind.

The starting products for the preparation of ramelteon can be 2,3- dihydrobenzofuran or 6-hydroxy-indanone. The cyclisation for formation of the third ring can therefore follow two paths:

(D (2)

The amine function is introduced by Wittig reaction on an intermediate of type (3) followed by reduction of the -C=N group to give an intermediate of type (4):

(3) (4)

Reduction of the double bond resulting in position 8 in the intermediate (4) must provide the end product with stereochemistry S. For this purpose chiral catalysts can be used, or achiral catalysts with subsequent separation of the mixture obtained.

(4)

The transformation from amine to amide occurs in the usual way, with the use of chloride of the acid in the presence of an organic base, and is schematised by the following reaction:

One of the critical points of the synthesis pathways of optically active products like ramelteon is control of the process stereochemistry in order to obtain the desired product with correct spatial arrangement of all the atoms.

In EP 885210 B1 , as described in the experimental part, two pathways are followed to obtain the above.

According to the first pathway, illustrated in paragraph [380], example 11 , the ramelteon is optically resolved by preparative HPLC with chiral column working on a small amount of product. The example gives data of [αjo²⁰, melting point and NMR without, however, providing the most indicative datum, i.e. the enantiomeric excess, of the product obtained. The indication "optically resolved", in the absence of a numerical datum, does not clarify to what extent the ramelteon has been resolved, and therefore the text in this regard does not give exhaustive indications on the possibility of resolving the racemic mixture via this pathway. Furthermore, the option of resolution on a chiral column is clearly of analytical interest only and has no application for production on an industrial scale.

The second possibility described in EP 885210 B1 , in the reference examples 2O₃ 21 and 22, tackles the problem in a different way, intervening on the synthesis. In this case hydrogenations are performed with chiral catalysts, obtaining reduction products with enantiomeric excess (e.e.) up to 90%. The reference example 20, paragraph [302], obtains an e.e. of 100%, but only after repeated crystallisations starting from an e.e. of 88.8%. From the experimental procedures of the examples cited it can be observed that the hydrogenation pressure varies between 50 and 100 bar. Such high pressure values, which already at laboratory level require specific equipment, cannot be easily applied to ordinary plant reactors; rather, they require specific dedicated and constantly controlled reactors.

A similar observation can be made with regard to the reference example 29, paragraphs [310] and [311], in which the intermediate (E)-N-[2-(6-methoxyindan-1- ylidene)ethyl]propionamide is hydrogenated at 70 ⁰C and at a pressure of 90 bar; in this example an e.e. of 99% is reached after chromatographic purification and crystallisation. From the stereochemical point of view the result is more than satisfactory except that it is obtained on one of the first intermediates of the synthesis. This means that the short column chromatography described in paragraph [311] is such and can be performed with ordinary equipment only at laboratory level; it certainly does not apply in the case of industrial production.

The article "Approach to the stereoselective synthesis of melatonin receptor agonist ramelteon via asymmetric hydrogenation", Tom Yamano et al., Tetrahedron: Asymmetry, vol. 17 (2006), 184-190, which was published roughly ten years after the patent EP 885210 B1 , describes purification of the asymmetric hydrogenation products of some substrates (indicated as 3, 4a and 4b) and shows how the technique illustrated always requires a final chromatographic purification (see in particular hydrogenation of substrate 3, performed on a few mg, and substrate 4a). In the conclusions of the article the results obtained are defined as encouraging for the development of more efficient processes.

Lastly, the recent patent application EP 1792899 A1 describes a synthesis of (S)-2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine with a high degree of purity, applicable industrially and characterised by high process yields. This application touches on another crucial aspect of synthesis of pharmaceutical products, i.e. the impurities generated by the synthesis itself. The description of said (numerous) impurities is detailed, the structures are given in full and their final content in the ramelteon is good, each being below 0.15%, but the method of obtaining the results appears complicated and costly. As described in example 2, the process comprises a double hydrogenation on (E)-2-(1 ,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-ylidene)ethylamine with two different catalysts followed by a crystallisation, then transformation, in a separate operation, of the amine thus obtained to propionamide (i.e. ramelteon) and further purification.

It is therefore evident that there is still the need to develop production processes for ramelteon which are alternative to the known processes and are simpler to apply on an industrial scale.

Summary of the invention

One object of the present invention is therefore to provide a process for the synthesis of ramelteon which is industrially applicable without the need for special plants and which, at the same time, allows the compound to be obtained in a pharmaceutical quality and with high yields in a simple manner, limiting reprocessing and chromatography.

A further object of the invention is to provide a process for the synthesis of ramelteon which comprises more practical stereoselective reductions than those previously known.

These and further objects are obtained according to the present invention with a process for the preparation of N-[2-(8S)-1 ,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-il]ethyl]propionamide (ramelteon) of formula (I)

(I) comprising the following reactions: a) alkylation of the hydroxyl of 6-hydroxy-indanone, (II), to obtain 6-allyIoxy- indan-1 -one, (III):

(II) (III) b) thermal Claisen rearrangement on (III) to obtain 7-allyl-6-hydroxy-indan-1- one, (IV):

(III) (IV) c) protection of the free hydroxyl of (IV) to obtain an intermediate of formula

(V):

(IV) (V) in which (PG-OH) indicates the hydroxyl group protected with a protective group stable in a basic environment; d) reaction of the intermediate of formula (V) with a dialkyl cyano methylphosphonate to obtain an intermediate of formula (Vl)

(V) (Vl)

Having obtained an intermediate of type (Vl) two synthesis pathways can be followed: a sequence (indicated below as e → f_→ 3_. → h ^→ i) in which the reaction e is enantioselective; or a sequence (indicated below as E → F → G → H → 1) in which the reaction ] is enantioselective.

Sequence e -→i → g → h → i e) enantioselective reduction on the intermediate of formula (Vl)₁ to obtain an intermediate of formula (VII)

(Vl) (VII) f_) oxidative demolition of the double bond of the intermediate of formula (VII), to obtain an intermediate of formula (VIII):

(VII) (VIII)

§) reduction of the carbonylic function present in the intermediate of formula (VIII), to obtain an intermediate of formula (IX):

(VIII) (IX) h) transformation of the free hydroxylic group present in the intermediate of formula (IX) in order to make it a good leaving group, to obtain an intermediate with general formula (X)₁ in which (LG) indicates a leaving group:

(IX) (X) i) intramolecular cyclisation of the intermediate of formula (X) to obtain (1 ,6_>7_J8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile_l (Xl):

(X) (Xl)

Sequence E_→ F_→ G_→ H_→ I

E) selective oxidative demolition of the terminal double bond on the intermediate of formula (Vl), to obtain an intermediate of formula (7):

(Vl) (7) F) reduction of the carbonylic function present in the intermediate of formula (7), to obtain an intermediate of formula (8):

(7) (8)

G) transformation of the free hydroxylic group present in the intermediate of formula (8) in order to make it a good leaving group, to obtain the intermediate of formula (9), in which (LG) indicates the leaving group:

(8) (9)

H) intramolecular cyclisation of the intermediate of formula (9) to obtain (I ^J.δ-tetrahydro-EH-indenofδ^-bjfuran-δ-ylideneJacetonitrile of formula (10):

(9) (10)

I) enantioselective reduction on the intermediate of formula (10) to obtain (1 ,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile of formula (Xl):

(10) (Xl) The intermediate (Xl)₁ a common product of the two synthesis pathways, can be made to react to obtain ramelteon according to one of the following two pathways: g) hydrogenating the triple bond -C=N in the presence of propionic anhydride to obtain ramelteon (I):

(XI) (I) or βl) reducing the triple bond of the group -C=N to -CH₂NH₂ to obtain the intermediate (XII); and βf) reacting the intermediate (XII) with propionic anhydride or propionyl chloride, to obtain ramelteon (I):

......................................(Xl)......................... (XII)................................. (I)

EXAMPLE 9

This example refers to reaction g of the process of the invention (preparation of ramelteon).

470 g of product of formula (Xl), obtained as described in Example 8, are dissolved in 84 kg of THF. 615 g of propionic anhydride and 150 g of Pt/C Escat 22 (Pt at 5% on carbon) are added to the solution. The suspension is brought to T = 65 ± 5 ⁰C and hydrogenated at P = 8/9 bar. After 4 h the progress of the reaction is checked (TLC), it is filtered and a further 50 g of Pt/C Escat 22 are loaded. The suspension is brought to T = 65 ± 5 ⁰C and hydrogenated at P = 8/9 bar, checking the progress of the reaction (TLC). At the end of the reaction, the catalyst is filtered and the solvent is eliminated at reduced pressure. The residue is recovered with 11 kg of isopropyl acetate. The organic phase is washed with a basic aqueous solution (900 g of NaHCO₃ in 10 I of water), with an aqueous solution of NaC! (500 g of NaCI in 10 I of water) and then with water until neutral pH is reached. The solvent is distilled at reduced pressure and T = 55 ± 5 ⁰C. The residue obtained, which tends to crystallise spontaneously, is crystallised with heptane and ethyl acetate. 380 g of ramelteon are obtained, the analytical characteristics of which match the data reported in literature.

This product, analysed with chiral HPLC (Ceramospher Chiral RU-1 ) shows an e.e. of 100%.

EXAMPLE 10

This example refers to reaction g of the process of the invention (preparation of ramelteon).

20 g of product of formula (Xl) are dissolved in 1.8 kg of THF. 26 g of propionic anhydride and 5 g of Pt/C Escat 22 are added to the solution. The suspension is brought to T = 65 ± 5 ⁰C and hydrogenated at P = 10/12 bar. After 4 h the progress of the reaction is checked (TLC)₁ it is filtered and a further 2.5 g of Pt/C Escat 22 are loaded. The suspension is brought to T = 65 ± 5 ⁰C and hydrogenated at P = 10/12 bar, checking the progress of the reaction (TLC). At the end of the reaction, the catalyst is filtered and the solvent is eliminated at reduced pressure. The residue is recovered with 1 I of isopropyl acetate. The organic phase is washed with a basic aqueous solution (10 g of NaHCO₃ in 1 I of water), with aqueous solution of NaCI (10 g of NaCI in 1 I of water) and lastly with water until neutral pH is reached. The solvent is distilled at reduced pressure and T = 55 ± 5 °C. The residue obtained, which tends to crystallise spontaneously, is crystallised with heptane and ethyl acetate. 16.7 g of ramelteon are obtained, the characteristics of which match the data reported in literature.

http://www.google.im/patents/WO2010103553A1?cl=en

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21047 Saronno (VA)

Saronno, Italy.

Phone:+ 39-02-964.26.411

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ichimica@chemogroup.com

Founded in 1984, Industriale Chimica is a subsidiary of the CHEMO Group and is devoted to the manufacture of APIs for the pharmaceutical industry.

Industriale Chimica makes a big investment in its research and development departments. The activity is conducted by a highly-qualified team of researchers and staff. Industriale Chimica laboratories, are totally equipped with the most advanced instruments of analysis.

The development and production comprises: development of small sizes batches, methods of analysis, identification and isolation of impurities, and a stability program in order to supply customers with the data needed to prepare the DMF.

SARANNO ITALY

Process for the preparation of optically pure indeno [5,4-b] furan derivatives WO 2008062468 ..Ramelteon

The present invention relates to process for the preparation of (-)-(S)-N-[2- (l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (RAMELTEON) (I) in its pure isomeric form and free from its enantiomeric isomer.

1

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTl and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTl or MT2 receptors, and high selectivity for human MTl and MT2 receptors compared to the

MT3 receptor.

Ramelteon is a selective melatonin receptor agonist that has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complain of some type of insomnia and 20 million Americans suffer from chronic insomnia. It is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, leading to impairment of next day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. Ramelteon is the first and only prescription sleep medication that has shown no evidence of abuse and dependence, and as a result, has not been designated as a controlled substance by the DEA. Its approval also allows physicians to prescribe ramelteon for long-term use in adults. Ramelteon provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. However, clinical comparisons with other hypnotic agents are not available and will be needed to better differentiate these products.

Our objective is to prepare either racemic Ramelteon (±)-l or it's intermediate 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (+)-(2) and separations of desired isomers of either (1) or (2) using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

United State patent 6,034,239 reports formation of chiral intermediate (-)-(S)-N- [2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)]ethylamine (S)-2 by the catalytic asymnjetric hydrogenation of 2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethylamine (3) in the presence of catalytic amount of BINAP -ruthenium complex in approximately 89% ee followed by purification by preparing acid salt and its condensation with propionyl chloride to get Ramelteon (1) in pure form.

An alternate process for preparing Ramelteon is reported in JMC, 45,

4222-4239 (2002). Herein the exo double bond of the intermediate (A) was asymetrically reduced using (S)-2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (binap)- Ru complex as the catalyst to obtain enantiomerically pure compound (B). Compound (B) is subsequently converted to (S)-(-) Ramelteon (1) through intermediate steps of Claisen condensation, ozonolysis and finally cyclization.

Thus both the above process uses expensive catalyst and involves very sophisticated reaction conditions which make them commercially less viable. Therefore, there exists a need to develop a process for obtaining Ramelteon in an enantiomerically pure form which is cost effective, uses easily available reagents, is scalable with ease and overall commercially more viable. We herein disclose such a process. The process is provided in the following Scheme 1 below:

A process for preparing enantiomerically pure Ramelteon (S)-I comprising the steps of i) reacting a compound of formula (2) either in racemic or enantiomerically pure form with propionyl chloride (4) to obtain Ramelteon (1) with retention of configuration;

Process for the preparation of optically pure indeno [5,4-b] furan derivatives
WO 2008062468 A2......http://www.google.com/patents/WO2008062468A2?cl=en

Reference
1	*	RIVARA ET AL: "Reassessing the melatonin pharmacophore-Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 10, 15 May 2006 (2006-05-15), pages 3383-3391, XP005364989 ISSN: 0968-0896
2	*	T. YAMANO ET AL: "Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation" TETRAHEDRON ASYMMETRY, vol. 17, no. 2, 23 January 2006 (2006-01-23), pages 184-190, XP002481301 NLELSEVIER, AMSTERDAM.
3	*	UCHIKAWA O ET AL: "Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 45, 1 January 2002 (2002-01-01), pages 4222-4239, XP002990691 ISSN: 0022-2623 cited in the application

Intermediates and processes for the synthesis of Ramelteon US 20080242877

ROZEREM® (Ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. The empirical formula for Ramelteon is C₁₆H₂₁NO₂, and its molecular weight is 259.34. Ramelteon is freely soluble in methanol, ethanol, dimethylsulfoxide (DMSO), 1-octanol and is highly soluble in water and aq. buffer. Ramelteon has the following chemical structure:

Ramelteon is the active ingredient and sold under the brand name of ROZEREM®. Ramelteon is approved by the United States Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset.

Different processes for preparing (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide i.e. Ramelteon are disclosed in U.S. Pat. No. 6,034,239, JP 11080106, JP 11140073 and WO 2006/030739.

U.S. Pat. No. 6,034,239 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11080106 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11140073 discloses the following processes for the preparation of an intermediate of Ramelteon:

PCT Publication No. 2006/030739 discloses the following processes for the preparation of an intermediate of Ramelteon:

The present invention provides additional processes for preparation Ramelteon and intermediates thereof.

Synthesis of Ramelteon (I) 
Example 10

The hydrochloride salt of compound of formula XIII (100.0 gm, 418 mmol) is suspended in the THF at 4000 ml, triethyl amine (116.0 ml, 836 mmol) is added and the reaction is cooled to 10° C. or less. Propionyl chloride (74 ml, 836 mmol) is added dropwise followed by agitation at 25-35° C. for 2-3 hrs. Then 1000 ml, of water is added and the THF is distilled off under reduced pressure. It dissolved in ethyl acetate and wash twice with 10% brine solution. Dry the organic layer with sodium sulfate, distill off under vacuum and product is isolated. Dry the product under vacuum.

Intermediates and processes for the synthesis of Ramelteon
US 20080242877 A1......http://www.google.com/patents/US20080242877

Process for the preparation of ramelteon WO 2010055481

Ramelteon (1) is a melatonin receptor agonist with both high affinity for melatonin MTi and MT₂ receptors and selectivity over the MT₃ receptor.

Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTi or MT₂ receptors, and high selectivity for human MTi and MT₂ receptors compared to the MT₃ receptor.

Ramelteon has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complains of some type of insomnia, and 20 million Americans suffer from chronic insomnia, which is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, often leading to impairment of next-day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. 

Ramelteon has also been prescribed for long-term use in adults, provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. United States Patent No. 6,034,239 discloses the formation of chiral intermediates (S)-(- )-N-[2-(l,6,7,8,-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (sometimes referred to as compound S-2 or intermediate compound S-2) by the catalytic asymmetric hydrogenation of 2- (l,2,6,7,-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine (compound 3 in the reaction scheme shown below) in the presence of a catalytic amount of BINAP-ruthenium complex in approximately 89% e.e. (enantiomeric excess). 

Following the catalytic reaction, the product is purified by preparing acid salts and acylated with propionyl chloride (compound 4 in the reaction scheme shown below) to obtain ramelteon (compound 1 in the reaction scheme shown below) in its pure (S) isomer form.

|S)*2

An alternate process for preparing ramelteon is disclosed in the Journal of Medicinal Chemistry, Vol. 45, pp. 4222-4239 (2002), wherein the exo double bond of intermediates (A) shown below was asymmetrically reduced using (S)-2, 2'-bis-(diphenylphosphino)-l, 1 '- binaphthyl (binap)-Ru complex as the catalyst to obtain the enantiomerically pure compound (B). Compound (B) is subsequently converted to ramelteon (1) through the intermediate steps of Claisen condensation, ozonolysis and cyclization.

m Both of the above processes uses expensive catalyst and give poor enantioselectivity. Additionally, these processes are expensive due to the need to perform multiple purifications steps in order to achieve an enantioselectivity of at least about 99% or greater of the desired isomer.

PCT Patent Publication No. WO 2008/062468 A2 discloses the following process for the preparation of ramelteon:

RAMELTEON

WO 2008/062468 teaches that separation of the enantiomers of intermediate (2) may be accomplished by: i) optical resolution of the racemic amine intermediate (2) by preparing acid salts with chirally pure acids; or ii) chromatographic techniques using chiral and/or achiral stationary phases for batch process, super critical or sub critical chromatography and/or continuous process chromatography. 

Although WO 2008/062468 mentions the possible use of optical resolution with chirally pure acids, there is no further teaching, discussion or disclosure of this method. WO 2008/062468 does, however, provide detailed descriptions of chromatographic methods for separating the isomers of intermediate compound (2). 

The disclosed chromatographic process suffers the following disadvantages:

• Preparative chromatography is time consuming & expensive;

• Highly sophisticated instrumentation required; • Not commercially feasible.

PCT Patent Publication No. WO 2008/106179 discloses a process for the preparation of ramelteon that involves the following reaction steps:

wherein X= O-alkyl or NH₂ and chiral reduction of the compound of formula IV in the presence of Ru-BINAP complex under hydrogen atmosphere in an organic solvent.

IV V

The process disclosed in WO 2008/106179 is similar to the process disclosed in United States Patent No. 6,034,239 and the Journal of Medicinal Chemistry, Vol. 45 in that a Ru-BINAP complex is employed.

Resolution of racemic mixtures via reaction with optically active acids and the subsequent crystallization of the resulting salts is preferably employed when the chiral carbon of the racemic compound is an alpha carbon {i.e., one carbon removed) to the functional group forming the acid addition salt.

 As the distance between the chiral carbon of the racemic compound to the functional group of the racemic compound increases to beta (i.e., two carbon removed) & gamma (i.e., three carbon removed), the resolution of the diastereomeric salt becomes more difficult and not very useful.

Ramelteon has a chiral center at the gamma carbon, which makes the separation of the isomer with an optically active acid quite a daunting task. Similarly, N-[2-(l, 6, 7, 8,- tetrahydro-2H-indeno [5, 4-b]furan-8-yl)]ethylamine (compound T), an intermediate useful in the production of ramelteon has a chiral center at the gamma carbon which would lead a skilled artisan to believe that optical resolution with an optically active acid could prove difficult.

http://www.google.com/patents/WO2010055481A1?cl=en

Inventors	Manjunath Narayan Bhanu, Chandrasekhar Sinha, Bhupesh Aher, Amol Bandal, Atul Parab, Less «
Applicant	Watson Pharma Private Limited

The present invention further includes a process for the synthesis of ramelteon that comprises the step of separating N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl)]ethylamine (compound 2) into its isomers using an optically active acid to achieve high enantioselectivity of the desired isomer. This embodiment may further include the step of acylating the substantially pure enantiomer, (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)]ethylamine (compound (S)-2) using a suitable acylating agent, such as propionyl chloride) to provide (S)-7V-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propionamide (ramelteon or compound 1) substantially free of the (R)-isomer.

One embodiment of the present invention for the preparation of ramelteon is shown below in Scheme 1.

Example 2

Preparation of (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)ethyl] propionamide (ramelteon)

Triethyl amine (15.15 g, 0.15 mol) and propionyl chloride (13.66 g, 0.15 mol) were added to a solution of S-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)]ethylamine (25 g, 0.12 mol) (compound (S)-2) (prepared in Example 1) in dichloromethane and stirred at room temperature for 2 hours. 75 mL water was added to the reaction mixture, and the layers were separated. The dichloromethane layer was concentrated under reduced pressure and purified from a mixture of acetone and hexane to give (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan- 8-yl) ethyl] propionamide (compound 1) having a chiral purity of 99% or greater enantioselectivity.