WO2005028437A1

WO2005028437A1 - Process for the preparation of secondary aminoalcohols

Info

Publication number: WO2005028437A1
Application number: PCT/GB2004/003947
Authority: WO
Inventors: Andrew John Blacker; Juliette Martin; Michael Scott Howarth
Original assignee: Avecia Pharmaceuticals Limited
Priority date: 2003-09-18
Filing date: 2004-09-16
Publication date: 2005-03-31
Also published as: GB0322559D0

Abstract

There is provided a process for the preparation of a compound of Formula (1) wherein Arl and Ar2 each independently represent organic groups comprising an aromatic moiety; and R1 represents an alkyl or aryl 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).

Description

PROCESS FOR THE PREPARATION OF SECONDARY AMINOALCOHOLS

The present invention concerns a process for the preparation of secondary aminoalcohols, particularly the stereospecific preparation of chiral secondary aminoalcohols. According to the present invention, there is provided a process for the preparation of a compound of Formula 1 :

Ar' Ar ' N I H OH Formula 1 wherein Ar¹ and Ar² each independently represent organic groups comprising an aromatic moiety; and

R¹ represents an alkyl or aryl group; said process comprising: a) reducing a compound of Formula 2 to form a compound of Formula 3:

R¹ R¹ Ar¹^0 -^OH Formula 2 Formula 3

b) activating the compound of Formula 3 to form a compound of Formula 4: R¹ Ar^l/^OX Formula 4

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

Ar' H₂N OH Formula 5 to form a compound of Formula 1. Ar¹ and Ar² each independently may represent a substituted or unsubstituted phenyl or naphthyl group, or a heteroaryl group. Preferably Ar¹ represents an alkyl group, preferably a C_1- alkyl group substituted by an aromatic moiety, most preferably by a phenyl group. Most preferably, Ar¹ represents a group of formula -CH₂-Ar³, wherein Ar³ represents an optionally substituted indolyl group. Ar² preferably represents an optionally substituted phenyl group. When any of Ar¹, Ar² or Ar³ is substituted, one or more substituents may be present. Substituents are commonly selected from the group consisting of optionally substituted alkoxy (preferably C_1-4-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphato, sulpho, nitro, cyano, halo, ureido, -S0₂F, hydroxy, ester, -NR^aR^b, -COR^a, -CONR^aR , -NHCOR⁸, carboxyester, sulphone, and -S0₂NR^aR^b wherein R^a and R^b are each independently H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially C^-alkyl) or, in the case of -NR^aR^b, -CONR^aR^b and -S0₂NR^aR^b, R^a and R^b 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_1-4 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 P¹ represents a protecting group, and Q represents a group of formula -NR^aR as previously described, especially a group of formula -NEt₂. Compounds of Formula 2a can be prepared by protecting a compound of formula:

where Q is as previously defined, which may be prepared by the method disclosed in JP-

A-2000279190. Examples of protecting groups which may be represented by P¹ include those known in the art for the protection of indolyl nitrogens. Examples of suitable protecting groups for indolyl nitrogen atoms are given in "Protective Groups in Organic Synthesis" by TW Greene & PGM Wuts, Wiley-lnterscience, 3rd Edition, 1999, ISBN 0- 471-16109-9, incorporated herein by reference, and include alkylsilyl, especially trialkyl silyl, such as t-butyldimethylsilyl or trimethylsilyl groups. Preferred protecting groups which can be represented by P¹ are electron withdrawing relative to the indolyl nitrogen, and include alkanoyl and alkoxycarbonyl groups, for example t-butoxycarbonyl. In certain other embodiments, the compound of Formula 2 is a compound of Formula 2b:

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, W098/42643, and WO02/44111 each of which is incorporated herein by reference. The preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A): \ ,^B Y ^•V Formula (A)

wherein: R³ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents -NR⁴-, -NR⁵-, -NHR⁴, -NR⁴R⁵ or -NR⁵R⁶ where R⁴ is H, C(0)R⁶,

S0₂R⁶, C(0)NR⁶R¹⁰, C(S)NR⁶R¹⁰, C(=NR¹⁰)SR¹¹ or C(=NR¹⁰)OR¹¹, R⁵ and R⁶ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁰ and R¹ are each independently hydrogen or a group as defined for R⁶; B represents -0-, -OH, OR⁷, -S-, -SH, SR⁷, -NR⁷-, -NR⁸-, -NHR⁸, -NR⁷R⁸, -NR⁷R⁹,

-PR⁷- or -PR⁷R⁹ where R⁸ is H, C(0)R⁹, S0₂R⁹, C(0)NR⁹R¹², C(S)NR⁹R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁷and R⁹ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹² and R ³ are each independently hydrogen or a group as defined for R⁹; 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 when Y is not a vacant site that at least one of A or B carries a hydrogen atom. 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^5"7 or R^9'11 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^5"7 or R^9"11 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^5"7 or R9^9"11 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^5"7 or R^9"11 include C_2-20, and preferably C₂.₆ 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^5"7 or R^9"11 include

C₂.₂₀, and preferably C_2-ι₀ 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^5"7 or R^9"11 may contain

1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^5"7 or R^9"11 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^5"7 or R^9"11 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^5"7 or R^{9" 1} include -CF₃ and -C₂F₅. Heterocyclic groups which may be represented by one or more of R^5"7 or R^9"11 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 heterocyclic rings. The heterocyclic group will contain at least one heterocyclic 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 heterocyclic groups which may be represented by R^5"7 or R^{9" 1} include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups. When any of R^5"7 or R^9"11 is a substituted hydrocarbyl or heterocyclic 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^5"7 or R^9"11 above. One or more substituents may be present. R^5"7 or R^9"11 may each contain one or more chiral centres. The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R³ includes optionally substituted aryl and alkenyl ligands. Optionally substituted aryl ligands which may be represented by R³ may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic 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 enantiomehc and/or diastereome c centres, it is preferred that the enantiomerically and/or diastereomerically 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 R³ include C_2-30, and preferably C_6-ι₂, 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-norbornadiene. Cyclo-octa-1 ,5-diene is especially preferred. Optionally substituted cyclopentadienyl groups which may be represented by R³ 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 diastereomerically 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 -NR⁴-, -NHR⁴, NR⁴R⁵, -NR⁸-, -NHR⁸ or NR⁷R⁸ wherein R⁵ and R⁷ are as hereinbefore defined, and where R⁴ or R⁸ is an acyl group represented by -C(0)R⁶ or -C(0)R⁹, R⁶ and R⁹ independently are often linear or branched C_1-7alkyl, C_1-8-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R⁴ or R⁹ include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl, groups. When either A or B is present as a sulphonamide group represented by -NR⁴-, - NHR⁴, NR⁴R⁵, -NR⁸-, -NHR⁸ or NR⁷R⁸ wherein R⁵ and R⁷ are as hereinbefore defined, and where R⁴ or R⁸ is a sulphonyl group represented by -S(0)₂R⁶ or -S(0)₂R⁹, R⁶ and R⁹ independently are often linear or branched C_1-8alkyl, d-βcycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl and especially p-toluenesulphonyl groups and naphthylsulphonyl groups. When either of A or B is present as a group represented by -NR⁴-, -NHR⁴, NR⁴R⁵, -NR⁸-, -NHR⁸ or NR⁷R⁸ wherein R⁵ and R are as hereinbefore defined, and where R⁸ or R⁸ is a group represented by C(0)NR⁶R¹°, C(S)NR⁶R¹⁰, C(=NR¹⁰)SR¹¹, C(=NR¹⁰)OR¹¹, C(0)NR⁹R¹², C(S)NR⁹R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁶ and R⁹ independently are often linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, Cι.₈cycloalkyl or aryl, for example phenyl, groups and R^10-13 are often each independently hydrogen or linear or branched C_halky!, such as methyl, ethyl, isopropyl, Cι.₈cycloalkyl or aryl, for example phenyl, groups. When B is present as a group represented by -OR⁷, -SR⁷, -PR⁷- or -PR⁷R⁹, R⁷ and R⁹ independently are often linear or branched Cι.₈alkyl, such as methyl, ethyl, isopropyl, Cι.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 heterocyclic 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^5"7 or R^9"11 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_1-6 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_1-4- 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)-(+)-norephedhne, (1R,2S)-(+)-cis-1-amino-2-indanol, (1 S,2R)-2-amino-1 ,2-diphenylethanol, (1 S,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 R³ is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when R³ is an optionally substituted cyclopentadienyl ligand. It is preferred that M, the metal, is rhodium present in valence state III and R³ 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_1-4 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, R³ 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. Particularly preferred transfer hydrogenation catalysts are those Ru, Rh or Ir catalysts of the type described in WO97/20789, W098/42643, 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 with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene or optionally substituted cyclopentadiene ligands. Examples of these especially preferred catalysts include that catalysts obtained by reacting rhodium pentamethylcyclopentadiene dichloride dimer with N-sulphonyl- diphenylethylenediamines, for example N-p-tolylsulphonyl-(S,S)-diphenylethylenediamine, under the conditions described in Example 6 of W098/42643 to give a catalyst of Formula

Cp* = Pentamethylcyclopentadiene

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 acetonit le, 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 piperidine. 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; trimethylamine, triethylamine, di-isopropylethylamine and py dine. 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 are propan-2-ol, butan-2-ol, triethylammonium 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 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 groups, especially a chloro or bromo group. Examples of preferred leaving groups which may be represented by X include acetyl, trifluoroacetyl, mesyl, trifluoromethylsulphonyl and tosyl groups, and preferred compounds of formula X-L are the corresponding chloro compounds. Compounds of Formula 5 can be prepared by cyanating a compound of formula Ar^-CHO, followed by reduction of the cyano group to form an amino group, and hydrolysis. Preferably a chiral cyanation system is employed, most preferably a cyanation system as described in J. Am. Chem. Soα, 1999, 121, 3968-73 or in International patent application publication number WO02/10095, both of which are incorporated herein by reference. A preferred cyanation system comprises a trialkylsilyl cyanide source, especially trimethylsilylcyanide, and a chiral vanadiumoxide-Salen ligand complex. Cyano groups are can be reduced by reduction systems known in the art for reducing cyano groups to form amino groups, and include hydrogenation, for example with hydrogen gas in the presence of a catalyst, such as Raney nickel, or with a hydride reducing agent, such as NaBH₄, LiAIH₄, and preferably a borane, such as a borane/THF complex. Hydrolysis is commonly effected by contact with an aqueous mineral acid, for example HCI. Preferred compounds of Formula 5 are compounds of Formula 5a and 5b, and enantiomers thereof:

The coupling of the compounds of Formulae 4 and 5 preferably takes place under conditions known in the art for nucleophilic displacement, commonly in the presence of a base. Preferably, biphasic reaction conditions, wherein one of the phases is an aqueous phase are employed, optionally in the presence of a phase transfer agent. Where the compound of Formula 1 comprises a protecting group, this may be removed if desired using conditions appropriate to the protecting group present. Compounds of Formula 2a, and the corresponding compounds of Formulae 3 & 4 are novel. Accordingly, a further aspect of the present invention provides compounds of formulae

and

wherein P¹, Q and X are as previously described, including enantiomers of the compounds of formula 3 and 4. The present invention is illustrated without limitation by the following examples. General scheme:

THF Stereoselective Reduction

2) purification

R = CH₂CONEt₂

Step l

Compound 1 Compound 2

Materials:

Procedure Compound 1 (60.56g) was charged to a 2L round bottom flask. DMAP (4- (dimethylamino)-pyridine, 2.50g) and BOC-anhydride (20. Og, 0.46 eq) were charged with 600 mis of THF. Using an oil bath, the contents were heated to 40°C and held at this temperature. After 1 hour a second charge of BOC-anhydride (24.32g, 0.56 eq) was added. This was then held at 40°C for a further 2 hours. Water (300 mis) and DCM (300 mis) were added to the reaction mass. This was agitated at ambient and the layers allowed to separate. The bottom organic layer (1044.6 g) was removed and the aqueous phase was back extracted with DCM (300 mis). The organic layers were then combined and concentrated by rotary evaporation to afford a brown/ black oil of mass 88. Og. Compound 2 was purified by column chromatography. A 50/50 % v/v ethyl acetate/ n-hexane eluent was used. Approximately 30g of silica was used per 1g of crude material. The material was dissolved in a small amount of DCM prior to loading in order to reduce the viscosity to a suitable working level. Silica TLC plates were used to monitor the column fractions. A total of four separate columns were carried out, in parallel.

The fractions containing pure Compound 2 were combined. These were concentrated in vacuo down to give a total of 19g pure Compound 2.

Step 2

Scheme:

Compound 2 Compound 3 Materials: -

Cp^* = pentamethylcyclopentadiene A 250 ml jacketed reactor set up with overhead stirrer, condenser, thermocouple and sparge pipe situated below the level of the agitator was assembled. The purified Compound 2 (9g) was charged to the reactor with DMF (39.5g). Freshly made catalyst (Rh Cp*CI₂)₂ (69.1 mg) and ligand S,S-Ts DPEN (N-p-toluenesulphonyl-1 ,2- diphenylethylene-1 ,2-diamine, 817 mg) in DMF (7.5g) was then charged. The contents were cooled to 10°C and a nitrogen sparge rate of 1.2 L/min was established. The agitation was on full at 400 RPM. A solution of TEAF (thethylamine:formic acid mixture in 2:5 mole ratio, 4.65 mis) was added drop-wise over 11.5 hrs overnight. The reaction was quenched with water (50mls), a 15°C exotherm (10-25°C) was observed upon addition of the first 20 mis. The remaining 30 mis was added at <20°C (bath temperature: 0°C). Toluene was then charged (60 mis) at 20°C. The reaction mass was agitated and allowed to settle respectively for 30 minutes each. The sparge was switched off at this point. The bottom red aqueous phase was back extracted with toluene (3x50mls). The three resulting toluene phases were combined with the first black/brown organic phase. The combined reaction mass was concentrated down to a residual mass of 14.18g. The material obtained was then subjected to 3 repeats of the reduction and work up procedure, using freshly prepared catalyst for each repeat, to achieve 87% conversion, and a product mass of 7.8 g.

Step 3

Scheme: -

Compound 3 Compound 4 Materials:

Compound 3 was dissolved in 70 ml of DCM and 3.63 ml of Et₃N was added in one portion. The reaction was then cooled to 0°C in an ice/ salt bath and placed under a N₂ atmosphere. 1.41 ml of MsCI (methanesulphonyl chloride) was added drop-wise keeping the temperature below 10°C. The reaction was then stirred at 0-5°C for 15 minutes then allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of 100 ml of water. The organic layer was separated then washed using 2x100 ml of water. The organic layer was then dried using Na₂S0₄ and concentrated to dryness to give 7.3g of product corresponding to 89% yield of Compound 4. Step 4

Materials: -

(S,S) VO(salen) catalyst was charged to a 2L 3-neck RB flask fitted with a large ptfe bladed agitator, thermometer and condenser (connected to a bleach/caustic scrubber), washing in with 459mls DCM. Agitation was started and 3-chlorobenzaldehyde was washed in with 46mls DCM. The TMSCN (thmethylsilyl cyanide) was then charged quickly as a steady stream and washed in with the remaining 89 mis DCM. The temperature was observed to rise from 19 to 25°C before a cooling water bath was applied, and the reaction cooled back to 23°C. The reaction was agitated at ambient for 23 hours sampling at various intervals. Once disappearance of starting material was observed, the DCM was removed by evaporation in vacuo and the green residues were eluted through a ca138g silica bed on a 10cm split funnel eluting with ca 827 mis 10:1 v/v hexane:ethyl acetate. The solvent was then removed from the filtrates in vacuo. Weight of residues = 115.4g, a 98% conversion with an 83.4% ee.

Step 5 1. Borane.THF THF

TMS-Nitrile Aminoalcohol

Materials:

TMS-Nitrile (100g) was charged to a jacketed 3L split neck reaction flask fitted with a 4 bladed agitator, thermometer and condenser. The bath was set at 10°C. THF

(200mls) was then charged to wash in the TMS-Nitrile. Borane.THF complex (818 mis) was charged over 45 minutes via an equalizing dropping funnel. The temperature was observed to rise to 22°C from 15°C after approximately 250 ml of the borane complex had been added. The bath temperature was lowered to 5°C and maintained at this temperature throughout the addition. At the end of addition an orange solution resulted.

The reaction mixture was then heated to reflux temperature (65°C) and maintained at this temperature for 1 hour. HPLC analysis indicated that no starting material was present.

The resulting yellow solution was cooled to ambient (jacket at 10°C) and methanol (202 ml) was carefully added over 40 minutes. Effervescence was observed and a temperature rise from 25°C to 32 °C. The reaction mixture was held at 10°C overnight resulting in a purple solution. HCI in Ether (865ml) was then charged to the reaction mixture at 10°C over 6 hours. White fumes were seen initially and then some precipitation. The crystallization was held at 10°C for two days resulting in a white precipitate formation and pale blue/ green solution. The solids were filtered through a Buchner funnel, washed with diethyl ether (3x150 ml) and pulled dry on the filter for 2 hours. Mass of aminoalcohol = 62.01 g (71.3% yield), % ee: 99.0%

Step 6

Scheme: -

Compound Aminoalcohol

Materials:

Procedure: - Bu NHS0₄, aminoalcohol and Compound 4 were all charged to a flask, cooled to 0°C, then DCM (173ml) was added, with stirring. NaOH (25% aq solution, 173ml) was then charged drop-wise which gave rise to a biphasic mixture. The mixture was then warmed to room temperature and left to stir overnight. LC analysis then indicated complete consumption of Compound 4 and formation of the desired product. The mixture was worked up by addition of 200ml each of DCM and water, separation of the phases, further extraction of the aqueous phase with DCM (2 x 100ml). The combined organic extracts were dried (Na₂S0₄) and concentrated in vacuo to afford a crude product as an oil.

Claims

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

Formula 1 wherein

Ar¹ and Ar² each independently represent organic groups comprising an aromatic moiety; and

R¹ R¹ Ar¹^0 Ar¹-"^OH Formula 2 Formula 3

b) activating the compound of Formula 3 to form a compound of Formula 4: R¹ Ar¹-^OX Formula 4

Ar' H₂N OH Formula 5 to form a compound of Formula 1.

2. A process according to Claim 1 where the compound of Formula 2 is a compound of Formula 2a:

wherein P¹ represents a protecting group, and Q represents a group of formula

-NR^aR^b wherein R^a and R^b are each independently H, optionally substituted aryl, especially phenyl, or optionally substituted alkyl (especially

or, R^a and R^b together with the nitrogen atom to which they are attached represent an aliphatic or aromatic ring system.

3. A process according to Claim 1 where the compound of Formula 2 is a compound of Formula 2b:

4. A process according to any one of Claims 1 to 3 wherein the compound of Formula 5 is a compound of Formula 5a or 5b, and enantiomers thereof:

Formula 5a

5. A process according to any one of Claims 1 to 4 wherein the reduction of compounds of Formula 2 is accomplished employing a stereoselective reduction system.

6. A process according to Claims 5 wherein the stereoselective reduction system comprises transfer hydrogenation of a compound of Formula 2 in the presence of a chiral coordinated transition metal catalyst.

7. A process according to Claim 6 wherein the chiral coordinated transition metal catalyst is a catalyst of Formula (A): \ ,^B _γ' .3 Formula (A) wherein: R³ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents -NR⁴-, -NR⁵-, -NHR⁴, -NR⁴R⁵ or -NR⁵R⁶ where R⁴ is H, C(0)R⁶,

S0₂R⁶, C(0)NR⁶R¹°, C(S)NR⁶R¹⁰, C(=NR¹⁰)SR¹¹ or C(=NR¹⁰)OR¹¹, R⁵ and R⁶ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R ⁰ and R¹¹ are each independently hydrogen or a group as defined for R⁶; B represents -0-, -OH, OR⁷, -S-, -SH, SR⁷, -NR⁷-, -NR⁸-, -NHR⁸, -NR⁷R⁸, -NR⁷R⁹,

-PR⁷- or -PR⁷R⁹ where R⁸ is H, C(0)R⁹, S0₂R⁹, C(0)NR⁹R¹², C(S)NR⁹R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁷and R⁹ 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 R⁹; 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 when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

8. A process according to Claim 7 wherein the chiral coordinated transition metal catalyst is a catalyst of Formula

Cp* = Pentamethylcyclopentadiene

9. A process according to any one of Claims 6 to 8 wherein transfer hydrogenation process comprises the use of triethylamine-formic acid as a hydrogen source.

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