Title of Invention

A PROCESS FOR PREPARING 5-[(R)-2-(5,6-DIETHYL-INDAN-2-YLAMINO)-1-HYDROXY-ETHYL]-8-HYDROXY-(1H)-QUINOLIN-2-ONE SALTS

Abstract

ABSTRACT 2065/CHENP/2005 A process for preparing 5-[{R)-2-(5,6-Dlethyl-lndan-2-Ylamino)-1-Hydroxy-Ethyl]-8-Hydroxy-(1H)-Quinolin-2-One" A process for preparing 5-I(R)-2-{5,6-diethy]-mdan-2-yiamino)-l-riydroxy-ethyl]-8-hydroxy (IH)-quino!in-2-one salt. The process involves forming an acid salt of 5-[(R)-2-(5,6-diethyI-indan-2-ylamino)-l-hydroxy-ethylJ-8-subsrituted oxy-(lH)-quinolin-2-one; and converting the acid salt to a salt of S-[(R)-2-(5,6-diethyI-indan-2-yIamino)-l-hydroxy-ethyl]-8-hydroxy-(IH)-quinoIin-2-one without isolating the free base of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-quino]in-2-one.

Full Text

The present invention provides a process for preparing 5-\{K)-2-(5t6~disihy\-indsn'2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-qiiinolin-2-one salt without isolating the free base thereof which is unstable in organic solvents. 5-[{R)-2-(5,6-diethyI-indan'2ylamino}-l-hydroxy-ethy]]-8-hydroxy-(?/f)-quinolinone-2-one salts are p-selective adrenoceptor agonists with potent bronchodilator activity. For example, 5-I(R)-2-|5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-{IH)-quinolinone-2-one maleate is especially useful for treating asthma and COPD. In addition, the maleate salt has been shown to have a very long duration of action in vitro and in vivo. In a process for preparing 5-JfR)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethylJ-8-hydroxy-(f H)-quinoIinone-2-one maleate, an epoxide, such as 8-substitutcd oxy-5-(R(-oxiranyl-(lH)-quinolin-2-one (Formula (I)], is reacted with an amine, such as 2-amino-(5-6-diethyl)-indan, to form a desired intermediate 5-((R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one {Formula (II)]. However, the reaction is not regjoselective and delivers various amounts of a regioisomer (Formula (III)] and a Generally, the reaction mixture above contains only about 60% to 80% of the desired intermediate having Formula (II). In addition, it is difficult to purify the intermediate having Formula (H) by crystallization without a high loss of yield. For example, silica gel chromatography has been used for such a purification, however, scale-up of silica gel chromatography is tedious and requires large volumes of solvents. It would be desirable to develop a more efficient process for preparing 5-[{R)-2-(5,6-dtethyl indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(2H)-quino)inone-2-one salts especially for large scale production, which provides the salts in high enantiomeric purity and high yield. The invention provides a process for preparing 5-[(R)-2-(5,6-diethyi-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-{lH)-quinolin-2-one sale or an acceptable solvate thereof comprising: (ii) treating the reaction mixture prepared in Step (i) with an acid in the presence of a solvent to form a corresponding salt; (iii) isolating and crystallizing a salt having Formula (V) Terms used in the specification have the following meanings: As used herein, "alkyl" means straight chain or branched alky!, which may be, e.g., d-Cioalky], such as methyl, ethyl, rc-propyl, isopropyl, rt-butyl, isobutyf, see-butyl, tert-butyl, straight- or branched-pentyl, straight- or branched-hexyl, straight- or branched-heptyl, straight- or branched-nonyl or straight- or branched-decyl. Preferably alkyl is Ci-C4alkyl. "Aryl" means Cs-Cuaryl, preferably Ce-Cioaryl, and may be, e.g., substituted by at least one group selected from mercapto, dialkylammo, nitro, alkoxy, halogen, keto, cyano or a combination. Preferably aryl is phenyl. "Alkoxy" means straight chain or branched alkoxy and may be, e.g., G-Goalkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-buroxy, teri-butoxy or straight- or branched-pentoxy, -hexyloxy, -hepryloxy, -octyloxy, -nonyloxy or -decyloxy. Preferably alkoxy is G-Gaikoxy. "Alkenyi" means straight chain or branched-alkenyl, which may be, e.g., C2-Cioalkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyi, or straight- or branched-penrenyJ, -hexenyl, -heptenyl, -octenyl, -nonenyl or -deceny!. Preferred alkenyi is G-G»alkenyl. "Cycloalkyl" means C3-Gocycloalkyl having 3- to 8-ring carbon atoms and may be, e.g., cyciopropyl, cyclobutyi, cyclopentyl, cyclohexyl, cycloheptyi or cycloheptyi, any of which can be substituted by one, two or more C]-C4alkyl groups, particularly methyl groups. Preferably, cycloalkyl is Ca-Cscycloalkyl. "Benzocycloalky!" means cycloalkyl, e.g., one of the C3-Ciocycloalkyl groups mentioned hereinbefore, attached at two adjacent carbon atoms to a benzene ring. Preferably, benzocycloalkyl is benzo-G-Qcycloalkyl, especially, benzocyclohexyi (tetrahydronaphthyl). "Cycloalkylalkyl" means CvGocycloalkylQ-Goalkyl, where the G-Gocycloalkyl group has 3- to 8-ring carbon atoms and may be, e.g., one of the G-Cioalky! groups mentioned hereinbefore, particularly one of the G-Galkyl groups, substituted by one of the C3-Gocycloalky] groups mentioned hereinbefore. Preferably cycloalkylalkyl is C3-C6cycloaIky!Ci-C4aIkyl. "Aralkyl" means straight-chain or branched-Ce-CioarylQ-Cioalkyl and may be, e.g., one of the Ci-Qoalkyl groups mentioned hereinbefore, particularly one of the Ci-C4alkyl groups, substituted by phenyl, tolyl, xyly] or naphthy!. Preferably, aralkyl is phenyl Ci-Qalkyl, particularly benzyl or 2-phenylethyl. "Heterocyclic" means a monovalent heterocyclic group having up to 20 carbon atoms and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, the group optionally having an alkyl, alkylcarbonyl, hydroxyaikyf, alkoxyalkyl or aralkyl group attached to a ring carbon or nitrogen atom and being linked to the remainder of the molecule through a ring carbon atom, and may be, e.g., a group, preferably a monocyclic group, with one nitrogen, oxygen or sulfur atom, such as pyrryl, pyridyl, piperidyl, furyl, tetrahydrofuryi or thienyl, or a group, preferably a monocyclic group, with two hetero atoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinyl, oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholinyl. Preferably, heterocyclic is a monocyclic group having 5- or 6-ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring and optionally substituted on a ring nitrogen atom by Ci-C4alkyl, hydroxyQ-Qalkyl, G-C4alkylcarbony] or phenylCi-C4alkyl. "HeteroaralkyI" means straight-chain or branched-aralkyl, e.g., one of the Cs-CioarylCi-Cioaikyl groups mentioned hereinbefore, substituted by one ot more heterocyclic groups. "HaloaJkyl" means srraighr-charn or branched-aJkyl, e.g., O-GoaJky], such as one ol the Ci-Cioalkyl groups mentioned hereinbefore, substituted by one or more, e.g., one, two or three, halogen atoms, preferably fluorine or chlorine atoms. Preferably haloalkyl is Ci-Qalkyl substituted by one, two or three fluorine or chlorine atoms. "Substituted silyl group" is preferably a silyl group substituted with at least one alky! group as herein defined. In a second aspect the invention provides a process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-er.hyl]-8-hydroxy-(lH)-quinolin-2-one salt or an acceptable solvate thereof comprising: (a) reacting an 8-(substituted oxy)-5-haloaceryl-(JH)-quinolin-2-one with a reducing agent in the presence of a chiral catalyst to form 8-(substituted oxy)-5-((R)-2-halo-l- hydroxy-ethyl)-(lH)-quinolin-2-one; (b) treating the 8-(substituted oxy)-5-((R)-2-ha)o-l-hydroxy-ethyI)-(lH)-quinolin-2-one with a base in the presence of a solvent to form 8-(substituted oxy)-5-(R)-oxiranyl- (ZH)-quinolin-2-one; (d) treating the reaction mixture prepared in Step(c} with an acid in the presence of a solvent to form a corresponding salt; The present invention provides a process for preparing 5-[(R)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxy-ethyl]-8-hydroxy-(IH)-quinolin-2-one salt or an acceptable solvate thereof. Preferred protecting groups are phenol protecting groups which are known to those skilled in the art. More preferably, the protecting group is selected from the group consisting of an alkyl, aryl, aikoxy, alkeny!, cycloalkyl, benzocycioalkyl, cycloalkylalkyl, aralky!, heterocyclic, heteroaralkyl, haloalkyl, and a substituted silyl group. Most preferably, the protecting group is benzyl or t-butyldimethylsilyl. Preferably, Step (i) is conducted in the presence of a solvent. Preferred solvents include: alcohols, e.g., Ci-salkyl alcohols, such as methanol, ethanol, propanol, butanol, and pentanol; aliphatic Cc-uhydrocarbons, e.g., isooctane, heptane;dimethyiformamide; aromatic hydrocarbons, such as toluene and benzene; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyi ether, 2-methoxyethyI ether and diethylene ether; dimethyl sulfoxide; tetrahydrothiophene 1,1-dioxide, also known as tetramethylene sulfone or as tetramethyiene sulfolane; dialkyl carbonate, e.g., dimethyl carbonate and diethyl carbonate; aqueous solvents, such as water; ionic liquids; and chlorinated solvents, such as methylenechloride. A combination of solvents may also be used. More preferably, the solvent is 2-methoxyethyl ether or butanol. The temperature used in Step (i) is preferably from about 10 eC to about 160 °C. More preferably, the temperature is from about 30 °C to about 120 °C; and most preferably from about 90 "C to about 120 °C Preferably, Step (i) is conducted with a molar excess of the 2-amino>(5-6-diethyl)-indan with respect to the 8-substituted oxy-5-(R)-oxiranyl-(2H)-quinolin-2-one. Preferably, 1.05 mole equivalent to 3 mole equivalents of 2-amino-(5-6-diethyl)-indan is used with respect to 8-substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one. Most preferably, 1.1 mole equivalents to 1.5 mole equivalents of 2-amino-(5-6-diethyI)-indan is used with respect to 8-substituted oxy-5-(R)-oxiranyl-(IH)-quinolin-2-one. The 8-substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one is preferably 8-pheny!methoxy-5-(R)-oxiranyl-(lH)-quinolin-2-one. The 5-[{R)-2-(5,6-diethyI-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(IH)-quinoIin-2-one is preferably 5-[(R)-2-(5,6-diethyl-indan-2-ylarnino)-l-hydroxy-ethyl]-8-phenylmethoxy-(IH)-quinolin-2-one. The 8-substituted oxy-5-(R)-oxiranyl-(2H)-quinolin-2-one may be prepared by reacting an 8-(substituted oxy)-5-haloacetyl-(?H)-quinolin-2-one with a reducing agent in the presence of a chiral catalyst to form 8-(substituted oxy)-5-({R)-2-halo-l-hydroxy-ethyI)-(Itf)-quinoIin-2-one; and treating the 8-{substituted oxy)-5-({R)-2-halo-l-hydroxy-ethyl)-(IH)-quinolin-2-one with a base in the presence of a solvent to form 8-(substituted oxy)-5-(K)-oxiranyl-(ZH)-quinolin-2-one. This is described in greater detail below. In the second step, Step (ii), the reaction mixture prepared in Step (i) is treated with an acid in the presence of a solvent to form a corresponding salt. Preferred solvents for use in Step (ii) include: alcohols, e.g., Ct-ealkyl alcohols, such as methanol, ethanol, propanol, butano!, and pentanol; aliphatic Q-i2hydrocarbons, e.g., isooctane, hep rane;di methyl form amide,- aromatic hydrocarbons, such as toluene and benzene; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether, 2-methoxyethyl ether and diethylene ether; dimethyl sulfoxide; tetrahydrothiophene 1,1-dioxide, also known as tetramethylene sulfone or as tetramethylene sulfolane; dialkyl carbonate, e.g., dimethyl carbonate and diethyl carbonate; aqueous solvents, such as water; ionic liquids; and chlorinated solvents, such as methylenechloride. A combination of solvents may also be used. More preferably, the solvent is ethanol. The temperature used in Step (ii) is preferably from about -10 °C to about 160 CC. More preferably, the temperature is from about 0 °C to about 120 °C; and most preferably from about 0 °C to about 75 °C. is isolated and crystallized, wherein R is a protecting group; and A- is an anion. The anion corresponds to the acid used in Step (ii). The acid used in Step (ii) is preferably a carboxylic acid, such as benzoic acid, maleic acid, succinic acid, fumaric acid, or tartaric acid; or a mineral acid, such as hydrochloric acid. Most preferably, the acid used in Step (ii) is benzoic acid. The salt having Formula (V) is preferably a benzoate salt having Formula (VIII) un The removal of a protecting group is known to those skilled in the art and depends on the type of protecting group. In one embodiment where the protecting group is benzyl, a preferred method of removing the benzyl group on the salt having Formula (V) is by treating che salt with hydrogen in the presence of a catalyst. Preferred catalysts include palladium, palladium hydroxide, palladium on activated carbon, palladium on afumi'na, palladium on carbon powder, platinum, platinum on activated carbon and Raney™ nickel. A combination of catalysts may also be used. Most preferably, the catalyst is palladium on activated carbon, In one embodiment where the protecting group is f-butyldimethylsilyl, a preferred method of removing the t-butyldi methyl si lyl group on the salt having Formula (V) is by treating the salt with i-burylammonium fluoride or potassium fluoride. The solvent used in Step (iv) is preferably selected from an alky} acetate, e.g., Ci-salkyI acetates, such as ethyl acetate, isopropyl acetate and butyl acetate; lower alkyl alkylamines, e.g., Ci-ealkylamines; alcohols, e.g., Ci-salkyl alcohols, such as methanol, ethanol, propanol, butanol and pentanol; aliphatic Ce-^hydrocarbons, e.g., isooctane, heptane, dimethyiform-amide; aromatic hydrocarbons, such as toluene and benzene; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., di/sopropyf ether, 2-methoxyetriyJ ether, and diethylene ether; an acid, e.g., acetic acid, trifluoroacetic acid, and propionic acid; aqueous solvents, such as water; ionic liquids; and chlorinated solvents, such as methylenechloride. A combination of solvents may also be used. More preferably, the solvent is acetic acid or 2-propanol. The temperature used in Step (iv) is preferably from about 0 °C to about 70 °C. More preferably, the temperature is from about 10 "C to about 50 °C; and most preferably from about 10 °C to about 30 *C. The salt having Formula (VI) is preferably 5-((R)-2-(5,6-diethyl-indan-2-yiamino)-l-hydroxy-ethyi]-8-hydroxy-(3H)-quinolin-2-one benzoate. In the fifth step, Step (v), the salt having Formula (VI) is treated with an acid in the presence of a solvent to form a salt having Formula (VII) The solvent used in Seep (v) is preferably selected from an alkyl acetate, e.g., Ci.6alkyl acetates, such as ethyl acetate, isopropyl acetate and butyl acetate; alcohols, e.g., Cmalkyl alcohols, such as methanol, ethanol, propanol, isopropanol, butanol and pentanol; dimethylformamide; aromatic hydrocarbons, such as toluene and benzene; dialkyl ketones, e.g., acetone and methyl isoburyl ketone; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether, 2-methoxyethyl ether and diethylene ether; an acid such as acetic acid and propionic acid; aqueous solvents, such as water; ionic liquids; and chlorinated solvents, such as methylenechloride. A combination of solvents may also be used. More preferably, the solvent is ethanol. The temperature used in Step (v) is preferably from about 0 DC to about 70 °C. More preferably, the temperature is from about 10 DC to about 60 °C; and most preferably from about 20 °C to about 50 °C. As mentioned above, the 8-substituted oxy-5-(R)-oxiranyl-(2H)-quinolin-2-one may be prepared by (a) reacting an S-fsubstiruted oxy)-5-haloacetyH-7H)-qumo!in-2-one with a reducing agent in the presence of a chiral catalyst to form 8-(substituted oxy)-5-((R)-2-halo- l-hydroxy-ethyl)-UH)-quinolin-2-one; and then (b) treating the 8-{substituted oxy)-5-[{R)-2-halo-l-hydroxy-ethyl)-(IH}-quino!in-2-one with a base in the presence of a solvent to form 8-(substituted oxy)-5-(R)-oxiranyl-(IH)-quinolin-2-one. wherein R* and R> are, independently, selected from an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphatic residue. Preferably, R* and Rb are, independently, selected from phenyl, 4-methylphenyl, and 3,5-dimethylphenyl. More preferably, R'and Rfaare phenyl, and Rc is selected from aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphatic residue, which, in each case, may be linked to a polymer. More preferably, Rc is methyl. R», Rb and Rc are preferably unsubstituted but may be substituted, example, by one or more, e.g., two or three, residues, e.g., those selected from C-C7 alkyl, hydroxy, -O-CH2-O-, -CHO, Ci-C? substituted oxy, C2-CB alkanoyl-oxy, halogen, e.g., chlorine or fluorine, nitro, cyano and CF3. Aliphatic hydrocarbon residues include C1-C7 alkyl, C2-C7 alkenyl or secondarily C2-C7 alkynyl. C2-C7 Alkenyl is, in particular, C3-C7 alkenyl and is, e.g., 2-propeny! or 1-, 2- or 3-butenyl. C3-C5 Alkenyl is preferred. C2-C7 Alkynyl is, in particular, C3-C7 alkynyl and is preferably propylnyl. CycloaSiphatic residues include C3-Cscycloalkyl or, secondarily, C3-C8 cycloalkenyl. Cj-Ci cycloalkyl is preferably cyclopenty] or cyclohexyl. C3-C8 Cycloalkenyl is C3-C7 cycloalkenyl is preferably cyclopent-2-en-yl and cyclopent-3-enyl, or cyclohex-2-en-yl and cyclohex-3-en-yl. Cydoalipharic-aliphatic residues include Cj-Cgcycloalkyl-Ci-C? alkyl, preferably Cs-Cgcycloalkyl-Ci-O alkyl, but especially cyclopropylmethyl. The aryl residue may be, for example, a carbocyclic or heterocyclic aromatic residue, in particular, phenyl or, in particular, an appropriate 5- or 6-membered and mono or multicyclic residue which has up to four identical or different hetero atoms, such as nitrogen, oxygen or sulfur atoms, preferably one, two, three or four nitrogen atoms, an oxygen atom or a sulfur atom. Suitable 5-membered heteroaryl residues include monoaza-, diaza-, triaza-, tetraaza-, monooxa- or monothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl and thienyl, while suitable appropriate 6-membered residues are, in particular, pyridyl. Appropriate multicyclic residues are anthracenyl, phenanthryl, benzo[l,3]-dioxole or pyrenyl. An aryl residue may be mono-substituted by, e.g., NHj, OH, SO3H, CHO or di-substituted by OH or CHO and SO3H. Aryl-aliphatic residues include phenyl-Ci-C7 alkyl, phenyl-C^-C? alkenyl and phenyl-C}-C7 alkynyl. Suitable polymers include polystyrene (PS), cross-linked PS (J)i polyethylene glycol (PEG) or a silica gel residue (Si). Examples are NH-Rd, wherein Rd is C(0)(CH2)n-PS or C{0)NH(CH2),rPS; and -0-Si(R The reducing agent that is used to reduce the 8-{substituted oxy)-5-baloacetyl-(3H)-quinoIin-2-one is preferably a borane reagent such as borane-tetrahydrofuran complex, a borane-N,N-diethylamide complex or a borane-methyl sulfide complex. A borane-tetrahydrofuran complex is especially preferred. The oxazaborolidine chiral catalyst is preferably (R)-retr2hydro-l-raerhyl-3,3-diphenyJ-(Ji^,3H)-pyrroJo[l,2-c][l,3,2]-oxazaboro]e, also known as (J?)-2-methyl-CBS-oxazaboro!idine (Me-CBS). Preferably a solvent is used in Step (a). Preferred solvents include: an alkyl acetate, e.g., C« alky! acetates, such as ethyi acetate, isopropyl acetate and butyl acetate; alkylamines, e.g., Ci-salkylamines; lower alkyi alcohols, e.g., C].6 alkyl alcohols, such as methanol, ethanol, propanol, isopropanol, butano], and pentanol; aliphatic C^-u hydrocarbons, e.g., isooctane, heptane; dimethylformamide; aromatic hydrocarbons, such as toluene and benzene; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether, 2-methoxyethyl ether, and diethylene ether; aqueous solvents, such as water; ionic liquids; and chlorinated solvents, such as methylenechloride. A combination of solvents may also be used. The preferred solvent for use in Step (a) is tetrahydrofuran. The temperature used in Step fa) is preferably from about -20 °C to about 80 "C. More preferably, the temperature is from about 0 °C to about 50 "C. The 8-substituted oxy-5-((R)-2-halo-l-hydroxy-ethyl)-{2H)-quinoIin-2-one is preferably 8-phenylmethoxy-5-((i?i-2-chloro-l-hydroxy-ethyl)-(3H)-quinolin-2-one. Optionally, the 8-substituted oxy-5-((£)-2-haIo-l-hydroxy-ethyI)-(lH)-quinolin-2-one product may be purified by any of the various techniques known to the art, such as by crystallization, and may, optionally, be conducted in the presence of charcoal. In the Step (b), the 8-substituted oxy-5-((R)-2-halo-l-hydroxy-ethyl)-(IH)-quinolin-2-one is treated with a base in the presence of a solvent to form 8-subsrituted oxy-5-{i?)-oxJranyl-(JH)-quinolin-2-one. The 8-substituted oxy-5-(i?)-oxiranyl-(IH)-quinolin-2-one has Formula (I): Preferred bases include sodium ethoxide, sodium hydroxide, potassium phosphate, potassium carbonate, potassium hydrogencarbonate and caesium carbonate. A combination of bases may also be used. The base is most preferably potassium carbonate. The solvent used in Step (b) is preferably selected from an alkyl acetate, e.g., Q.$ alkyl acetates, such as ethyl acetate, isopropyl acetate and butyl acetate; alcohols, e.g., C\.t alkyl alcohols, such as methanol, ethanol, propanol, butanol, and pentanol; aliphatic Ce-n hydro¬carbons, e.g., isooctane, heptane; dimethylformamide; aromatic hydrocarbons, such as toluene and benzene; dialkyl ketones, e.g., acetone, methyl isobutyl ketone; acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropy! ether, 2-methoxyethyl ether, and diethylene ether; aqueous solvents, such as water; ionic liquids; and chlorinated solvents such as methylenechloride, A combination of solvents may also be used. A preferred solvent for use in Step (b) is a combination of acetone and water. The temperature used in Step (b) is preferably from about 10 °C to about 160 °C. More preferably, the temperature is from about 30 °C to about 80 DC; and most preferably from about 50 °C to about 60 °C. The 8-substituted oxy-5-(R)-oxiranyl-(IH)-quinolin-2-one is preferably 8-phenlymethoxy-5-(R}-oxirany]-{lI-f)-qmT)olin-2-one. Optionally, the 8-substituted oxy-5-{R)-oxirany}-(7H)-quinolm-2-one product may be purified by any of the various techniques known to the art, such as by crystallization. Crystallization from toluene or acetone is especially preferred, and may, optionally, be conducted in the presence of charcoal. The invention is illustrated by the following Examples. AIL hydrogenation vessel was charged with 40 grams of 8-phenylmethloxy-5-((R)-2-(5,6-diethyNindan-2-ylamino}-l-hydroxy-ethyI]-?tf-quinofin-2-one benzoate and 400 mL of acetic acid. Palladium on charcoal 5% (5.44 g) was added and the reaction mass was hydrogenated for 2-8 hours until complete conversion to 5-[{R}-2-(5,6-diethyI-indan-2-yIamino)-l-hydroxy-erhyl]-8-hydroxy-3//-quinoJin-2-one. The mixture was filtered over a pad of filter-aid. The filtrate was concentrated at 50-60 °C under vacuum (100 mbar) to a volume of 70-90 mL. This residue was dissolved in 400 mL of ethanol and heated to 50-60 °C. A solution of 11.6 g maleic acid in 24 mL ethanol was added and the resulting clear solution was seeded at an internal temperature of 50 °C with a suspension of 350 mg micronised 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-IH-quinolin-2-one in 20 mL isopropanol. The product was crystallized by slow cooling to 0-5 °C. Filtration and washing with 50 mL of ethanol followed by 25 mL of isopropanol provided 65 g crude 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyI]-8-hydroxy-IH-quinolin-2-one maleate which was further purified by crystallization from 1.36 L of ethanol. This gave 24.3 g pure 5-[(R)-2-(5,6-diethyi-indan-2-y!amino)-l-hydroxy-ethyI]-8-hydroxy-lW-quinolin-2-one maleate as a white crystalline powder. Example 3 Purity and Yield of Different Salts of 5-(fR)-2-f5.6-diethyl-indan-2-ylamjno)-l-h.ydroxy-ethyl]-8-substituted oxy-(JH)-quinoiin-2-one A 1 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 30.89 grams of 2-amino-5,6-diethylindan and diethylene glycol dimethyl ether. To this solurion was added 36.4 grams of 8-phenylmerhoxy-5-(R)-oxiranyl-ZH-quinolin-2-one. The resulting suspension was heated to a temperature of 110 °C and stirred at this temperature for 15 hours. The resulting brown solution was cooled to 70 °C. Thus, it has surprisingly been found that (a) the yield of 5-|(R)-2-(5,6-diethyl-indari-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(IH)-quinolin-2-one salt may be significantly increased by forming an acid salt of 5-[(R)-2-(5)6-diethyl-indan-2-y]an]ino)-l-h)'droxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one; and (b) the acid salt can be converted to a salt of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-{IH}-quinolin-2-one without isolating the free base oi 5-[(R)-2-(5,6-diethyl-indan-2-y]amino)-l-hydroxy-erhyl]-8-hydroxy-(IH)-quinolin-2-one. A dry 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser is charged with 50 g 8-(pheny!methoxy)-5-{a-chloroacetyl)-(lH)-quinolin-2-one and 600 mL dry THF under N2. Then 15 mL of a 1 molar solution of (Rj-tetrahydro-l-methyl-S^-diphenyl-tlHJWJ-pyrrololl^-cHl^^l-oxazaborole in toluene was added. The mixture was cooled to an internal temperature of 0-2 °C and while maintaining an internal temperature of 0-2 °C, 153 mL of a 1 moJar solution of BHj in THF was added over 1-2 hours. The reaction was stirred for another hour at an internal temperature of 0-2 °C and then quenched by addition of 65 mL methanol. The resulting solution was warmed to 25 "C and concentrated to a volume of 250 mL (50 °C / 200 mbar). To this concentrate was added a mixture of 713 mL water and 37 g HC1 37%. During the addition 8-(phenylmethoxy)-5-((R)-2-chloro-l-hydroxy-ethyl)-(IH)-quinolin-2-one precipitated as a nearly colourless precipitation. The resulting suspension was stirred for 30 minutes at 25 °C, filtrated and washed with 220 mL water in several portions. Drying in a vacuum drier at 50 °C for 12 hours resulted in 47.41 g of 8-(phenylmethoxy)-5-{(R)-2-chloro-l-hydroxy-ethyl}-(2H)-quinolin-2-one as a slightly yellowish powder. A 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 50 g 8-(phenylmethoxy)-5-((R)-2-chloro-l-hydroxy-ethy\)-(lH)-qumo\m-2-one, 52.42 g potassium carbonate, 2500 mL acetone and 25 mL warer. The mixture was heated under stirring to reflux. Refluxing was maintained for 5-10 hours until an in process control showed complete conversion of 8-phenylmethoxy-5-((/?)-2-chioro-l-hydroxy-ethyl)-(IH)-quinoiUv2-one to 8-phenylmethoxy-5-(R)-oxiranyl-(ZH)-quinolin-2-one. When the reaction was completed, the hot {45-50 C) reaction mixture was filtered to remove the inorganic salts. The residue was washed with several portions of acetone, and the combined mother liquor and acetone washings were concentrated to a volume of 450 mL To the resulting suspension was added 235 mL heptanes at 25 "C and then the suspension was cooled to an internal temperature of 0-2 °C and stirred at this temperature for 2-3 hours. Filtration and washing resulted in a crude 8-pheny!methoxy-5-(J!)-oxiranyl-(Z/f)-quinolin-2-one which was re-crystallized from toluene. This resulted in 36.7 g 8-(phenylmethoxy)-5-(i?)-oxiranyl-(JH)-quinolin-2-one as nearly colourless solid. ]WE CLAIM: 1. A process for preparing 5-[(R)-2-(5.6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-8-hydroxy-(IH)-quinolin-2-one salt or an acceptable solvate thereof comprising: (i) reacting 8-substituted oxy-5-(R)-oxiranyl-(IH)-quinolin-2-one having Formula ds wherein R is a protecting group; (ii) treating the reaction mixture prepared in Step (i) with an acid selected from the group consisting of benzoic acid, maleic acid, succinic acid, fumaric acid, tartaric acid and hydrochloric acid in the presence of a solvent to form a corresponding salt; wherein X' is an anion. 2. The process as claimed in claim 1, wherein the carboxylic acid in Step (ii) is benzoic acid. 3. The process as claimed in claim 1, wherein the carboxylic acid in Step (v) is maleic acid. 5. The process as claimed in any one of the preceding claims, wherein the protecting group is selected from the group consisting of Ci-Ci0alkyl, C6-C,4aryl, Cr Ci0alkoxy, C2-C10alkenyl, C.rC]0cycloalkyl, benzo-CrCi0cyc!oalkyl, C3-Ci0cycloalkylC]-Ci0alkyl, C6-C]oarylC,-C10alkyl, halo-CrC10alkyl, and a silyl group substituted with at least one CrC|0alkyl group. 6. The process as claimed in any one of the preceding claims, wherein the protecting group is benzyl or ;-butyldimethylsilyl. 7. The process as claimed in claim 6, wherein the protecting group on the salt having Formula (V) is benzyl and is removed by treating the salt with hydrogen in the presence of a catalyst. 8. The process as claimed in claim 7, wherein the catalyst is selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, palladium on carbon powder, platinum, platinum on activated carbon, Raney nickel and combinations thereof. 9. The process as claimed in claim 6, wherein the protecting group on the salt having Formula (V) is ?-butyldimethylsilyl and is removed by treating the salt with t-butylammon-ium fluoride or potassium fluoride. 10. The process as claimed in any one of the preceding claims, wherein the temperature in Step (i) is from 10 °C to 160 °C, the temperature in Step (ii) is from -10 °C to 160 °C, the temperature in Step (iii) is from 0 °C to 70 °C, the temperature in Step (iv) is from 0 °C to 70 °C, and the temperature in Step (v) is from 0 °C to 70 °C. 11. The process as claimed in any one of the preceding claims, wherein in Step (i) a molar excess of 2-amino-(5-6-diethyl)-indan is used based on the amount of 8-substituted oxy-5-(R)-oxiran\ l-(7#)-quinolin-2-one. 12. The process as claimed in any one of the preceding claims, wherein the salt having Formula (V) is 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8- phenylmethoxy-( ///)-quinolin-2-one benzoate.

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