WO2005058804A1

WO2005058804A1 - Process for the preparation of tertiary amines attached to a secondary carbon centre

Info

Publication number: WO2005058804A1
Application number: PCT/GB2004/005199
Authority: WO
Inventors: Robin Fieldhouse
Original assignee: Avecia Pharmaceuticals Limited
Priority date: 2003-12-18
Filing date: 2004-12-08
Publication date: 2005-06-30
Also published as: GB0329284D0

Abstract

There is provided a process for the preparation of a compound of Formula: (1) wherein Ar represents an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group comprising an aromatic moiety; and R1, R2 and R3 each independently represent an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group; said process comprising: a) reducing a compound of Formula: (2) to form a compound of Formula: (3) b) activating the compound of Formula: (3) to form a compound of Formula: (4) wherein X represents a leaving group; and c) coupling the compound of Formula: (4) to a compound of Formula: (5) to form a compound of Formula: (1). Stereoselective processes are also provided.

Description

PROCESS FOR THE PREPARATION OF TERTIARY AMINES ATTACHED TO A SECONDARY CARBON CENTRE

The present invention concerns a process for the preparation of tertiary amines attached to a secondary carbon centre, particularly aminoalkylphenylcarbamates. Aminoalkylphenylcarbamates are useful as pharmaceutical compositions (EP0193926). Aminoalkylphenylcarbamates comprise an amine attached to a secondary carbon centre. Traditionally, chiral amines have been obtained by chemical resolution techniques using tartaric acid or dibenzoyl tartrate. According to the present invention, there is provided a process for the preparation of a compound of Formula 1 :

Formula 1 wherein Ar represents an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group comprising an aromatic moiety; and R¹, R² and R³ each independently represent an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group; said process comprising: a) reducing a compound of Formula 2 to form a compound of Formula 3:

R¹ R¹ Ar'^O Ar-^^OH Formula 2 Formula 3

b) activating the compound of Formula 3 to form a compound of Formula 4:

R¹ Ar^^OX Formula 4

wherein X represents a leaving group; and c) coupling the compound of Formula 4 to a compound of Formula 5:

Formula 5 to form a compound of Formula 1. Hydrocarbyl groups which may be represented by R\ R² and R³ independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups. Alkyl groups which may be represented by R\ R² and R³ include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R¹, R² and R³ include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Alkenyl groups which may be represented by R¹, R² and R³ include C₂.₂o_> and preferably C₂^ alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups. Aryl groups which may be represented by R¹, R² and R³ may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocydic rings. Examples of aryl groups which may be represented by R\ R² and R³ include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. Perhalogenated hydrocarbyl groups which may be represented by R¹, R² and R³ independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R¹, R² and R³ include -CF₃ and -C₂F₅. Heterocydic groups which may be represented by R¹, R² and R³ independently include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocydic rings. The heterocydic group will contain at least one heterocydic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocydic groups which may be represented by R¹, R² and R³ include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups. When any of R\ R² and R³ is a substituted hydrocarbyl or heterocydic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of any of the reaction steps or the overall process. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbamates, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present. Examples of R¹, R² or R³ groups having more than one substituent present include -CF₃ and -C₂F₅. Optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group comprising an aromatic moiety which may be represented by Ar include optionally substitited aryl or heteroaryl groups, or an optionally substituted alkyl group, preferably a C_M alkyl group, substituted by an optionally substituted aryl or heteroaryl group. Alkyl and aryl groups are as defined for R¹. Heteroaryl groups are heterocydic groups as defined for R¹ which comprise at least one aromatic ring. Substituents include those substituents defined above for R¹. Substituents are commonly selected from the group consisting of optionally substituted alkoxy (preferably C^-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphate sulpho, nitro, cyano, halo, ureido, -SO₂F, hydroxy, ester, -NR^aR^b, -COR^a, -CONR^aR , -NHCOR^a, -OCONR^aR^b, carboxyester, sulphone, and -SO₂NR^aR wherein R^a and R^b are each independently H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C_1-4-alkyl) or, in the case of -NR^aR^b, -CONR^aR^b, -OCONR^aR^b and - SO₂NR^aR , R^a and R may also together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; or a combination thereof. In many embodiments, R¹ is different from Ar¹, ie the compound of Formula 2 is prochiral. It is preferred that R¹ represents a C_M alkyl group, and most preferably a methyl group. In many especially preferred embodiments, the compound of Formula 2 is a compound of Formula 2a:

wherein R^a and R are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C₁_₄-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; and R⁴ each independently represents hydrogen or a substituent group. Preferable R⁴ are all hydrogen. Preferably R^a and R^b are each independently H, Me or Et. Most preferably the group -NR^aR^b is the group -NMeEt. Compounds of Formula 2a can be prepared by reacting a compound of Formula 6:

with a compound of Formula 7: o R ^aaR^b -N-^ Cl

wherein R^a, R^b and R⁴ are as defined herein before. Compounds of Formula 7 can be prepared by reaction of an amine, R^aR^bNH, with phosgene. For convenience, triphosgene in the presence of a base, such as pyridine, is a suitable alternative to the use of phosgene. In certain preferred embodiments, the compound of Formula 2 is a compound of Formula 2b:

wherein R^a, R and R⁴ are as defined herein before. The reduction of compounds of Formula 2 is preferably accomplished employing a stereoselective reduction system. It is most preferred that the stereoselective reduction employs a chiral coordinated transition metal catalysed transfer hydrogenation process. Examples of such processes, and the catalysts, reagents and conditions employed therein include those disclosed in International patent application publication numbers WO97/20789, WO98/42643, and WO02/44111 each of which is incorporated herein by reference. Preferred transfer hydrogenation catalysts for use in the process of the present invention have the general formula (a):

A A B M Y' V (a) wherein: R⁵ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents an optionally substituted nitrogen; B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous; E represents a linking group; M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom. Particularly preferred transfer hydrogenation catalysts are those Ru, Rh or Ir catalysts of the type described in WO97/20789, WO98/42643, and WO02/44111 which comprise an optionally substituted diamine ligand, for example an optionally substituted ethylene diamine ligand, wherein at least one nitrogen atom of the optionally substituted diamine ligand is substituted, preferably with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene, or an optionally substituted cyclopentadiene ligand, for example pentamethylcyclopentadiene. Highly preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A):

Formula (A)

wherein: R⁵ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents -NR⁶-, -NR⁷-, -NHR⁶, -NR⁶R⁷ or -NR⁶R⁷ where R⁶ is H, C(O)R⁸,

SO₂R⁸, C(O)NR⁸R¹², C(S)NR⁸R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁷ and R⁸ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹² and R¹³ are each independently hydrogen or a group as defined for R⁸; B represents -O-, -OH, OR⁹, -S-, -SH, SR⁹, -NR⁹-, -NR¹⁰-, -NHR¹⁰, -NR⁹R¹⁰, -NR⁹R¹¹, -PR⁹- or -PR⁹R¹¹ where R¹⁰ is H, C(O)R¹¹, SO₂R¹¹, C(O)NR¹¹R¹⁴, C(S)NR¹¹R¹⁴, C(=NR¹⁴)SR¹⁵ or C(=NR¹⁴)OR¹⁵, R⁹ and R¹ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁴ and R¹⁵ are each independently hydrogen or a group as defined for R¹¹; E represents a linking group; M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom. Highly preferred are transfer hydrogenation catalysts of Formula (A) wherein at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre. The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support. Optionally substituted hydrocarbyl groups represented by R^7"9 or R ¹³ include alkyl, alkenyl, alkynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups. Alkyl groups which may be represented by R^7"9 or R^11"13 include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R^7"9 or R^11"13 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Alkenyl groups which may be represented by one or more of R^7"9 or R^11"13 include C_2-20, and preferably C_2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Alkynyl groups which may be represented by one or more of R^7"9 or R^11"13 include

C₂.₂₀, and preferably C₂.₁₀ alkynyl groups. One or more carbon - carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups. Aryl groups which may be represented by one or more of R^7'9 or R^11'13 may contain

1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocydic rings. Examples of aryl groups which may be represented by R^7"9 or R^11"13 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. Perhalogenated hydrocarbyl groups which may be represented by one or more of R^7"9 or R^11"13 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R^{7 9} or R^11"13 include -CF₃ and -C₂F₅. Heterocydic groups which may be represented by one or more of R^7"9 or R^11'13 independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocydic rings. The heterocydic group will contain at least one heterocydic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocydic groups which may be represented by R^7"9 or R^11"13 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and t azolyl groups. When any of R^7"9 or R^{11 13} is a substituted hydrocarbyl or heterocydic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R^7"9 or R^11"13 above. One or more substituents may be present. R^{7 9} or R^11"13 may each contain one or more chiral centres. The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R⁵ includes optionally substituted aryl and alkenyl ligands. Optionally substituted aryl ligands which may be represented by R⁵ may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocydic rings. Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomehcally purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands. Optionally substituted alkenyl ligands which may be represented by R⁵ include C₂_₃o, and preferably C₆.₁₂, alkenes or cycloalkenes with preferably two or more carbon- carbon double bonds, preferably only two carbon-carbon double bonds. The carbon- carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1 ,5- diene and 2,5-norbomadiene. Cyclo-octa-1 ,5-diene is especially preferred. Optionally substituted cyclopentadienyl groups which may be represented by R⁵ include cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomehcally purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl- cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred. When either A or B is an amide group represented by -NR⁶-, -NHR⁶, NR⁶R⁷, -NR¹⁰-, -NHR¹⁰ or NR⁹R¹⁰ wherein R⁷ and R⁹ are as hereinbefore defined, and where R⁶ or R¹⁰ is an acyl group represented by -C(O)R⁸ or -C(O)R¹¹, R⁸ and R¹¹ independently are often linear or branched C_1-7alkyl, C^-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R⁶ or R¹⁰ include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl groups. When either A or B is present as a sulphonamide group represented by -NR⁶-, -NHR⁶, NR⁶R⁷, -NR¹⁰-, -NHR¹⁰ or NR⁹R¹⁰ wherein R⁷ and R⁹ are as hereinbefore defined, and where R⁶ or R¹⁰ is a sulphonyl group represented by -S(O)₂R⁸ or -S(O)₂R¹¹, R⁸ and R¹¹ independently are often linear or branched C_1-12alkyl, C_1-12cycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl, more preferably p-toluenesulphonyl groups and naphthylsulphonyl groups and especially camphorsulphonyl. When either of A or B is present as a group represented by -NR⁶-, -NHR⁶, NR⁶R⁷, -NR¹⁰-, -NHR¹⁰ or NR⁹R¹⁰ wherein R⁷ and R⁹ are as hereinbefore defined, and where R⁶ or R¹⁰ is a group represented by C(O)NR⁸R¹², C(S)NR⁸R¹², C(=NR¹²)SR¹³, C(=NR¹²)OR¹³, C(O)NR¹ R¹⁴, C(S)NR¹¹R¹⁴, C(=NR¹⁴)SR¹⁵ or C(=NR¹⁴)OR¹⁵, R⁸ and R¹¹ independently are often linear or branched C^alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl, groups and R^12"15 are often each independently hydrogen or linear or branched C^alkyl, such as methyl, ethyl, isopropyl, C.,.₈cycloalkyl or aryl, for example phenyl, groups. When B is present as a group represented by -OR⁹, -SR⁹, -PR⁹- or -PR⁹R¹¹, R⁹ and R¹¹ independently are often linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl. It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons. The groups A and B are connected by a linking group E. The linking group E achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocydic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other rings. Often the atoms linking A and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B will carry substituents in addition to A or B. Substituent groups include those which may substitute R^7"9 or R^{11 13} as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C^ alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fused to a phenyl ring. E preferably comprises part of a compound having at least one stereospecific centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state. When B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group. Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1-aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1 ,4-diaminoalkanes, 1 ,3-diaminoalkanes, especially 1 ,2- or 2,3- diaminoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring. Further diamines that may be represented by A-E-B are 1 ,2-diaminocyclopentanes and 1 ,2-diaminocyclohexanes, preferably fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at least one alkyl group, such as a C^-alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group. Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:

Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1S,2R)-(+)-norephedrine, (1 R,2S)-(+)-cis-1-amino-2- indanol, (1 S,2R)-2-amino-1 ,2-diphenylethanol, (1S,2R)-(-)-cis-1-amino-2-indanol, (1 R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1-phenylethanol, (1 R,2S)-2-amino-1 ,2- diphenylethanol, N-tosyl-(1 R,2R)-1 ,2-diphenylethylenediamine, N-tosyl-(1 S,2S)-1 ,2- diphenylethylenediamine, (1 R,2S)-cis-1 ,2-indandiamine, (1 S,2R)-cis-1 ,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol. Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when R⁵ is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when R⁵ is an optionally substituted cyclopentadienyl ligand. It is preferred that M, the metal, is rhodium present in valence state III and R⁵ is an optionally substituted cyclopentadienyl ligand. Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction. Basic ligands which may be represented by Y include water, C^ alcohols, C_1-8 primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water. Most preferably, A-E-B, R⁵ and Y are chosen so that the catalyst is chiral. When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes. In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B. Especially preferred are catalysts of Formula B(i-iv):

B(i) B(ii)

B(iϋ) B(iv) The preferred catalyst may be prepared in-situ preferably by combining a chiral bidentate nitrogen ligand with a Rh(lll) metal complex containing a substituted cyclopentadienyl ligand. Preferably a solvent is present in this operation. The solvent used may be anyone which does not adversely effect the formation of the catalyst. These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone. Preferably the solvent is methanol. Any suitable reductant may be used in the preferred embodiment of step (a), examples of reductants able to be used in this process include hydrogen donors including hydrogen, primary and secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof. Primary and secondary alcohols which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms. Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol, especially propan-2-ol and butan-2-ol. Primary and secondary amines which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms. Examples of primary and secondary amines which may act as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine and pipe dine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine. Carboxylic acids and their esters which in a preferred embodiment of step (a) may act as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta- hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a C_1-10 alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid, especially formic acid. In certain preferred embodiments, when a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as salt, preferably an amine, ammonium or metal salt. Preferably, when a metal salt is present the metal is selected from the alkali or alkaline earth metals of the periodic table, and more preferably is selected from the group I elements, such as lithium, sodium or potassium. Amines which may be used to form such salts include; primary, secondary and tertiary amines which comprise from 1 to 20 carbon atoms. Cyclic amines, both aromatic and non-aromatic , may also be used. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include; thmethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine. When at least some of the carboxylic acid is present as an amine salt, particularly when a mixture of formic acid and triethylamine is employed, the mole ratio of acid to amine is between 1 :1 and 50:1 and preferably between 1 :1 and 10:1 , and most preferably about 5:2. When at least some of the carboxylic acid is present as a metal salt, particularly when a mixture of formic acid and a group I metal salt is employed, the mole ratio of acid to metal ions present is between 1 :1 and 50:1 and preferably between 1 :1 and 10:1 , and most preferably about 2:1. The ratios of acid to salts may be maintained during the course of the reaction by the addition of either component, but usually by the addition of the carboxylic acid. Readily dehydrogenatable hydrocarbons which may be employed in step (a) as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems. Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes. Clean reducing agents able to act as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV. Examples of suitable clean reducing agents include hydrazine and hydroxylamine. Preferred hydrogen donors in the preferred embodiment of step (a) are propan-2- ol, butan-2-ol, thethylammonium formate and a mixture of triethylammonium formate and formic acid. The most preferred transfer hydrogenation processes employ triethylamine-formic acid as hydrogen source. Compounds of Formula 3 can be activated by employing methods known in the art for rendering a hydroxy group susceptible to displacement with an amino group. Examples of activation methods include the use of Mitsonubo conditions, phosphine and carbodiimide see for example Lawrence, PharmaChem, (2002), 1 (9), 12-14 and Hughes, Organic Reactions (New York) (1992), 42 335-656, the Mitsonubu conditions described in both being incorporated herein by reference. In many embodiments, the compounds of Formula 3 are activated by reaction with a compound of formula X-L, wherein X is as previously described, and L is a halo group, especially a chloro or bromo group. Examples of preferred leaving groups which may be represented by X include acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl and toluenesulphonyl groups, and preferred compounds of formula X-L are the corresponding chloro compounds. Preferably, the compounds of Formula 3a:

wherein R^a, R^b and R⁴ are as defined herein before, are activated by reaction with a compound of formula X-O-X, wherein X is as previously described. Examples of preferred leaving groups which may be represented by X include acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl and toluenesulphonyl groups. A highly preferred compound of formula X-O-X is methanesulphonic anhydride. The present invention is illustrated without limitation by the following examples. Most preferably, the compounds of Formula 3b:

wherein R^a, R^b and R⁴ are as defined herein before, are activated by reaction with a compound of formula X-O-X, wherein X is an acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl or toluenesulphonyl group, to give a compound of Formula 4b which is reacted with a compound of Formula 5 to give a compound of Formula 1 b. Optionally, the compound of Formula 4b is isolated prior to reaction with the compound of Formula 5. Preferably, for compounds of Formula 5, R² and R³ are each independently optionally substituted C_1-4-alkyl, optionally substituted phenyl or optionally substituted benzyl groups. More preferably, R² and R³ are each independently C_1-4-alkyl, phenyl or benzyl groups. Most preferably, R² and R³ are each methyl groups. In a highly preferred embodiment, there is provided a process for the preparation of a compound of Formula 1 (i):

Formula 1 (i) wherein Ar represents an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group comprising an aromatic moiety; and R¹, R² and R³ each independently represent an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group; said process comprising: a) reducing a compound of Formula 2 with a stereoselective reduction system to form a compound of Formula 3(i):

R¹ R¹ Ar'^O Ar ^'''OH Formula 2 Formula 3(i)

b) activating the compound of Formula 3(i) to form a compound of Formula 4(i):

R¹ A ^'Ox Formula 4(i)

wherein X represents a leaving group; and c) coupling the compound of Formula 4(i) to a compound of Formula 5:

R²-^ . ³

Formula 5 to form a compound of Formula 1(i). Preferences for Ar, R¹, R², R³, the compounds of Formula 2 and 5 and the stereoselective reduction system are as described herein before. In a further preferred embodiment, the compound of Formula l(ii):

is prepared analogously from the corresponding compounds of Formula 3(ii) and 4(ii):

R¹ R¹ Ar-^*OH Ar^^OX Formula 3(ii) Formula 4(ii)

by reducing a compound of Formula 2 with a stereoselective reduction system to form a compound of Formula 3(ii); activating the compound of Formula 3(ii) to form a compound of Formula 4(ii); and coupling the compound of Formula 4(i) to a compound of Formula 5 to form a compound of Formula 1(ii). The invention is illustrated by the following Examples.

EXPERIMENTAL

Stage 1

Materials: -

Method: Triphosgene (23.25g) was dissolved in dry Toluene (140ml). The solution was cooled to -78°C, then N-methylethylamine (14g) added dropwise and the mixture allowed to warm to room temperature. Pyridine (65.6g) was dissolved in dry toluene (80ml), and this solution was added to the reaction mixture, which was stirred at room temperature. The mixture was sampled for analysis after 2 hours, then left to stir at room temperature overnight. A slurry of 3-hydroxyacetophenone (32.2g) in toluene (150ml) was prepared, and the previous reaction mixture was added to this. The combined reaction mixture was then heated to reflux overnight , whereupon GCMS analysis indicated > 90% conversion. After cooling to room temperature, the product was isolated from the reaction mixture by washing with aqueous NaOH (2M, 500ml), then concentration in vacuo. This afforded 35.4g of crude product, which was further purified by column chromatography

(silica gel, 1% MeOH in CH₂CI₂) to afford the desired product as a colourless oil (26g,

67%).

Stage 2

Materials:

Method:- In a 200ml round bottom flask was charged (RhCp^*CI₂)₂ (55.9mg) and acetonitrile (36ml). CSDPEN ligand (77.3mg) was then added and the mixture stirred to effect dissolution. The ketone substrate was then added and a controlled flow of Nitrogen (80- 100ml/min) passed through the solution. TEAF (5:2 formic acid : triethylamine) was then added dropwise over 2 hours, and the mixture then left to stir at ambient temperature overnight. Analysis then indicated 90% conversion. The mixture was worked-up by quenching with 200ml of 2M aqueous NaOH, extracting with CH₂CI₂ (200ml) and drying (Na₂SO₄) and concentrating the organic extracts to afford a dark oil (3.94g, 95%). Chiral shift NMR analysis indicated an enantiomeric excess of 95%.

Stage 3

Materials:

Method:- The alcohol obtained in stage 2, without further purification, (3.40g, 15.25mmol) was dissolved in dry THF (40ml) and cooled in an ice-water bath. Then, triethylamine (4.60g, 45.75mmol) was added and the solution kept cooled. Methanesulfonic anhydride (3.45g, 19.8mmol) was dissolved in dry THF (30ml) and added to the cold reaction mixture dropwise over 30 minutes. The reaction mixture was stirred at 0°C for 2 hours until conversion was 100% (GC) and then dimethylamine (46mmol, 2M solution in THF) was added and the reaction mixture allowed to reach room temperature. After 48 h stirring conversion was 70% (GC), additional dimethylamine (46mmol) was then added and 24 hours later the conversion achieved was 99%. The reaction mixture was poured into 1 M HCI_(aq) (350ml) and extracted with dichloromethane (350ml), the organic layer was extracted again with 1 M HCI_(aq) (200ml) and both aqueous layers were combined and neutralized with 2M NaOH_(aq) until the pH was above 10, then extracted with dichloromethane (3x350ml), the organic layers combined, dried and the solvent distilled to obtain 3.34g (87%) of the final product as a reddish oil. The specific optical rotation of the product was measured at -31° (3% solution in

MeOH) (lit. Rivastigmine -32°, Helv. Chim. Acta, 73(3), 1990, 739-753).

Claims

1. A process for the preparation of a compound of Formula 1 :

Formula 2 Formula 3

b) activating the compound of Formula 3 to form a compound of Formula 4:

R¹ Ar^^OX Formula 4

^R _,.^R3

Formula 5 to form a compound of Formula 1.

2. A process according to Claim 1 wherein Ar and R¹ are different and a stereoselective reduction system is employed.

3. A process according to Claim 2 wherein the stereoselective reduction system employs a chiral coordinated transition metal catalysed transfer hydrogenation process.

4. A process according to Claim 3 wherein the chiral coordinated transition metal catalysed transfer hydrogenation process employs a transfer hydrogenation catalyst of formula (a) E M Y' V (a) wherein: R⁵ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents an optionally substituted nitrogen; B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous; E represents a linking group; M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

5. A process according to Claim 4 where the transfer hydrogenation catalyst is a transition metal catalyst of Formula B(i-iv)

B(iϋ) B(iv)

6. A process according to any one of Claims 1 to 5 wherein he compound of Formula 2 is a compound of Formula 2a:

wherein R^a and R^b are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C_1-4-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; and R⁴ each independently represents hydrogen or a substituent group.

7. A process according to Claim 6 wherein the compound of Formula 2 is a compound of Formula 2b:

8. A process according to Claims 6 or 7 wherein R⁴ are all hydrogen and R^a and R^b are each independently H, Me or Et.

9. A process according to Claim 8 wherein the group -NR^aR^b is the group -NMeEt.

10. A process according to any one of Claims 1 to 9 wherein X an acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl or toluenesulphonyl group.

1 1. A process according to any one of Claims 1 to 10 wherein the compound of Formula 1 is obtained in enantiomeric excess.

12. A compound of Formula 2a:

13. A compound of Formula 2b:

wherein R^a and R are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C_1-4-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; and R⁴ each independently represents hydrogen or a substituent group.

14. A compound of Formula 3a:

wherein R^a and R^b are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C^-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; and R⁴ each independently represents hydrogen or a substituent group.

15. A compound of Formula 3b:

wherein R^a and R^b are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C_1-4-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system; and

R⁴ each independently represents hydrogen or a substituent group.

16. A compound of Formula 4a:

wherein R^a and R are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C^-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system;

R⁴ each independently represents hydrogen or a substituent group; and

X an acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl or toluenesulphonyl group.

17. A compound of Formula 4b:

wherein R^a and R^b are each independently represents H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C^-alkyl) or, together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system;

R⁴ each independently represents hydrogen or a substituent group; and X an acetyl, trifluoroacetyl, methanesulphonyl, trifluoromethylsulphonyl or toluenesulphonyl group.

18. A compound according to any one of Claims 14 to 17 wherein the compound is the R or the S isomer.