All about Patents and Intellectual property by DR ANTHONY MELVIN CRASTO, worlddrugtracker, Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry, Serving chemists around the world. THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, firstname.lastname@example.org, +91 9323115463 India
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:
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):
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.
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 , 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 , 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  and , 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  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
(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)
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):
§) 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>7J8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrilel (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):
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:
H) intramolecular cyclisation of the intermediate of formula (9) to obtain (I ^J.δ-tetrahydro-EH-indenofδ^-bjfuran-δ-ylideneJacetonitrile of formula (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):
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%.
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.
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.