FORM 2

1 PROCESS FOR PREPARING ISOMERS OF CARMOTEROL
Technical Field of Invention
The present invention relates to a novel process for the synthesis of R,R-Carmoterol.
Background of the Invention


10 Carmoterol, chemically termed as 8-hydroxy-5-[1-hydroxy{[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl]-2(1H)-quinolinone, is a highly potent (^selective adrenoceptor agonist having a long lasting bronchodilating effect. The structure of carmoterol is as shown below:

15
The asterisks indicate that carmoterol has two chiral centers in the molecule, each of which can exist in two possible configurations (R or S). This gives rise to four possible configurations of carmoterol: (R, R), (S, S), (S, R) and (R, S). Throughout this
20 specification, the first "R" or "S" refers to the configuration of the asymmetric carbon atom at the position of -CH(OH)- and the second "R" or "S" refers to the configuration of the asymmetric carbon atom at the position of -CH(CH3)-. For example, the term "R,S" refers to the diastereomer of carmoterol wherein the asymmetric carbon atom at the position of -CH(OH)- has the R configuration and the asymmetric carbon atom at the position of -
25 CH(CH3)- has the S configuration. (R, R) and (S, S) are mirror images of each other and


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are therefore enantiomers. These two enantiomers are referred to as a-isomers. Similarly, (S, R) and (R, S) are an enantiomeric pair and are referred to as p-isomers.
All four isomers of carmoterol have been synthesized and the (R, R) isomer is reported to 5 be the most potent, while the others are less potent.
Carmoterol and its isomers were first disclosed in the US patent 4,579,854. The process is disclosed in preparation 1 and in examples 2, 3 and 4. The synthetic process employed is depicted in the following Scheme 1. 10
Scheme 1

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5 A similar process is disclosed in example (5) of US 4,579,854, where compound (e) is reacted with optically pure (R)-N-(2-(p-methoxyphenyl)-1-methylethylamine of compound (f) to give a diastereomeric mixture of carmoterol, which diastereomers are then separated by column chromatography to give the R,R and S,S isomers. These isomers are hydrolysed and reduced to give R, R-carmoterol. 10

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The preparation of optically pure (R)-8-benzyloxy-5-oxiranylcarbostyril was disclosed in WO 95/25104 which involves multisteps for the synthesis and it employs the use of an expensive reagent like benzyltrimethylammonium dichloroiodate. The product is isolated using a tedious process. 5
WO 95/25104 also relates to a process for preparing (R)-8-benzyloxy-5-oxyranylcarbostyril, an intermediate of carmoterol, and there is no disclosure of a process for preparing carmoterol itself. A compound of formula (III) of WO95/25104 is reacted with the (R)-8-benzyloxy-5-oxiranylcarbostyril compound (II) to form a protected precursor to a 10 carmoterol derivative. The compound (III) is in the form of a free amine. A disadvantage of the process for preparing the carmoterol derivative is that the use of free amine in excess gives rise to dimeric impurities as well as regioisomers which are difficult to separate.
15 The dimeric impurity of a precursor to carmoterol would have the following structure.


Dimeric impurity

The regiosiomer of carmoterol would have the following structure. 20

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Regio Isomer
A process for preparing an 8-(substituted oxy)-5-(R)-oxiranylcarbostyril oxiranyl compound is disclosed in patent application, WO 2004/076422. The process involves the use of a 5 halo derivative for preparation of the corresponding halohydrin and cyclisation of the halohydrin to obtain the oxiranyl compound. However, there is no example disclosing the use of any halo compound other than the chloro compound.
WO 2004/076422 also relates to a process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-yl-10 amino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one salt or solvate, and there is no disclosure of a process for preparing carmoterol itself. The compound 2-amino-(5,6-diethyl)-indan is reacted with the 8-(substituted oxy)-5-oxiranylcarbostyril compound to form a protected precursor to the indanyl compound. The 2-amino-(5,6-diethyl)-indan compound is in the form of a free amine. A disadvantage of the process for preparing 5-15 [(R)-2-(5,6-diethyl-indan-2-yl-amino)-1 -hydroxy-ethyl]-8-hydroxy-(1 H)-quinolin-2-one salt or solvate is that the use of free amine in excess gives rise to dimeric impurities as well as regioisomers which are difficult to separate.
The processes disclosed in the prior art are cumbersome. Therefore, there exists a need 20 for a more economical and efficient method of making optically pure carmoterol which is suitable for industrial scale up.
The present invention provides a process for synthesis of carmoterol which avoids all the disadvantages associated with prior art.

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Objects of the Invention
The object of the present invention is to provide an improved process for preparing (R,R)-5 carmoterol and its salts.
Another object of the present invention is to provide novel intermediates for the synthesis of (R,R)-carmoterol.
10 Yet another object of the present invention is to provide an improved process for preparing the novel intermediates used in the synthesis of (R,R)-carmoterol.
Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale up. 15
Statements of Invention
comprising condensing the R or S enantiomer of an oxiranyl compound of formula (I) 25
According to a first aspect of the present invention, there is provided a process for preparing the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of a compound of formula (III) 20


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(I)
with the R or S enantiomer of an amine of formula (II) or a salt thereof


wherein: R1 is a group selected from alkyl, aryl, allyl, alkoxy, cycloalkyl, heterocyclic, alkenyl, benzocycloalkyl, aralkyl, haloarylalkyl, heteroaralkyl, haloalkyl, alkoxyaralkyl, and
10 optionally substituted silyl; R2 is (a) optionally substituted silyl, (b) optionally substituted benzyl or (c) hydrogen; when R2 is optionally substituted silyl, either: R2' and R3 are the same as R2; R2' is the same as R2 and R3 is hydrogen; or R2' is hydrogen and R3 is the same as R2; when R2 is optionally substituted benzyl, R2' is hydrogen and R3 is the same as R2; and when R2 is hydrogen, R2' is hydrogen and R3 is hydrogen.
15
Compound (III) is depicted above in the form of the (R,R)- diastereomer.
In an embodiment, the (R.R)-diastereomer of compound (III) is prepared by reacting the R enantiomer of compound (I) with the R enantiomer of compound (II). Alternatively, the 20 (R,S)-diastereomer of compound (III) is prepared by reacting the R enantiomer of compound (I) with the S enantiomer of compound (II). Alternatively, the (S,S)-diastereomer of compound (III) is prepared by reacting the S enantiomer of compound (I) with the S enantiomer of compound (II). Alternatively, the (S,R)-diastereomer of

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compound (III) is prepared by reacting the S enantiomer of compound (I) with the R enantiomer of compound (II).
In an embodiment, Ri is straight chain or branched alkyl, for example, d-Cio alkyl, such 5 as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight- or branched-pentyl, straight- or branched-hexyl, straight- or branched-heptyl, straight- or branched-nonyl or straight- or branched-decyl. Suitably, alkyl is C1-C4 alkyl.
In an embodiment, R1 is C6-CM aryl, preferably C6-C10 aryi. The aryl group may be 10 substituted by at least one group selected from mercapto, dialkylamino, nitro, alkoxy, halogen, keto, cyano or a combination. Preferably aryl is benzyl.
The term "alkoxy" means "alkyloxy", wherein "alkyl" has the same meanings as given above. In an embodiment, R1 is straight chain or branched alkoxy, for example C1-C10 15 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or straight-or branched-pentoxy, -hexyloxy, -heptyloxy, -octyloxy, -nonyloxy or -decyloxy. Suitably, R1 is C1-C4 alkoxy.
In an embodiment, R1 is C3-C10 cycloalkyl having 3-to 8-ring carbon atoms, for example 20 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloheptyl, any of which may be substituted by one, two or more substituents such as C1-C4 alkyl groups, particularly methyl groups. Suitably, R1 is C3-C6 cycloalkyl.
In an embodiment, R1 is a monovalent heterocyclic group having up to 20 carbon atoms 25 and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, the group optionally having an alkyl, alkylcarbonyl, hydroxyalkyl, 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, for example a group, preferably a monocyclic group, with one nitrogen, oxygen or sulfur atom, such as pyrryl, pyridyl, piperidyl, furyl, 30 tetrahydrofuryl or thienyl, or a group, preferably a monocyclic group, with two hetero atoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinyl,

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9 oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholinyl. Suitably, 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 CrC4 alkyl, hydroxy C1-C4 alkyl, C1-C4 alkylcarbonyl or phenyl C1-C4 alkyl.
In an embodiment, fy is straight chain or branched-alkenyl, for example C2-C10 alkenyl, for example vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, or straight- or branched-pentenyl, -hexenyl, -heptenyl, -octenyl, -nonenyl or -decenyl. Suitably, R1 is C2-C4 alkenyl.
10 In an embodiment, R1 is benzocycloalkyl wherein cycloalkyl is as defined above, attached at two adjacent carbon atoms to a benzene ring. Suitably, R1 is benzo-Cs-Ce-cycloalkyl, or benzocyclohexyl (tetrahydronaphthyl).
In an embodiment, R1 is aralkyl meaning arylalkyl, wherein aryl and alkyl have the same 15 meanings as given above, such as straight- or branched- chain C6-C10 aryl-C6-C10 alkyl, for example one of the C1-C10 alkyl groups mentioned above, particularly one of the C1-C4 alkyl groups, substituted by phenyl, tolyl, xylyl or naphthyl. Suitably, aralkyl is phenyl-C1-C4 alkyl, particularly benzyl or 2-phenylethyl.
20 In an embodiment, R1 is haloalkyl wherein alkyl is as defined above substituted by one or more, for example one, two or three, halogen atoms, preferably fluorine or chlorine atoms. Suitably, R1 is C1-C4 alkyl substituted by one, two or three fluorine or chlorine atoms.
In an embodiment, R1 is haloarylalkyl wherein aralkyl is as defined above, substituted by 25 one or more heterocyclic groups as defined above.
In an embodiment, R1 is heteroaralkyl wherein aralkyl is as defined above wherein one, two, three or four carbon atoms are replaced with heteroatoms selected from nitrogen, oxygen and sulfur. 30

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In an embodiment, R1 is alkoxyaralkyl wherein alkoxy and aralkyl have the same definitions as given above.
In an embodiment, R1 is substituted silyl group wherein the silyl group is substituted with at 5 least one alkyl group as defined above.
In an embodiment, the salt of compound (II) is the hydrochloride salt.
In an embodiment, R2 is optionally substituted silyl, R2' is optionally substituted silyl and R3 10 is hydrogen. In an embodiment, R2 and R2' are silyl. Suitably R2 and R2' are trialkylsilyl, wherein alkyl has the same meanings as given above and each alkyl may be the same or different. Suitably, the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl. Alternatively, R2 may be diarylalkyisilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or 15 different. Suitably, the diarylalkyisilyl is t-butyldiphenylsilyl.
In an alternative embodiment, R2 is optionally substituted silyl, R2' is hydrogen and R3 is optionally substituted silyl. In an embodiment, R2 and R3 are silyl. Suitably R2 and R3 are trialkylsilyl, wherein alkyl has the same meanings as given above and each alkyl may be 20 the same or different. Suitably, the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl. Alternatively, R3 may be diarylalkyisilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or different. Suitably, the diarylalkyisilyl is t-butyldiphenylsilyl.
25 In a further embodiment, R2, R2' and R3 are all optionally substituted silyl, preferably silyl. Suitably the silyl is trialkylsilyl, wherein alkyl has the same meanings as given above and each alkyl may be the same or different. Suitably, the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl. Alternatively, the silyl may be diarylalkyisilyl, wherein aryl and alkyl have the same meanings as given above
30 and each aryl may be the same or different. Suitably, the diarylalkyisilyl is t-butyldiphenylsilyl.

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In an alternative embodiment, R2 is benzyl, R2' is hydrogen and R3 is benzyl.
In another embodiment, R2 is hydrogen, R2' is hydrogen and R3 is hydrogen 5
In an embodiment, compounds (I) and (II) are optically pure. Throughout this specification "optically pure" is to mean having an enantiomeric excess greater than 97%. Preferably greater than 98%, most preferably greater than 99%.
10 In an embodiment, the condensation is carried out in the presence of a solvent. The solvent may be an organic solvent, for example the organic solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, toluene, t-amylalcohol, acetonitrile, diglyme, dimethylsulphoxide (DMSO) xylene and hexamethylphosphoramide (HMPA). Alternatively, the condensation may be
15 carried out in the absence of solvent. In this embodiment, the condensation is suitably carried out at a temperature ranging from about 100 to about 140°C.
In an embodiment, the condensation step is carried out below 140°C, suitably below 120°C. 20
In another embodiment, the condensation step is carried out in the presence of a base. The base may be an organic base or an inorganic base. The base may be selected from triethylamine, potassium carbonate, sodium carbonate and diisopropylethylamine.
25 In an embodiment, R2 is silyl and the compound of formula (II) is designated (Ha). It has surprisingly been found that the use of the silylated compound of formula (Ha) minimizes the formation of the dimeric impurity and regioisomer.
The compound of formula (lla) may be obtained by reacting the compound of formula (II)
30 wherein R2 is hydrogen (designated compound (lie)) with a suitable silylating agent. The
silylating agent comprises a silyl group and may comprise a trialkylsilyl group, wherein the

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12 term "trialkylsilyf has the same meaning as given above. Alternatively, the silytating agent may comprise a diarylalkylsilyl group, wherein the term "diarylalkylsilyl". has the same meaning as given above. In an embodiment, the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl and t-butyldimethylsilyl. 5
The compound of formula (lie) can be made by any process known in the art, for example as described in US 4,579,854.
In an embodiment, the compound of formula (Ha) is condensed with the compound of 10 formula (I) wherein Ri is benzyl, optionally at about 110°C, to give the corresponding compound of formula (III).
In another embodiment, R2 is substituted benzyl and the compound of formula (II) is designated (lib). It has surprisingly been found that the use of the benzylated compound
15 of formula (lib) minimizes the formation of the dimeric impurity and regioisomer. The substituent(s) may be selected from the group consisting of: halo, such as fluoro, chloro, bromo, or iodo; alkoxy such as methoxy; and nitro. In an embodiment, R2 is pentafluorobenzyl (i.e. five fluoro substituents). Suitably, there is one halo, alkoxy or nitro group situated at the 4-position (i.e. the para position).
20
In another embodiment, the condensation step is carried out in a solvent, preferably HMPA, which minimizes the formation of the dimeric impurity and regioisomer.
Further, in yet another embodiment, when R-i is not silyl, the reaction is carried out using 25 HMPA solvent preferably at a temperature below 100°C. It has surprisingly been found that these reaction conditions minimize the formation of the dimeric impurity and regioisomer.
The compound of formula (lib) may be synthesized by using methods known in the prior 30 art.

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In an embodiment, compound (I) is prepared by converting a compound of formula (Ig) to the compound (I). The conversion may be according to any process described in this specification.

5 In an embodiment, compound (Ig) is prepared by converting a compound of formula (If) to the compound (Ig). The conversion may be according to any process described in this specification.

In an embodiment, compound (If) is prepared by converting a compound of formula (le) to the compound (If). The conversion may be according to any process described in this specification.

15

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In an embodiment, compound (le) is prepared by converting a compound of formula (Id) to the compound (le). The conversion may be according to any process described in this specification.

In an embodiment, compound (Id) is prepared by converting a compound of formula (Ic) to the compound (Id). The conversion may be according to any process described in this specification.
COCH,

In an embodiment, compound (Ic) is prepared by converting a compound of formula (lb) to the compound (Ic). The conversion may be according to any process described in this specification.
COCH,

In an embodiment, compound (lb) is prepared by converting a compound of formula (la) to the compound (lb). The conversion may be according to any process described in this specification.

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The process of the present invention may further comprise converting the (R,R)-, (S,S)-, (R.S)- or (S,R)~diastereomer of compound of formula (III) to the corresponding (R,R)-, 5 (S,S)-, (R,S)- or (S.R)-diastereomer of carmoterol.
In an embodiment, the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of the compound of formula (III) is hydrolyzed in the presence of an acid to obtain the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of a compound of formula (IV)
10

OMe

(IV)

The acid may be a carboxylic acid, such as benzoic acid, oxalic acid, maleic acid, succinic acid, fumaric acid or tartaric acid; or a mineral acid, such as hydrochloric acid. Other 15 acids include salicylic acid, di-p-toluyl-D-tartaric acid, di-benzoyl-D-tartaric acid, di-pivaloyl-D-tartaric acid, glutamic acid, ethylenediaminetetraacetic acid, mandelic acid, malonic acid, acetic acid, anthranilic acid, nicotinic acid and furoic acid.
The condensation and hydrolyzation steps may be carried out without isolation of the 20 compound (III).

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16 The compound (IV) may be isolated in the form of its acid addition salt as a compound of formula (V)

wherein R1 is as defined above and A- is an anion. The anion corresponds to the acid used in the hydrolysation step. Thus, the anion may be selected from oxalate, fumarate, tartrate, benzoate, salicylate, di-p-toluyl D-tartrate, di-benzoyl D-tartrate, di-pivaloyl D-tartrate, succinate, glutamate, ethylenediaminetetraacetate, maleate, mandelate, 10 malonate, acetate, anthranilate, nicotinate and furcate.
In an embodiment, the compound of formula (IV) or (V) is isolated by crystallization. Suitably, the crystallisation of (V) involves converting the acid addition salt to a different salt, such as the hydrochloride salt. The conversion of the acid addition salt may either 15 involve isolation of the free base or no isolation of the free base.
In a further embodiment, the (R,R)-, (S,S)-, (R,S)- or (S.R)-diastereomer of the compound of formula (IV) or (V) is converted to the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of carmoterol. Suitably, the conversion comprises deprotection of the ORi 20 group using a suitable deprotecting reagent. As is well known to the skilled person, the deprotection reagent depends on the nature of the protecting group.
The hydrolyzation and deprotection steps may be carried out without isolation of the compound (IV) or (V). 25

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17 The condensation, hydrolyzation and deprotection steps may be carried out without isolation of the compounds (III) and (IV) or (V).
When Ri is a benzylic group, the deprotection may comprise hydrogenolysis of the 5 compound of formula (IV) or (V) in the presence of a noble metal catalyst and hydrogen gas.
Alternatively, other deprotecting reagents may be used, such as mineral acids, strong acids, Lewis acids or aqueous mineral bases in a suitable solvent. 10
When Ri is substituted silyl, the deprotection may comprise treating the compound of formula (IV) or (V) with t-butylammonium fluoride or potassium fluoride.
When Ri is arylalkyl or substituted arylalkyl, the deprotection may comprise catalytic 15 reduction using palladium-based or platinum-based catalysts such as palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel.
In an embodiment, the deprotection of compound (IV) or (V) is carried out in the presence 20 of a solvent. The solvent may be selected from an organic solvent such as an alkyl
acetate, lower alkylamines for example C1 to C6 alkylamines, alcohols, aliphatic
hydrocarbons, aromatic hydrocarbons, heterocycles or dialkylethers, an acid, a mixture of
water and a water miscible solvent, ionic liquids, halogenated solvents and mixtures
thereof. 25
In a further embodiment, the R,R-carmoterol base is converted to a pharmaceutically
acceptable salt thereof.
According to another aspect of the present invention, there is provided a process for
30 preparing the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of carmoterol comprising
converting the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of a compound

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of formula (III) to the compound of formula (V) in the presence of an acid having the formula HA,

wherein R1 R2, R2', R3 and A" have the same meanings as given above. The acid may be a carboxylic acid, such as benzoic acid, oxalic acid, maleic acid, succinic acid, fumaric 10 acid or tartaric acid; or a mineral acid, such as hydrochloric acid. Other acids include salicylic acid, di-p-toluyl-D-tartaric acid, di-benzoyl-D-tartaric acid, di-pivaloyl-D-tartaric acid, glutamic acid, ethylenediaminetetraacetic acid, mandelic acid, malonic acid, acetic acid, anthranilic acid, nicotinic acid and furoic acid.
15 In an embodiment, the (R,R)-diastereomer of the compound of formula (III) is converted to (R,R)-carmoterol.
According to another aspect of the present invention, there is provided the R or S enantiomer of a compound of formula (II)
20

wherein R2 is optionally substituted silyl.

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In an embodiment, compound of formula (II) is in the form of the R enantiomer.
In an embodiment, R2 is silyl. In an embodiment, R2 is a trialkylsilyl group, wherein the 5 term "alky!" has the same meaning as given above and each alkyl may be the same or different. In an embodiment, the trialkylsilyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl. Alternatively, R2 may be diarylalkylsilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or different. Suitably, the diarylalkylsilyl is t-butyldiphenylsilyl. 10
According to another aspect of the present invention, there is provided a process for preparing the R or S enantiomer of a compound of formula (II)

15
wherein R2 is optionally substituted silyl, comprising converting (R)-N-(2-{p-methoxyphenyl)-1-methylethyl)amine to the compound of formula (II).
In an embodiment, compound of formula (II) is in the form of the R enantiomer.
20
In an embodiment, R2 is silyl and the conversion comprises reacting (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine with a suitable silylating agent. The silylating agent comprises a silyl group and may comprise a trialkylsilyl group or a diarylalkylsilyl group, wherein the terms "trialkylsilyl" and "diarylalkyl silyl" have the same meanings as given
25 above. In an embodiment, the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl and t-butyldimethylsilyl. The silylating agent may be hexamethyldisilazane (to form compound (II) wherein R2 is trimethylsilyl) or hexaethyldisilazane (to form compound (II) wherein R2 is triethylsilyl).

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The (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine may be made by any process known in the art, for example as described in US 4,579,854.
Alternatively, the (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine may be prepared by 5 resolving 4-methoxyphenylacetone using R-(+)-phenyl ethyl amine in the presence of a first reducing agent to produce (R>-(+)-N-(1-phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine, optionally converting the (R)-(+)-N-(1-phenylethyl)-N-[1-{p-methoxyphenyl)-2-propyl)]amine hydrochloride to a salt such as the hydrochloride salt, followed by converting the (RH+)-N^1-phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine or salt 10 thereof to the (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine in the presence of a second reducing agent.
In an embodiment, the first reducing agent is Raney Nickel and methanol.
15 In an embodiment, the second reducing agent is 10% palladium on carbon and methanol.
25 wherein R-i has the same meanings as given above.
According to another aspect of the present invention, there is provided a process for preparing the R or S enantiomer of a compound of formula (I) comprising subjecting a compound of formula (If) to chiral reduction to form the R or S enantiomer of a compound 20 of formula (Ig) followed by cyclisation to the R or S enantiomer of the compound of formula (I)


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In an embodiment, the R enantiomer of the compound of formula (I) is prepared by subjecting the compound of formula (If) to chiral reduction to form the R enantiomer of the compound of formula (Ig) followed by cyclisation to the R enantiomer of the compound of formula (I). 5
In an embodiment, the S enantiomer of the compound of formula (I) is prepared by subjecting the compound of formula (If) to chiral reduction to form the S enantiomer of the compound of formula (Ig) followed by cyclisation to the S enantiomer of the compound of formula (I).
10
In an embodiment, the bromoacetyl compound (If) is subjected to chiral reduction using a chiral reducing agent selected from the group consisting of (-)-DIP-chloride, p-isopinocamphinyl-9BBN (R-Alpine-Borane), a chiral p-oxoaldiminatocobalt (II) complex and a borane reducing agent, and optionally in the presence of a catalytic amount of a
15 single enantiomer of an oxazaborolidine derived from a chiral oxazaborolidine catalyst.
Suitably, the chiral reducing agent is a chiral p-oxoaldiminatocobalt (II) complex, and the complex is present in an amount of about 1 mo!%.
20 Suitably, the chiral reducing agent is a borane reducing agent, and the borane reducing agent is present in about one equivalent.
In an embodiment, the borane reducing agent is BH3.THF (THF = tetrahydrofuran) or borane-methyl sulfide.
25
In an embodiment, the chiral oxazaborolidine catalyst is selected from the group consisting of cis-(1R, 2S)-aminoindanol, R-diphenyl prolinoi, R-methyl oxazaborolidene (derived from R-diphenyl prolinoi, trimethyiboroxine and methyl boronic acid) and non-a-substituted (R)-indoline-2-carboxylic acid. The oxazaborolidine catalyst may be generated in situ from R-
30 diphenyl prolinoi and diborane.

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The reduction is highly enantioselective (a single isomer is typically formed with an enantiomeric excess greater than 98% ee even when using a low mol% of the catalyst per mole of ketone (If). In an embodiment, the oxazaborolidine catalyst is present in an amount ranging from about 5 to about 10 mol% per mole of ketone (If). 5
In an embodiment, compound of formula (Ig) is treated with at least one equivalent of a base to produce the compound of formula (I). The base may be an organic base or inorganic bases. Suitably, the base may be aqueous NaOH or K2C03. Optionally, the aqueous NaOH or K2CO3 is present in an alcohol solvent or solvent mixture such as 10 MeOH/TH, acetone/THF. Alternatively, the base is piperidine, pyridine or pyrrolidine, preferably piperidine.
In an embodiment, the compound of formula (I) is obtained without isolation of the compound of formula (ig). 15
The compound of formula (I) may be purified by recrystallisation from an inert organic solvent.
In an embodiment, the compound of formula (I) used to prepare the compound of formula 20 (III) as described above is prepared according to the process as described above.
In an embodiment, the compound of formula (If) is prepared by brominating a compound of formula (le) in the presence of a brominating agent

25

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wherein R-\ has the same meanings as given above.
In an embodiment, the brominating agent is N-bromosuccinimide or bromine. The brominating agent may be present in a solvent selected from the group consisting of 5 tetrahydrofuran, methylene chloride, chloroform, methanol, carbon tetrachloride, or a mixture thereof; preferably dichloromethane.
According to another aspect of the present invention, there is provided a process for preparing a compound of formula (le) comprising heating a compound of formula (Id) in 10 the presence of a reagent

15
wherein Ri has the same meanings as given above and the reagent is present in a volume ranging from about 1.5 volumes to about 5 volumes.
A "volume" refers to the volume of the solvent (in ml) used per gram of the compound 20 being dissolved.
In US 4,579,854 (column 21, preparation 1), 5 grams of 5-acetyl-8-benzyloxyquinoline is used to produce 5 acetyl-8-benzyloxyquinoline-N-oxide. Theoretically, 5 grams of 5-acetyl-8-benzyloxyquinoline (compound (Ic) wherein Ri is benzyl) will yield 5.27 grams of 25 5 acetyl-8-benzyloxyquinoline-N-oxide (compound (Id) wherein Ri is benzyl). The 5 acetyl-8-benzyloxyquinoline-N-oxide is stirred in 60 ml acetic anhydride. This corresponds to

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11.3 volumes of acetic anhydride. It has surprisingly been found that a smaller number of volumes of reagent can be used in the process of the present invention. For example, 10 grams of 5-Acetyl-8-benzyloxycarbostyril are dissolved in 20ml of acetic anhydride, i.e. 2 volumes of acetic anhydride. This avoids the handling of a large quantity of solvent. The 5 work up procedure required is simplified to give the product in high purity and it also minimizes the formation of impurities which are formed when the work up procedure given in the prior art is employed.
In an embodiment, the reagent is present in a volume ranging from about 1.5 volumes to 10 about 3 volumes,, preferably 2 volumes.
In an embodiment, the reagent is an anhydride, suitably acetic anhydride or trifluoroacetic anhydride, preferably acetic anhydride. Most preferably, the reagent is acetic anhydride present in about 2 volumes. 15
In an embodiment, the compound of formula (le) used to prepare the compound of formula (If) as described above is prepared according to the process described above.
wherein R1 has the same meanings as given above
According to another aspect of the present invention, there is a provided a process for 20 preparing a compound of formula (Id) comprising oxidising a compound of formula (Ic) in the presence of an oxidizing agent and a solvent selected from dichloromethane, ethyl acetate or a mixture thereof


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In an embodiment, the oxidizing agent is selected from the group consisting of: peracids such as peroxybenzoic acid, m-chloroperbenzoic acid, peracetic acid, peroxytrifluoroacetic acid, peroxysulfuric acid, perboric acid, performic acid, peroxymaleic acid and 5 peroxydichloromaleic acid (for example, prepared from hydrogen peroxide and dichloromaleic anhydride); tert-butyl hydroperoxide in the presence of a vanadium catalyst; dimethyl dioxirane; selenium dioxide; m-phenanthroline di-N-oxide (for example prepared from H202 and m-phenanthroline); nitric acid and hydrogen peroxide. Preferably, the oxidizing agent is m-chloroperoxybenzoic acid. 10
In US 4,579,854, chloroform is used as solvent and the reaction time is 95.5 hours. It has surprisingly been found that the use of dichloromethane, ethyl acetate or a mixture thereof as solvent drastically reduces the reaction time, for example to around 5 hours.
15 In an embodiment, the process for preparing compound (Id) is carried put for a period of time less than 10 hours, preferably less than 8 hours, more preferably less than 6 hours.
In an embodiment, the compound of formula (Id) used to prepare the compound of formula (le) as described above is prepared according to the process described above. 20
According to another aspect of the present invention, there is a provided a process for preparing a compound of formula (Ic) comprising reacting a compound of formula (lb) with a protecting group in the presence of a low boiling point solvent


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wherein R1 has the same meanings as given above.
The low boiling solvent may have a boiling point below 70°C, , preferably below 60°C. In an embodiment, the solvent is acetone. 5
Suitable protecting groups for hydroxy groups are well known to those skilled in the art and include a compound comprising a group selected from lower alkanoyl for example a Ci to C6 alkanoyl, substituted or unsubstituted benzyl and substituted or unsubstituted phenyl. Preferably, the protecting agent is benzyl bromide and this results in the work up 10 procedure being simplified by distillation, avoiding any extraction procedure.
In US 4,579,854, benzyl chloride is used as the protecting reagent, and this necessitates that the reaction mass be extracted in ethyl acetate (see US 4,579,854, column 20, preparation 1). Furthermore, the prior art reaction is carried out using a high boiling 15 solvent such as DMF. The process of the present invention uses a low boiling solvent, such as acetone. This also results in the work up procedure being simplified by distillation, avoiding any extraction procedure.
In an embodiment, the compound of formula (Ic) used to prepare the compound of formula 20 (Id) as described above is prepared according to the process described above.
According to another aspect of the present invention, there is a provided a process for preparing a compound of formula (lb) comprising acylating a compound of formula (la) with an acylating agent and an acid catalyst in the presence of a low boiling point solvent 25


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The low boiling solvent may have a boiling point below 90°C, preferably below 80°C. The solvent used is preferably selected from a halogenated solvent, carbon disulfide and mixtures thereof, preferably dichloroethane. The solvent used for the above process of 5 invention is advantageous over solvents used in the prior art (for example, Journal of American Chemical Society 1930, Vol 52, pp 4433-4436, which uses nitrobenzene) in that the latter are high-boiling point, hazardous solvents that require steam distillation to be removed, in order to isolate the product. The product of the process of the present invention is easily isolated, for example by quenching the reaction mass in water and 10 optionally converting the product to base.
In an embodiment, the acylating agent is a haloacetyl compound, wherein halo is chloro, bromo, iodo or fluoro, preferably chloro.
15 In an embodiment, the acid catalyst is a Lewis acid catalyst, for example boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride or zinc chloride.
In an embodiment, the compound of formula (lb) used to prepare the compound of formula (Ic) as described above is prepared according to the process described above.
20
According to another aspect of the present invention, there is provided (R,R)-carmoterol prepared according to the process described above. The intermediates (lb) to (lg), (I), (II), (IV) and (V) prepared according to the processes described above also form further aspects of the present invention.
25
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising (R.R)-carmoterol as described above together with one or more pharmaceuticaly acceptable excipients.
30 According to yet another aspect of the present invention, there is provided the use of (R,R)-carmoterol as described above in medicine.

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According to a still further aspect of the present invention, there is provided the use of (R,R)-carmoterol as described above in the treatment of asthma or chronic obstructive pulmonary disease (COPD). A study, conducted over an 8-day treatment period, has 5 shown that carmoterol provides significant improvements in lung function.
According to a still further aspect of the present invention, there is provided the use of (R,R)-carmoterol as described above in the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD). 10
According to another aspect of the present invention, there is provided a method of treating asthma and chronic obstructive pulmonary disease (COPD) comprising administering to a patient in need thereof (R,R)-carmoterol as described above.
15 Detailed Description of the Invention
The present invention provides an improved process for the synthesis of optically pure carmoterol, more particularly (R,R) and (S,S)-carmoterol.


20

In its broadest aspect, the invention relates to a process for preparing compound (III) (a precursor to carmoterol) or a salt thereof, which comprises the steps of:
25 (i) condensing an optically pure oxiranyl compound of formula (I)

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(I)
wherein R1 = alkyl, aryl, allyl, alkoxy, cycloalkyi, heterocyclic, alkenyl, benzocycloalkyi, aralkyi, haloarylalkyi, heteroaralkyl, haloalkyi, aralkyi, alkoxyaralkyl, substituted benzyl, substituted silyl group; with an optically pure amine of formula (II)

10

15

wherein a - R2 = optionally substituted silyl group or b - R2 = optionally substituted benzyl group or c - R2 = hydrogen;
to obtain a compound of formula (III) which can be optionally isolated.

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When R2 is optionally substituted silyl, either R2' and R3 are the same as R2; R2' is the same as R2 and R3 is hydrogen; or R2' is hydrogen and R3 is the same as R2; when R2 is optionally substituted benzyl, R2' is hydrogen and R3 is the same as R2; and when R2 is hydrogen, R2' is hydrogen and R3 is hydrogen. 5
Typically, the compound of formula (I) is condensed with the compound of formula (II) in a solvent such as methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, toluene, t-amyialcohol, acetonitrile, diglyme, dimethylsulphoxide (DMSO) xylene or HMPA below 140°C. This reaction can be optionally carried out in the absence 10 of solvent at a temperature ranging from about 100 to about 140°C, to give an optically pure compound (III). Further, this reaction can also be carried out optionally in the presence of, either organic or inorganic base, such as triethylamine, potassium carbonate, sodium carbonate, diisopropylethyiamine to accelerate the reaction.
15 More particularly, the compound of formula (Ha) wherein R2 is silyl, may be condensed with the compound of formula (I) wherein R-\ is benzyl at about 110°C, to give the corresponding compound of formula (III) in a substantially pure form. Use of the silylated compound of formula (Ha) minimizes the formation of the dimeric impurity and regio isomer, this forms another aspect of the present invention. The compound of formula (lla)
20 can be obtained by reacting the compound of formula (lie) with a suitable silylating agent. The suitable silylating agent used to protect the amine functionality may comprise a group selected from trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, etc. The compound of formula (He) can be made by any process known in the art.
25 The process of the present invention may further comprise (ii) hydrolyzing the compound of formula (III) with an acid to obtain a compound of formula (IV)

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Steps (i) and (ii) may be carried out without isolation of the compound (III).
5 The compound (IV) may be isolated in the form of its acid addition salt of compound of formula (V).

10 wherein R1 is as defined above and A~ is an anion. The anion corresponds to the acid. The acid optionally used in step (ii) is preferably a carboxylic acid, such as benzoic acid, oxalic acid, maleic acid, succinic acid, fumaric acid or tartaric acid; or a mineral acid, such as hydrochloric acid.
15 The compound of formula (IV) or (V) may be isolated by crystallization. Crystallization helps in eliminating the impurities associated with the reaction, as it reduces the amount of regioisomer formed during the condensation step. The acid addition salt may be converted to a different salt, such as the hydrochloride salt. The conversion of the acid addition salt may either involve isolation of the free base or no isolation of the free base. This
20 conversion further reduces dimeric and regio isomeric impurities below the detection limit.

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32 The process of the present invention may further comprise (iii) deprotection. of the OR1 group under suitable deprotecting conditions. As is well known to the skilled person, the deprotection conditions depend on the nature of the protecting group. For example, the deprotection may involve hydrogenolysis of the compound of formula (V) in the presence 5 of a noble metal catalyst and hydrogen gas or using a phase transfer hydrogenation, to obtain optically pure R,R-carmoterol base. Alternatively other deprotecting reagents may be used, such as mineral acids, strong acids, Lewis acids or aqueous mineral bases in a suitable solvent.
10 When R1 is substituted silyl, a preferred method for deprotection is by treating the compound of formula (V) with t-butylammonium fluoride or potassium fluoride.
When R1 is arylalkyl or substituted arylalkyl, a preferred method for deprotection is catalytic reduction using catalysts such as palladium, palladium hydroxide, palladium on 15 activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel.
The solvent used in step (iii) is preferably selected from an alkyl acetate, lower alkylamines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles, 20 dialkylethers, an acid, mixture of water and water miscible solvents, ionic liquids, halogenated solvents and mixtures thereof.
The process of the present invention may further comprise: (iv) converting R,R-carmoterol base to a pharmaceutically acceptable salt thereof. 25
Alternatively, (R,R)-carmoterol may be synthesized by reacting a compound of formula (lib), wherein R2 is substituted benzyl, with a compound of formula (I), followed by debenzylation.
30 The compound of formula (Mb) may be synthesized by using methods known in the prior art.

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The compound of formula (I) may be prepared from a bromoacetyl compound of formula (If) as shown in Scheme 2.

wherein the bromoacetyl compound is subjected to chiral reduction using chiral reducing agents such as (-)-DIP-chloride, p-isopinocamphinyl-9BBN (R-Alpine-Borane). The
10 reduction may be carried out in the presence of 1 mol% of chiral (3-oxoaldiminatocobalt (II) complexes or in about one equivalent of a borane reducing agent such as BH3.THF (THF = tetrahydrofuran) or borane-methyl sulfide, and optionally in the.presence of a catalytic amount of a single enantiomer of an oxazaborolidine derived from chiral oxazaborolidine catalyst, to obtain a compound of formula (Ig).
15
Examples of chiral oxazaborolidine catalysts are cis-(1R, 2S)-aminoindanol, R-diphenyl prolinol, R-methyl oxazaborolidene (derived from R-diphenyl prolinol, trimethylboroxine and methyl boronic acid), non-a-sustituted (R)-indoline-2-carboxyiic acid, etc.
20 Further, the optically pure halohydrin of formula (Ig) may be treated with at least one equivalent of a base to produce an optically pure epoxide of formula (I) without racemization. Various organic and inorganic bases such as aqueous NaOH or K2CO3 may be employed in an alcohol solvent or solvent mixture such as MeOH/TH, acetone/THF.
25 In the process of the present invention, the epoxide of formula (I) may be obtained without isolation of the bromohydrin of formula (Ig), preferably in the presence of a base such as

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piperidine, pyridine or pyrrolidine. The epoxide obtained may be purified by recrystallisation from an inert organic solvent.
The catalyst optionally used for the preparation of (Ig), for example the single enantiomer 5 of an oxazaborolidine, may be generated in situ from R-diphenyl prolinol and diborane.
The intermediate compound of formula (If) useful in the synthesis of an oxiranyl compound of formula (I) may be prepared as shown in Scheme 3.

wherein, compound (la) i.e. 8-hydroxy quinoline, may be acylated with a haloacetyi 15 compound using a suitable Lewis acid catalyst in the presence of a suitable solvent to obtain the corresponding 5-acetyl compound of formula (lb).
The Lewis acid catalyst used may be selected from boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride. 20
The solvent used is preferably selected from a halogenated solvent, carbon disulfide and mixtures thereof, preferably dichloroethane.

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In compound (lb), the hydroxyl group may be protected using a wide variety of protecting groups such as lower alkanoyl for example a C1 to C6 alkanoyl, substituted or unsubstituted benzyl and substituted or unsubstituted phenyl to give compound (Ic). In the 5 process of the present invention, benzyl bromide is a preferred reagent for protection of the hydroxy group and this results in the work up procedure being simplified by distillation, avoiding any extraction procedure.
The compound of formula (Ic) may be oxidized to the corresponding N-oxide of formula 10 (Id) by an oxidizing agent. Suitable oxidizing agents are peracids such as peroxybenzoic acid, m-chloroperbenzoic acid, peracetic acid, peroxytrifluoroacetic acid, peroxysulfuric acid, perboric acid, performic acid, peroxymaleic acid, peroxydichloromaleic acid (for example, prepared from hydrogen peroxide and dichloromaleic anhydride), tert-butyl hydroperoxide in the presence of vanadium catalyst, dimethyl dioxirane, selenium dioxide, 15 m-phenanthroline di-N-oxide (for example prepared from H202 and m-phenanthroline), nitric acid and hydrogen peroxide.
Solvents used for the process are selected from dioxane, tetrahydrofuran, diethyl ether, methanol, tert-butanol, acetic acid, sulfuric acid, water, trifluoroacetic acid, chloroform and 20 mixtures thereof. Preferably the reaction is carried out in dichloromethane, ethyl acetate or mixture thereof.
The compound (Id) may be heated in reagents such as anhydrides including acetic anhydride and trifluoroacetic anhydride, preferably acetic anhydride, to obtain the 25 compound of formula (le). The reaction may be carried out with the reagent being present in a reduced volume, for example in 2 volumes of acetic anhydride. The compound (le) may be isolated by crystallization using substantially low volumes of a suitable solvent such as acetic anhydride.
30 The compound of formula (le) may be brominated to obtain a bromoketone of formula (If) using a brominating agent such as N-bromosuccinimide or bromine in a solvent selected

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from the group consisting of tetrahydrofuran, methylene chloride, chloroform, methanol, carbon tetrachloride, or a mixture thereof; preferably dichloromethane.
The other diastereomers of carmoterol may be prepared by reacting the appropriate 5 epoxide (I) and amine (II) following the synthetic protocol given above for (R,R)-carmoterol. Thus, the compound of formula (I) (which is depicted in the form of the R enantiomer) may be synthesised in the form of the S enantiomer and reacted with the compound of formula (I) (which is depicted in the form of the R enantiomer) in accordance with the process described above to prepare the (S, R) diastereomer of compound (III) 10 followed by conversion to the (S, R) diastereomer of compound (IV) or (V) in accordance with the process described above, then converted to (S, R)-carmoterol in accordance with the process described above.
Alternatively, the compound of formula (II) may be synthesised in the form of the S 15 enantiomer and reacted with the compound of formula (I) in accordance with the process described above to prepare the (R,S) diastereomer of compound (III) followed by conversion to the (R,S) diastereomer of compound (IV) or (V) in accordance with the process described above, then converted to (R,S)-carmoterol in accordance with the process described above. 20
Alternatively, the compound of formula (II) may be synthesised in the form of the S enantiomer and the compound of formula (I) may be synthesised in the form of the S enantiomer, and the two S enantiomers reacted in accordance with the process described above to prepare the (S,S) diastereomer of compound (III) followed by conversion to the 25 (S,S) diastereomer of compound (IV) or (V) in accordance with the process described above, then converted to (S,S)-carmoterol in accordance with the process described above.
The details of the invention given in the examples which are provided below for illustration 30 only and therefore these examples should not be construed to limit the scope of the invention.

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Example 1
Preparation of 5-acetyl-8-hydroxyquinoline (compound (lb))
5 8-hydroxyquinoline (500gms/3.44moles) was dissolved in ethylene chloride (Slits) at 25-30°C in an inert atmosphere. To this solution was added acetyl chloride (260 ml/4.12 moles) drop wise in 2 hours. The reaction mass was stirred for 15-20 minutes. Then aluminium chloride (1.15 Kg/ 8.62 moles) was added in lots in 2 hours. The reaction mass was stirred at 25-30°C for 15-20 minutes and heated to 70°C for 13-14 hours. After
10 completion of reaction, the reaction mass was cooled to 25-30°C and slowly quenched in a mixture of crushed ice (10 Kg) and cone. HCI (500 ml). The resulting slurry was stirred for 15-20 minutes. The crude 5-acetyl-8-hydroxyquinoline hydrochloride was isolated by filtration, washed with 2 liters of acetone and dried under vacuum for 1 hour. Yield: 680 gms.
15
A 20 liter round bottom flask was charged with wet cake (680 gms) and water (5 liters). The mixture was basified using liquor ammonia (300 ml) and stirred for 15-20 minutes. The resulting slurry was extracted with dichioromethane (3.5 liters) twice. The solution was stirred with charcoal (40 gms) and silica gel (500 gms) for 15 hours. The reaction mass
20 was filtered on hyflo bed and washed with dichioromethane (2 liters). The clear solution was distilled under vacuum at 40°C. The residue was stripped with diisopropyl ether (500 ml) to remove traces of dichioromethane. Residue was charged with diisopropyl ether (1 liter) and stirred. The reaction mass was warmed to 30-40°C, cooled slowly to 25-30°C, chilled to 0-5°C and stirred for 30 minutes at the same temperature. The resulting 5-acetyl-
25 8-hydroxyquinoline was isolated by filtration, washed with diisopropyl ether (500 ml) and dried under vacuum at 60-65°C for 5-6 hours. Yield: 252 gms.
Example 2
Preparation of 5-acetyl-8-benzyloxyquinoline (compound (Ic); R1 = benzyl)

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A 5 liter 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 5-acetyl-8-hydroxyquinoline (300 gms/1.44 moles) and acetone (3 liters). To this solution was added anhydrous potassium carbonate (443 gms/1.6 moles) in 30 minutes followed by benzyl bromide (229 ml/1.92 moles) slowly 5 in 90 minutes. The resulting slurry was heated to reflux for 12 hours. The reaction mass was filtered through hyflo bed, after completion of reaction and washed with hot ethyl acetate (300 ml). The clear filtrate was distilled out completely at 55-60°C under high vacuum. The residue was dissolved in acetone (300ml) and warmed to 50°C for 5-10 minutes, cooled to 25-30°C, chilled further to 0-5°C and stirred for 30 minutes. The 10 resulting 5-Acetyl-8-benzyloxyquinoline was isolated by filtration and washed with 1:1 mixture of acetone and diisopropyl ether (150 ml) and dried under vacuum at 60-65°Cfor 4-5 hours. Yield-202 gms
Example 3 15 Preparation of 5-Acetyl-8-benzyloxyquinoline-N-oxide (compound (Id); R1 = benzyl)
5-Acetyl-8-benzyloxyquinoline (200 gms/0.72 moles) was dissolved in dichloromethane (4 liters) at room temperature. To this solution was added m-chloroperoxybenzoic acid (355.64 gms/1.44 moles) in 90 minutes under stirring. The mixture was stirred at 25-30°C
20 for 2 hours. After completion of reaction, reaction mass was quenched with 8% sodium bicarbonate solution ( 3.04 liter) slowly in 30 minutes and stirred for 5-10 minutes at same temperature. The organic layer was separated and aqueous layer was extracted with dichloromethane (2.5 liters). The organic layers were combined and washed with brine solution (2.5 liters). The dichloromethane was distilled out under vacuum at 40°C. The
25 residue was stripped with acetone (500 ml) to remove traces of dichloromethane. The residue was stirred with acetone (200ml) and chilled to 0-5°C for 2 hours. The resulting 5-Acetyl-8-benzyloxyquinoline-N-oxide was isolated by filtration and washed with diethyl ether (200 ml), dried under vacuum at 60-65°Cfor 2-3 hours. Yield-116 gms
30 Example 4
Preparation of 5-Acetyl-8-benzyloxycarbostyril (compound (le); R1 = benzyl)

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5-Acetyl-8-benzyloxyquinoline-N-oxide (10gms/0.034 moles) was charged in acetic anhydride (20 ml) at 25-30°C. The resulting slurry was heated to 40°C and stirred for 2 hours at 40°C. After completion of reaction, the reaction mass was cooled to 25-30°C, 5 chilled to 0-5°C and stirred for 30 minutes at 0-5°C. The resulting 5-Acetyl-8-benzyloxycarbostyril was isolated by filtration and washed with diisopropyl ether (50 ml), dried under vacuum at 60-65°Cfor 2-3 hours. Yield- 7gms
Example 5 10 Preparation of 5-Bromoacetyl-8-benzyloxycarbostyril (compound (If); R, = benzyl)
A dry 3 liter, 4-necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 5-Acetyl-8-benzyloxycarbostyril (50 gms/0.17 moles) and dry dichloromethane (lliter) under argon.
15 To this solution was added boron trifluoride etharate (25.7ml/0.204moles). The reaction mass was heated to reflux. To this reaction mass was added slowly solution of bromine (8.4 ml/0.17 moles) in dichloromethane (100 ml) at reflux in 4 hours. The mixture was refluxed for additional 30 minutes. The mass was cooled to 30°C and adjusted to pH 8-9 using 10%.aqueous potassium carbonate solution (470 ml).
20
The solvent was partially distilled under vacuum at 35°C, chilled to 0-5°C and stirred for 10-15 minutes. The resulting crude 5-Bromoacetyl-8-benzyloxycarbostyril was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-55°C for 14 hours. Yield 56.58 gms
25
Purification of crude 5-Bromoacetvl-8-benzvloxvcarbostvril (compound (If); Ri = benzyl) The crude 5-Bromoacetyl-8-benzyloxycarbostyril (56gms) was charged along with chloroform (280 ml) in a round bottom flask. The reaction mass was heated to reflux for 30 minutes, cooled to 25-30°C in 2-3 hours. The reaction mass was further chilled to 0-5°C
30 and stirred for 30 minutes. The resulting solid was isolated by filtration, washed with

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40 chloroform (55ml) and dried under vacuum at 55-60°C for 4-5 hours to yield 41 gms of 5-Bromoacetyl-8-benzyloxycarbostyril.
Example 6 5 Preparation of 8-benzyloxy-5-[(R)-(2-bromo-1-hydroxyethyl)J-carbostyril (compound (Ig); R1 = benzyl)
A dry 5 liter flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 5-Bromoacetyl-8-benzyloxycarbostyril (100 gms/
10 0.268 moles) and dry THF (1.2 liter) under argon. A solution of (R>tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazoborolidine catalyst in toluene (43 ml/ 0.388 moles) was added and reaction mass was chilled to 0-2°C. Then 1M solution of borane-methyl sulfide (32.42 ml/ 0.3417 moles) in THF (342ml) was added in 3 hours while maintaining temperature at 0-2°C. The reaction was stirred for another 15-20 minutes at
15 same temperature. The reaction mass was quenched by addition of methanol (171 ml) in 15-20 minutes . The temperature of resulting solution was raised to 25-30°C and concentrated to a volumes of 500 ml under vacuum at 50°C. To this concentrate was added a mixture of water (1.45 liters) and concentrated HCI (74 ml) in 10-15 minutes. The resulting suspension was stirred for 30 minutes at 25°C. The solid 8-benzyloxy- 5-[( R )-(2-
20 bromo-1-hydroxyethyl)]- carbostyril obtained was isolated by filtration and washed with water till neutral pH, dried under vacuum at 60-65 °C for 12-14 hours. Yield- 70-73 gms
Example 7
Preparation of 8-benzyloxy-5-(R)-oxiranylcarbostyril (compound (I); Ri = benzyl)
25
A 5 liter flask equipped with a mechanical stirrer, thermometer, and refluxing condenser was charged with 8-benzyloxy-5-[(R)-(2-bromo-1-hydroxyethyl)]-carbostyril (70gms/0.187 moles), potassium carbonate (74 gms/ 0.536 moles), acetone (3.5 liters) and water (35 ml). The resulting slurry was heated to reflux and maintained for 21/2 hours. After
30 completion of reaction, the hot mass was filtered on hylo bed to remove inorganics. The residue was slurried in dichloromethane (200 ml) and filtered on hyflo bed. The filtrates

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were combined together and concentrated under vacuum completely. The residue was dissolved in dichloromethane (500ml) and filtered on hyflo bed to remove traces of insolubles and washed with dichloromethane(100 ml). The clear filtrate was distilled completely to obtain residue. The residue was charged with methanol (70 ml), stirred and 5 heated to 50DC for 30 minutes. The slurry obtained was cooled to 25-30eC, chilled to 0-5°C, stirred for 1 hour. The resulting solid was isolated by filtration, washed with methanol (30ml), followed by diisopropylether (100ml) and dried under vacuum at 60-65 °C for 10-12 hours to yield 40-41 gms of 8-benzyloxy- 5-( R )-oxiranylcarbostyril.
10 Example 8
Preparation of 8-benzyloxy-5-(R)-oxiranylcarbostyril from 5-Bromoacetyl-8-benzyloxycarbostyril (compound (I); Ri = benzyl)
A dry 250 ml flask equipped with a mechanical stirrer, thermometer, addition funnel and
15 refluxing condenser was charged with of 5-Bromoacetyl-8-benzyloxycarbostyril (5gms/ 0.0134 moles) along with dry THF (60ml) under argon. A solution of (R)-tetrahydro-l-methyl-3,3-diphenyl-(1 H, 3H )-pyrrolo[1,2-c][1,3,2]-oxazoborolidine catalyst (2.15 ml/ 0.002 moles) in toluene was added and reaction mass was cooled to 0-2°C. Then, 1 molar solution of boron dimethyl sulfide (1.62 ml/ 0.017 moles) in THF (17ml) was added in 45
20 minutes while maintaining temperature of 0-2°C. The reaction was stirred further for 1 hour at same temperature and then quenched by adding solution of piperidine (8.5ml/0.0861 moles) in water (80 ml) in 30 minutes. The reaction mass was stirred at 0-2 °C for 30 minutes. After completion of reaction, reaction mass was brought to 20-22°C and extracted with dichloromethane (50ml) thrice. The combined dichloromethane extracts
25 were washed with water (100 ml) thrice. The organic layer was distilled out completely under vacuum at 30°C. To the resulting residue was added methanol (12ml), and warmed to 50°C for 5-10 minutes. The slurry obtained was cooled to 25-30°Cand stirred for 30 minutes. The resulting 8-benzylOxy- 5-(R)-oxiranylcarbostyril was isolated by filtration and washed with methanol (10ml), followed by diisopropylether (30 ml), dried under vacuum at
30 60-65 °C for 10-12 hours. Yield-1.2 gms

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42 Example 9
Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril oxalate (oxalate salt of compound (IV); Ri = benzyl) 5
(Step-D- Preparation of (R)-N-trimethylsilyl[2-(p-methoxyphenvl)-1-methvlethvl)1amine (compound (II): Rg = trimethylsilvl)
(R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride (22.6 gms/ 0.112 moles) 10 was dissolved in dichioromethane (226 ml), water (452 ml ) and basified with liquor ammonia (22 ml). The organic layer was separated, dried on sodium sulfate and concentrated under vacuum at 30°C. The residue obtained was dissolved in diglyme (60 ml) under argon. Then added hexamethyldisilazane (25.6 ml /0.121 moles) at 25°C. The reaction mass was heated to 110°C for 1 hour and cooled to 30°C to get a clear solution. 15
(a) Preparation of 8-benzvloxv-5-{((1RH-hvdroxv-2-fN-(1R)-2-(p-methoxvphenvl)-1-methvlethvDaminolethvDcarbostvril oxalate (compound (V): R^ = benzyl; A" = oxalate)
A dry 250 ml flask equipped with a mechanical stirrer, thermometer, addition funnel and 20 refluxing condenser was charged with of 8-benzyloxy-5-(R)-oxiranylcarbostyril (30 gms/0.102 moles) and diglyme (60 ml) under argon. The reaction mass was heated to 100°C and charged with solution prepared in Step-1, slowly in 5 hours. The clear solution obtained was further heated at 100°C for 25 hours. After completion of reaction, reaction mass was cooled to 80°C. Then solution of oxalic acid dihydrate (25.6 gms / 0.203 moles) 25 in ethanol (150 ml) charged to reaction mass at 80°C slowly. The reaction mass was stirred for 30 minutes at 80°C, cooled to 25°C gradually and stirred for 16 hours, The resulting solid was isolated by filtration, washed with ethanol (100 ml), and dried under vacuum at 60-65 °C for 10-12 hours to yield 50 gms of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxypheny!)-1 -methyl ethyl)amino]ethyl}carbostyril oxalate.

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Similarly, using the procedure described in Example 9a, the following compounds were prepared.
(b) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
5 amino]ethyl}carbostyril fumarate.
(c) 8-benzyloxy-5-{((1 R)-1 -hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
amino]ethyl}carbostyril tartrate
10 (d) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-{1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril benzoate
(e) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
amino]ethyl}carbostyril salicylate
15
(f) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-{1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril di-p-toluyl D-tartrate
(g) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
20 amino]ethyl}carbostyril di-benzoyl D-tartrate
(h) 8-benzyloxy-5-{((1 R)-1 -hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
amino]ethyl}carbostyril di-pivaloyl D-tartrate
25 (i) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
amino]ethyl}carbostyril succinate
(j) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril glutamate

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(k) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril ethylenediaminetetraacetate
(I) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-{1 R)-2-(p-methoxyphenyl)-1-methylethyl
5 amino]ethyl}carbostyril maleate
(m) 8-benzyloxy-5r{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril mandelate
10 (n) 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril malonate
(o) 8-benzyloxy-5-{(( 1 R)-1 -hydroxy-2-[N-( 1 R)-2-(p-methoxyphenyl)-1 -methylethyl
aminojethyljcarbostyril acetate 15 '
(p) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril anthranilate
(q) 8-benzyloxy-5-{({1 R)-1 -hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl
20 amino]ethyl}carbostyril maliate
(r) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril nicotinate
25 (s) 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl
amino]ethyl}carbostyril furoate
Example 10
Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-tN-(TR)-2-(p-methoxyphenyl)-1-30 methylethyl)amino]ethyl}carbostyril oxalate (compound (V); R1 = benzyl, A" = oxalate)

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(Step-1)- Preparation of (+HRVN-r2-(p-methoxyphenyl)-1-methylethyiyiamine
(R)-N- [2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride (22.6 gms/ 0.112 moles) 5 was dissolved in dichloromethane (226 ml), water (452 ml ) and basified with liquor ammonia (22 ml). The organic layer was separated, dried on sodium sulfate and concentrated under vacuum at 30°C. The residue obtained was dissolved in HMPA (60 ml) under argon.
10 (a) Preparation of 8-benzyloxy-5-f((1 R)-1-hydroxy-2-fN-(1 R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril oxalate
A dry 250 ml flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 8-benzyloxy-5-(R)-oxiranylcarbostyril (30 gms/
15 0.102 moles) and hexamethylphosphoramide (60 ml) under argon. The reaction mass was stirred and charged with solution prepared in Step-1 at 25°C. The clear solution obtained was further heated at 80DC for 45 hours. After completion of reaction, the reaction mass was cooled to 80°C. Then a solution of oxalic acid dihydrate (25.6 gms / 0.203 moles ) in ethanol (150 ml) was charged to the reaction mass at 80°C slowly. The reaction mass was
20 stirred for 30 minutes at 80°C, cooled to 25°C gradually and stirred for 16 hours. The resulting solid was isolated by filtration, washed with ethanol (100 ml), and dried under vacuum at 60-65 °C for 10-12 hours to yield 30 gms of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl)amino]ethyl}carbostyril oxalate.
25 Example 11
Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril oxalate (compound (V); Ri = benzyl, A" -oxalate)
30 (Step-1) Preparation of (R)-N-Trimethvlsilvir2-(p-methoxyphenv0-1-methvlethyl)1amine (compound II; R? = trimethylsilyl)

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(R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride (7.55gms/0.0375moles) dissolved in dichloromethane (75ml) water (150ml and basified with liquor ammonia (8ml). The organic layer was separated, dried on sodium sulfate and concentrated under vacuum 5 at 30CC. The residue obtained was dissolved in HMPA (10ml) under argon. Then added hexamethyldisilazane (9ml /0.0409moles) 25°C. The reaction mass was heated to 80°C for 1 hour and cooled to 30°C to obtain a clear solution.
(a) Preparation of 8-benzvloxv-5-((( 1RH -hvdroxv-2-rN-(1 RV2-(p-methoxvphenvl)-1-10 methvlethynaminolethvDcarbostvril oxalate (compound (V); R1 = benzyl; A" = oxalate)
A dry 250 ml flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 8-benzyloxy- 5-(R)-oxiranylcarbostyril (10g 0.102 moles) and HMPA (20 ml) under argon. The reaction mass was heated to 80°C and
15 charged with solution prepared in Step-1, slowly in 5 hours. The clear solution obtained was further heated at 80°C for 45 hours. After completion of reaction, reaction mass was cooled to 506C. Then a solution of oxalic acid dihydrate (6 gms/ 0.0477 moles ) in ethanol (100 ml) was charged to the reaction mass at 50°C slowly. The reaction mass was stirred for 30 minutes at 50°C, cooled to 25°C gradually and stirred for 16 hours. The resulting
20 solid was isolated by filtration, washed with ethanol (100 ml), and dried under vacuum at 60-65 °C for 10-12 hours to yield 10 gms of 8-benzyloxy- 5-{((1R)-1 -hydroxy -2-[N-(1R)-2-(p-methoxyphenyl)-1 -methylethyl)amino]ethyl}carbostyril oxalate.
Example 12 25 Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride (compound (V); R1 = benzyl; A' = chloride)
8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino] 30 ethyljcarbostyril oxalate (50 gms /0.0912 moles) prepared as per example 9a, was charged in round bottom flask along with dichloromethane (100 ml). The reaction mass

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47 was basified with 10% sodium hydroxide (50 ml). The organic layer was separated and washed with water (100 ml) thrice. The organic layer was dried on sodium sulfate, concentrated under vacuum completely at 35°C. The residue obtained was dissolved in isopropanol (450 ml) and IPA-HCI (50 ml) was charged dropwise to adjust the pH 3 to 4. 5 The reaction mass was heated to reflux to obtain thick slurry. Then while maintaining reflux, water (50 ml) was added drop wise in 30 minutes. The clear solution obtained was cooled to 25°C in 14 hours and further chilled to 10°C for 1 hour. The resulting 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-
methylethyl)amino]ethyl}carbostyril hydrochloride was isolated by filtration and washed 10 with isopropanol (100 ml), dried under vacuum at 60-65 °C for 10-12 hours. Yield- 40 gms
The title compound was similarly prepared using the process of Example 10 but using products from Examples 9b to 9s as starting material.
15 Example 13
Preparation of 8-benzyloxy-5-{((1 R)-1 -hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1 -methylethyl) amino]ethyl}carbostyril hydrochloride (compound (V); Ri = benzyl; A' = chloride)
20 A mixture of methanol (500ml), THF (500 ml), 8-benzyloxy-5-(R)-oxiranylcarbostyril (83gms / 0.283 moles), (R)-(+)-N-(1-phenylethyl)-N- [1-(p-methoxyphenyl)-2-propyl)]amine hydrochloride (83 gms/ 0.271 moles) and powdered potassium carbonate (37.4gms/0.271 moles) were charged in a dry flask under argon at RT under stirring. The reaction mass was stirred at 25-30°C for 1 hour and concentrated under vacuum at 30-35°C. The slurry
25 obtained was stirred with toluene (1 liter) for 30 minutes. The reaction mass was then charged with water (1 liter) and stirred for 30 minutes at same temperature. The organic layer was separated and aqueous layer was back extracted with toluene (200 ml).The organic layers were combined together, washed with water until neutral pH (4x 500 ml ), dried on sodium sulfate and concentrated under vacuum below 35°C to remove solvent.
30 The residue was stripped with heptane (500 ml) thrice to remove traces of toluene. The residue was heated to 140°C slowly under stirring in an inert atmosphere. The heating was

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48 continued for 30-35 hours. The reaction mass was cooled to 35°C and stirred with dichloromethane (1 liter) and continued to stir for 30 minutes more at the same temperature. The mass was cooled to RT. The solution was stirred with charcoal (20 gms) and silica gel (40gms) for 30 minutes at room temperature, filtered on hyflo bed and 5 washed with dichloromethane (100ml). The clear filtrate was acidified with IPA-HCI (100ml) and distilled completely under vacuum at 50°C. The residue obtained was stripped with diisopropyl ether (100 ml) thrice to remove traces of dichloromethane and IPA. The residue was charged with diisopropyl ether (500 ml ) at 50°C and stirred for 30 minutes. The slurry obtained was brought to 25-30°C and further stirred for 30 minutes at same 10 temperature. The solid obtained was isolated by filtration and washed with diisopropyl ether (200 ml), dried under vacuum at 40-45°C for 4-5 hours. To yield 105 gms of 8-benzyloxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride.
15 Example 14
Preparation of 8-hydroxy-5-{((1 R)-1-hydroxy-2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl) amino]ethyl}carbostyril hydrochloride (R,R-carmoterol hydrochloride)
A mixture of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)r2-(p-methoxyphenyl)-1-methylethyl)
20 amino]ethyl}carbostyril hydrochloride (25 gms / 0.050 moles), methanol (250 ml) and slurry
of 10% Pd/C catalyst (2.5 gms ) in water (25 ml) ware charged in a hydrogenator at 25°C.
The reaction was hydrogenated at 25°C by applying 40-45 psi for 1 hour. After completion
of reaction, the reaction mass was filtered on hyflo bed. The hyflo bed was washed with
methanol (100 ml ).The clear filtrate was stirred with 2 % charcoal for 30 minutes at 25-
25 30°C, filtered on hyflo bed and washed with methanol (100 ml). The clear filtrate was
distilled completely under vacuum at 50°C. The residue obtained was stripped with ethanol
(100 ml) thrice to remove traces of methanol. To the residue was charged ethanol (125
ml). The reaction mass was heated to reflux for 1 hour and then cooled to 256C slowly in 6
hours. The resulting solid was isolated by filtration and washed with ethanol (50 ml), dried
30 under vacuum at 50-55 °C for 12-14 hours to yield- 11 gms of 8-hydroxy- 5-{((1R)-1-

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hydroxy -2-[N-(1 R)-2-(p-methoxyphenyl)-1-methylethyl) amino]ethyl}carbostyril
hydrochloride i.e. R,R-carmoterol hydrochloride.
Example 15 5 Preparation of (+)-(R)-N-(1-phenylethyl)-N-[1-{p-methoxyphenyl)-2-propyl)]amine hydrochloride
4-methoxy phenyl acetone (400 gms / 2.439 moles), R(+)- phenyl ethyl amine (300 gms/ 2.479 moles), RaneyNickel (100 gms) and methanol (2.4 liters) were charged in a
10 hydrogenator. Reaction mass was hydrogenated at 70°C by applying hydrogen pressure of 10 Kg/cm2 for 25 hours. After completion of reaction, reaction mass was cooled to 25-30°C and filtered on hyflo bed and washed with methanol (400 ml). The pH was adjusted to 1-2 using solution of HCI in IPA (1.1 liter). The clear filtrate was distilled out under vacuum at 65°C to volume of 500 ml. The residue was stripped with ethyl acetate (500 ml)
15 thrice to remove traces of methanol. The residue was charged with ethyl acetate (2.0 liters) at 65°C and stirred for 30 minutes. The slurry obtained was brought to 25-30°C, chilled to 0-5°C and further stirred for 30 minutes. The resulting (+)-(R)-N-(1-Phenylethyl)-N~[1-(p-methoxyphenyl)-2-propyl)]amine hydrochloride was isolated by filtration and washed with ethyl acetate (200 ml), dried under vacuum at 60-65 °C for 12-14 hours.
20 Yield-470 gms
Example 16
Preparation of (+)-(R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride
(hydrochloride salt of compound (II))
25
(R)-(+)-N-(1-Phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine hydrochloride (464 gms/1.591 moles), slurry of 10% Pd/C (93gms) in methanol (4.64liters) were charged in a hydrogenator. Hydrogenated reaction mass at 50°C for 8-10 hours by applying 5 Kg hydrogen pressure. The reaction mass was cooled to room temperature, filtered on hyflo
30 bed to remove catalyst and washed with methanol (500 ml). The filtrates were combined and acidified to pH 1-2 using IPA-HCI (750 ml). The clear filtrate was distilled out

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completely under vacuum at 50°C. The residue was stripped with acetone (500 ml) twice
to remove traces of methanol. The residue was charged with ethyl acetate (2.0 liters) at
65°C and stirred for 30 minutes. The residue was slurried in acetone (1.6 liters), cooled to
25-30°C. The resulting (+)-(R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine
5 hydrochloride was isolated by filtration and washed with acetone (400 ml), dried under vacuum at 50-55 °C for 2-4 hours. Yield- 285 gms
Example 17
Preparation of 8-hydroxy-5-{((1R)-1-hydroxymethyl-2-[N-(1R)-2-(p-methoxyphenyl)-1-10 methylethyl)amino]ethyl}carbostyril oxalate (Regio isomer)
(a) A dry 250 ml flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with (R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride (3.78 gms/ 0.0187 moles), dichloromethane (50 ml), water (100 ml) and
15 basified with liquor ammonia (5 ml). The organic layer was separated, dried on sodium sulfate and concentrated under vacuum at 30°C. The residue obtained was dissolved in diglyme (10ml) under argon. Then added hexamethyldisilazane (4.275 ml/ 0.02 moles) at 25°C. The reaction mass was heated to 110°C for 1 hour and cooled to 75°C. The reaction mass was charged with solution of 8-benzyloxy- 5-(R)-oxiranylcarbostyril (5 gms/ 0.017
20 moles) in diglyme(10ml) followed by methane sulfonic acid (0.5ml). The reaction mass was slowly heated to 100°C. The clear solution obtained was further heated at 100°C for 25 hours. After completion of reaction, reaction mass was cooled to 80°C. Then solution of oxalic acid dihydrate (4.15gms/ 0.0329 moles) in ethanol (25 ml) charged slowly to reaction mass at 80°C. The reaction mass was stirred for 30 minutes, cooled to 25CC
25 gradually and stirred for 16 hours. The resulting solid was isolated by filtration and washed with ethanol (15ml), dried under vacuum at 60-65 °C for 10-12 hours to yield 5.0 gms of 8-benzyloxy-5-{((1R)-1-hydroxymethyl-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl) amino]ethyl} carbostyril oxalate.

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51 (b) The oxalate salt obtained in the Example 15a was then hydrogenated using the process of Example 12, to yield 3.0 gms of 8-hydroxy-5-{((1R)-1-hydroxymethyl-2-[N-(1R)-2-{p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril oxalate.
5 Example 18
Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (compound (IV); Ri = benzyl)
(R)-N-[2-(p-methoxyphenyl)-1-methylethyl)]amine hydrochloride (7.56 gms/0.0375moles)
10 was dissolved in dichloromethane (200 ml), water(400 ml) and basified with sodium
hydroxide (1.6 gms/0.04 moles). The organic layer was separated, dried on sodium sulfate
and concentrated under vacuum at 30°C. The residue obtained was dissolved in IPA (200
ml) under argon. Then added 8-benzyloxy-5-(R)-oxiranylcarbostyril (10 gms/ 0.0341
moles). The reaction mass was slowly heated to 85-906C for 20-25 hours, cooled to 30°C,
15 filtered on hyflo bed, washed bed with IPA (50 ml). The clear filtrate was concentrated
under vacuum at 50°C. The residue was stripped with diisopropyl ether (100 ml) twice to
remove traces of IPA. The residue was charged with diisopropyl ether (100 ml) at 50°C,
stirred for 30 minutes and cooled to 30°C. The resulting (+) (R)-N- [2-{p-methoxy phenyl) -
1-methylethyl)]amine was isolated by filtration and washed with diisopropyl ether (50 ml),
20 dried under vacuum at 35-40 °C for 2-4 hours. Yield- 7.2 gms
Example 19
Preparation of 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride (compound (V); Ri = benzyl; A' = 25 chloride) without isolation of base
8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyI} carbostyril oxalate (1gms/0.00182 moles) prepared as per example 9a, was charged in round bottom flask along with isopropanol (10 ml). The reaction mass was heated to 80°C 30 and charged with IPA-HCI (1ml) dropwise to pH 3 to 4. The reaction mass was heated to reflux for 5-10 minutes. The clear solution obtained was cooled to 25°C, stirred for 12 to 14

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hours at same temperature and further chilled to 10°C for 1 hour. The resulting 8-benzyloxy-5-{((1R)-1-hydroxy-2-[N-(1R)-2-(p-methoxyphenyl)-1-
methylethyl)amino]ethyl}carbostyril hydrochloride was isolated by filtration and washed with isopropanol (5 ml), dried under vacuum at 60-65 °C for 5-6 hours. Yield- 0.6 gms 5 The (R,R)-carmoterol or other diastereomers of carmoterol as described above may be formulated into pharmaceutical compositions suitable for treating conditions requiring a bronchodilating effect, such as asthma and chronic obstructive pulmonary disease (COPD). Such compositions are well known in the prior art. For example, the carmoterol may be administered as a liquid (aqueous or hydroalcoholic) formulation through a 10 nebuliser, as a dry powder by means of a Dry Powder Inhaler (DPIs) or in a halogenated hydrocarbon propellant which requires a suitable pressurized metered-dose inhaler (pMDIs) releasing a metered dose of medicine upon each actuation. .
The carmoterol may be in the form of a liquid, propellant-free pharmaceutical formulation, 15 as disclosed in US 2007/0065366.
It will be appreciated that the invention may be modified within the scope of the appended claims.

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CLAIMS
1. A process for preparing the (R,R)-, (S,S)-, (R,S)- or (S.R)-diastereomer of a compound of formula (III)

comprising condensing the R or S enantiomer of an oxiranyl compound of formula (I)


10

with the R or S enantiomer of an amine of formula (II) or a salt thereof

15
wherein: R1 is a group selected from alkyl, aryl, aDyl, alkoxy, cycloalkyl, heterocyclic, alkenyl, benzocycloalkyl, aralkyl, haloarylalkyl, heteroaralkyl, haloalkyl, alkoxyaralkyl, and

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optionally substituted silyl and benzyl; and R2 is (a) optionally substituted silyl, (b) optionally substituted benzyl or (c) hydrogen; when R2 is optionally substituted silyl, either: R2' and R3 are the same as R2; R2' is the same as R2 and R3 is hydrogen; or R2' is hydrogen and R3 is the same as R2; when R2 is optionally substituted benzyl, R2' is 5 hydrogen and R3 is the same as R2; and when R2 is hydrogen, R2' is hydrogen and R3 is hydrogen.
2. A process according to claim 1, wherein compounds (I) and (II) are in the form of
their R enantiomers and compound III is in the form of the (R,R)-diastereomer.
10
3. A process according to claim 1 or 2, wherein the salt of compound (III) is the
hydrochloride salt.
4. A process according to claim 1, 2 or 3, wherein R1 is straight chain or branched
15 chain C1-C4alkyl, or C6-C14 aryl, preferably benzyl.
5. A process according to any preceding claim, wherein R2 and/or R2' and/or R3 are
trialkylsilyl.
20 6. A process according to claim 5, wherein R2 and R2' are trialkylsilyl and R3 is hydrogen.
7. A process according to claim 5, wherein R2 and R3 are trialkylsilyl and R2' is
hydrogen.
25
8. A process according to claim 5, 6 or 7, wherein the trialkylsilyl group is selected
from the group consisting of trim ethyl silyl, triethylsilyl and t-butyldimethylsilyl.
9. A process according to any one of claims 1 to 4, wherein R2 and/or R2' and/or R3 is
30 diarylalkylsilyl.

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10. A process according to claim 9, wherein R2 and R2' are diarylalkylsilyl and R3 is
hydrogen.
11. A process according to claim 9, wherein R2 and R3 are diarylalkylsilyl and R2' is
5 hydrogen.
12. A process according to claim 9, 10 or 11, wherein the diarylalkylsilyl is t-
butyldiphenylsilyl.
10 13. A process according to any one of claims 1 to 4, wherein R2 is benzyl.
14. A process according to any preceding claim, wherein compound (I) is optically pure.
15. A process according to any preceding claim, wherein compound (II) is optically 15 pure.
16. A process according to any preceding claim, wherein the condensation is carried
out in the presence of a solvent.
20 17. A process according to claim 16, wherein the solvent is an organic solvent.
18. A process according to claim 16, wherein the solvent is selected from the group
consisting of methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone,
toluene, t-amylalcohol, acetonitrile, diglyme, dimethylsulphoxide (DMSO) xylene and
25 hexamethylphosphoramide (HMPA), preferably HMPA.
19. A process according to any preceding claim, wherein the condensation step is
carried out at a temperature below 140°C.
30 20. A process according to claim 19, wherein the condensation step is carried out at a temperature below 120°C.

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21. A process according to any one of claims 1 to 15, wherein the condensation is carried out in the absence of solvent.
5 22. A process according to claim 21, wherein the condensation is carried out at a temperature ranging from about 100 to about 1406C.
23. A process according to any preceding claim, wherein the condensation is earned
out in the presence of a base.
10
24. A process according to claim 23, wherein the base is an organic base or an
inorganic base.
25. A process according to claim 23, wherein the base is selected from triethylamine,
15 potassium carbonate, sodium carbonate and diisopropylethylamine.
26. A process according to any one of claims 1 to 4, wherein R2 is silyl and the
compound of formula (II) is prepared by silylating (R)-N-(2-(p-methoxyphenyl)-1-
methylethyl)amine (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine with a silylating agent.
20
27. A process according to claim 26, wherein the silylating agent is
hexamethyldisilazane or hexaethyldisilazane.
28. A process according to any one of claims 1 to 25, wherein R2 is benzyl and the
25 compound of formula (II) is prepared by benzylating (R)-N-(2-(p-methoxypheny!)-1-
methylethyl)amine (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine with a benzylating agent.
29. A process according to claim 1, wherein R1 is benzyl and R2 is silyl. 30
30. A process according to 29, wherein R2 is trialkylsilyl.

WO 2008/104781 PCT/GB2008/000677
57
31. A process according to claim 30, wherein the trialkylsilyl is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
5 32. A process according to claim 29, wherein R2 is diarylalkylsilyl.
33. A process according to claim 32, wherein the diarylalkylsilyl is t-butyldiphenylsilyl.
34. A process according to any preceding claim, wherein compound (I) is prepared by 10 converting a compound of formula (Ig) to the compound (I).

35. A process according to claim 34, wherein compound (Ig) is prepared by converting a compound of formula (If) to the compound (Ig).

36. A process according to claim 35, wherein compound (If) is prepared by converting a compound of formula (le) to the compound (If).


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37. A process according to claim 36, wherein compound (le) is prepared by converting a compound of formula (Id) to the compound (le).

38. A process according to claim 37, wherein compound (Id) is prepared by converting a compound of formula (le) to the compound (Id).

39. A process according to claim 38, wherein compound (le) is prepared by converting a compound of formula (lb) to the compound (le).

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40. A process according to claim 39, wherein compound (lb) is prepared by converting a compound of formula (la) to the compound (lb).

41. A process according to any preceding claim, wherein the process further
comprises converting the (R,R)-, (S,S)-, (R,S)- or (S.R)-diastereomer of compound of
formula (III) to the corresponding (R.R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of
carmoterol.
10
42. A process according to claim 41, wherein the process further comprises converting
the (R,R)-diastereomer of compound of formula (III) to the (R,R)-diastereomer of
carmoterol.
15 43. A process according to any one of claims 1 to 40, wherein the process further comprises hydrolyzing the (R,R)-, (S,S)-, (R,S)- or (S.R)-diastereomer of the compound of formula (III) in the presence of an acid to obtain the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of a compound of formula (IV)

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wherein Ri is as defined in claim 1.
5 44. A process according to claim 43, wherein the process further comprises hydrolyzing the (R,R)-diastereomer of the compound of formula (III) to obtain the (R,R)-diastereomer of the compound of formula (IV).
45. A process according to claim 43 or 44, wherein the acid is a carboxylic acid or a
10 mineral acid.
46. A process according to claim 43 or 44, wherein the acid is selected from the group
consisting of benzoic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric
acid, hydrochloric acid, salicylic acid, di-p-toluyl-D-tartaric acid, di-benzoyl-D-tartaric acid,
15 di-pivaloyl-D-tartaric acid, glutamic acid, ethylenediaminetetraacetic acid, mandelic acid, malonic acid, acetic acid, anthranilic acid, nicotinic acid and furoic acid.
47. A process according to any one of claims 43 to 46, wherein the condensation and
hydrolyzation steps are carried out without isolation of the compound (III).
20
48. A process according to any one of claims 43 to 44, wherein compound (IV) is
produced in the form of its acid addition salt as a compound of formula (V)

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wherein Ri is as defined in claim 1 or 2 and A is an anion.
5 49. A process according to 48, wherein the anion is selected from the group consisting of oxalate, fumarate, tartrate, benzoate, salicylate, di-p-toluyl D-tartrate, di-benzoyl D-tartrate, di-pivaloyl D-tartrate, succinate, glutamate, ethylenediaminetetraacetate, maleate, maleate, mandelate, malonate, acetate, anthranilate, nicotinate and furoate.
10 50. A process according to any one of claims 43 to 49, wherein the compound of formula (IV) or (V) is isolated by crystallization.
51. A process according to 50, wherein the crystallisation of (V) involves converting the
acid addition salt to a salt of a different acid
15
52. A process according to claim 51, wherein the different acid salt is the hydrochloride
salt.
53. A process according to claim 51 or 52, wherein the conversion of the acid addition
20 salt involves isolation of the free base of compound (V).
54. A process according to claim 51 or 52, wherein the conversion of the acid addition
salt involves no isolation of the free base of compound (V).

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62 55. A process according to any one of claims 43 to 54, wherein the process further comprises converting the (R,R)-, (S,S>-, (R,S)- or (S,R)-diastereomer of the compound of formula (IV) or (V) to the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of carmoterol.
5 56. A process according to claim 55, wherein the process further comprises converting the (R,R)-diastereomer of the compound of formula (IV) or (V) to the (R,R)-diastereomer of carmoterol.
57. A process according to claim 55 or 56, wherein the conversion comprises
10 deprotection of the OR1 group using a deprotecting reagent.
58. A process according to claim 57, wherein the hydrolyzation and deprotection steps
are carried out without isolation of the compound (IV) or (V).
15 59. A process according to claim 57, wherein the condensation, hydrolyzation and deprotection steps are carried out without isolation of the compounds (III) and (IV) or (V).
60. A process according to claim 57, 58 or 59, wherein R1 is a benzylic group and the
deprotection comprise hydrogenolysis of the compound of formula (IV) or (V) in the
20 presence of a noble metal catalyst and hydrogen gas.
61. A process according to claim 57, 58 or 59, wherein the deprotecting reagent is a
compound selected from the group consisting of a mineral acid, a strong acid, a Lewis acid
and an aqueous mineral base, and a solvent for the deprotecting compound.
25
62. A process according to claim 57, 58 or 59, wherein R1 is silyl and the deprotection
comprises treating the compound of formula (IV) or (V) with t-butylammonium fluoride or
potassium fluoride.


63 63, A process according to claim 57, 58 or 59, wherein. R1 is arylalkyl or substituted arylalkyl and the deprotection comprises catalytic reduction using a palladium-based or platinum-based catalyst.
5 64. A process according to claim 63, wherein the catalyst is selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel.
65. A process according to any one of claims 57 to 64, wherein the deprotection of
10 compound (IV) or (V) is carried out in the presence of an organic solvent.
66. A process according to claim 65, wherein the solvent is selected from the group
consisting of an alkyl acetate, a C1 to C6 alkylamine, an alcohol, an aliphatic hydrocarbon,
an aromatic hydrocarbon, a heterocycle, a dialkylether, an acid, a mixture of water and a
15 water miscible solvent, an ionic liquid, a halogenated solvent and mixtures thereof.
• 67. A process according to any one of claims 55 to 66, wherein the carmoterol is converted to a pharmaceutically acceptable salt thereof.
20 68. A process according to claim 67, wherein the salt is the hydrochloride salt.
wherein R2 is silyl, comprising converting (R)-N-(2-(p-methoxyphenyl)-1-methylethyI)amine to the compound of formula (li).
AMENDED SHEET
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69. A process for preparing a compound of formula (II)


■RhnfelMMQTlSM?]

m$mMQ0Wmmm
AA Thornton & (^fflSPMlliX No, 0?n74fMRRn
PCT/GB 2008/000 677 - 09-02-2009

64
70. A process according to claim 69, wherein the conversion comprises reacting (R)-N-
(2-(p-methoxyphenyJ)-1-metfiylethyl)amine with a silylating agent.
71. A process according to claim 70, wherein the silylating agent is
5 hexamethyldisilazane or hexaethyldisilazane.
72. A process according to any one of claims 1 to 68, wherein the compound of
formula (II) is prepared according to any one of claims 69 to 71.
10 73. A compound of formula (II)

15
20

wherein R2 is optionally substituted silyl.
74. A compound according to claim 73, wherein R2 is a trialkylsilyl group.
75. A compound according to claim 74, wherein the trialkylsilyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
76. A compound of formula (ill)

AMENDED SHEET R^4lved at the EPO on Feb 09, 2009 15:12:00. Page 18 of 20

i09-02-2009i

prpd'illfHf9!21 AA Thornton & GClllSpMlx No. 0?(1740Wfln WmSmMdfr&m
PCI/GE 2008/666^677-W-62-2009
65
wherein R1 is as defined in claim 1, and either R2' is optionally substituted silyl and R3 is hydrogen; R2' and R3 are bothoptionally substituted silyl; or R2' is hydrogen, R3is optionally substituted silyl.
5 77. A compound according to claim 76, wherein R2" is a trialkylsilyl group.
78. A compound according to claim 76 or 77, wherein R3 is a trialkylsilyl group.
79. A compound according to claim 77 or 78, wherein the trialkylsilyl group is selected 10 from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
80. A compound according to claim 76, wherein R2' Is a diarylalkylsilyl group.
81. A compound according to claim 76 or 80, wherein R3 is a diarylalkylsilyl group. 15
82. A compound according to claim 80 or 81, wherein the diarylalkylsilyl group is t-
butyldiphenylsilyl.
83. (R,R)-, (S,S)-, (R.S)- or (S,R)-carmoterol prepared according to a process 20 according to any one of claims 55 to 67.
84. (R,R)-carmoterol according to claim 83,
85. A pharmaceutical composition comprising carmoterol according to claim 83 or 84, 25 together with one or more pharmaceutical^ acceptable excipients.
86. Use of carmoterol according to claim 83 or 84 in medicine.
87. Use of carmoterol according to claim 83 or 84 in the treatment of asthma or chronic 30 obstructive pulmonary disease (COPD).
-4SEP2009
AMENDED SHEET
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iffiSMfS^SPfei AA Thornton & ®ilis|AMD\x No, o?n74n^RRn WmWooMmmi
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66
88. Use of carmoterol according to claim 83 or 84 in the manufacture of a medicament
for the treatment of asthma or chronic obstructive pulmonary disease (COPD).
89. A method of treating asthma or chronic obstructive pulmonary disease (COPD)
5 comprising administering to a patient in need thereof carmoterol according to claim 83 or
84.
90. (R,R)-carmoterol substantially as herein described with reference to the examples.
/
10 91, A process substantially as herein described with reference to the examples.
AMENDED SHEET
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