GB2464101A - A dynamic thermodynamic resolution process for amines using an iridium catalyst - Google Patents

Abstract

The present invention is concerned with a process for the racemisation and recovery of optically active amines. After separation of the desired isomer from an isomer mixture, the remaining isomers may be recycled by racemisation and further amounts of the desired isomer then subsequently recovered. The present invention thus provides a process for racemising and recovering such isomers of primary, secondary and tertiary amines and to certain compounds which are produced in the process. The present invention also relates to a dynatnic thermodynamic resolution process for a primary, secondary or tertiary amine, such as sertraline. Racemisation is accomplished by the use of an iridium catalyst IrX2Cp, where X is dhloro, bromo or iodo and Cp is an optionally substituted cyclopentadienyl group. The catalyst can be recovered by passing NH3through the solution, which forms a solid IrX2Cp-NH3-complex.

Description

COMPOUNDS AND THEIR USE

The present invention is concerned wfth a process for the racemisation and recovery of optically active amines. Many therapeutically active compounds are primary or secondary amines which can exist as a number of different enantiomeric or diastereomeric forms.

After separation of the desired isomer, the remaining isomers may be recyded by racemisation and further amounts of the desired isomer then subsequently recovered.

The present invention thus relates to a process for racemising and recovering such isomers of primary, secondary and tertiary amines and to certain compounds which are produced in the process. Sertraline is a classic example of a therapeutically active amine that lends itself to this process. Thus, more specifically, the present invention relates to io the preparation of (1 S,4S) N-methyl-4-(3,4-dichlorophenyl)-1,2,34-tetahydro-1-naphthaleneamine (the compound of formula 1), commonly known as sertraline.

Sertraline is generally prepared in the form of its hydrochloride salt, from stereoisomers thereof, for example the cis (1R,4R) isomer of formula 2 [(1R,4R) N-methyl-4-(3,4-dichlorophenyl)-1,2,34-tetrahydro-1 -naphthalene-amine] the trans (1 S,4R) isomer of formula 3, or the trans (1 R,4S) isomer of formula 4, or mixtures or salts thereof. 0c

(1) 2) (3) (4) Sertraline has two chiral centres and hence has four stereoisomeric forms, namely, the (1R,4R), (1S,4S), (1R,4S), and (1S,4R) isomeric forms of sertraline. Of these, the active stereoisomer for therapeutic purpose is the cis (1 S,4S) isomer of formula 1.

These isomers of formulas 2, 3 and 4 are undesired stereoisomers of sertraline of formula 1, and are invariably co-produced during the manufacture of this drug by known processes such as that disclosed in US453651 8 and US4556676.

The developed commercial process to prepare sertrane employs an SMB (simulated moving bed) chromatographic resolution of sertralone in >99% ee followed by diastereoselective reductive amination to give 95% cis and 5% trans sertraline; the 4(R)-sertralone can be racemised with an alkoxide base.

Although a number of processes have been described for the production of setraline or intermediates used in the production of setraline, see US4536518, US4556676, US4777288 US4839104, W098/15516, US5196607, US5466880, Tetrahedron, 48(47), 10239 (1992), W095/15299, W098!27050, Organic Lett., 1(2), 293 (1999), in all the methods described, eventual isomer Separation is inevitable. These documents describe processes for producing sertralme and the disclosures in these documents illustrate the problems in producing optically pure sertraline and the resulting low yields and waste that arises due to production of unwanted isomers.

In US5082970 there is described a process for recycling the trans isomer of sertraline.

However, this process appears only to isomerise only one of the two chiral centres of the trans isomer of sertraline.

In WO01/49638 and W005!023752 there are described processes for the isomerisation of both chiral centres of setraline isomers. WO01!49638 requires that the amine first be oxidised to an imine. This imine intermediate is subjected to an isomerisation process at the benzylic chiral centre and then subsequently reducing the imine non-stereospecifically. W0051023752 seeks to isomerise the benzylic chiral centre first before subjecting the amine to oxidation and reduction either directly of the imine or indirectly by reaction of the ketone with an amine and reduction of the mine so produced.

Both of these methods suffer from the disadvantage that oxidation of amines to imines is difficult and not only requires the use of strong oxidants in stoichiometric amounts but often results in the production of unwanted ketone which adds to the complexity of the recycle.

US7408082 discloses a process for the production of sertraline for recycling the undesired stereoisomers produced during manufacture by an iterative process to increase the overall yield of sertraline. The process involves the use of a transition metal catalyst to isomerise the C-i position.

Dynamic kinetic resolution is a technique that has also been used in the art to effect resolutions of amines. However, there are a number of industrial imitations of enzymatic amine DKR processes. For example, the reaction scope is limited by the enzymes' ability to reso've of primary and secondary amines. Another problem is the availability of (R) selective enzymes. Furthermore, the activity of enzymes in organic solvents is generally low which necessitates high catalyst loadings, high temperatures and long reaction times.

These factors make the enzyme DKR process of limited utility.

Whilst diastereomeric crystallisations have the advantage of being robust and simple to operate, the low yields give inefficient performance, due to low productivity, long cycle times, poor asset usage and large waste streams, especially if multiple recrystalisation or chiral acid recovery is required. Racemisation of the soluble waste amine isomer would enable its conversion to product, improving the yield and productivity in these processes.

is A dynamic thermodynamic resolution (DTR) diastereomeric crystallisation process uses a selected homochiral acid to form a salt selectively with one enantiomer, the diastereomer thus formed has for example a lower solubility than the other diastereomeric salt and crystallises from the solution, concurrently the soluble isomer is racemised, making more of the less soluble diastereomer available for crystallisation. n this way the racemate is turned into a single isomer product, effectively doubling the yield.

The present invention aims to overcome some of the problems of the prior art processes.

It is thus an aim to provide a process for recovering, and optionally regenerating, catalyst from an amine racemisation process. It is a further aim to provide a process for racemising single isomers or mixtures of enantiomers and/or diastereolsomers of therapeutically active primary, secondary or tertiary amines in which more efficient use of the catalysts can be made and/or catalyst turnover can be extended. It is also an aim to provide a process from which the catalyst can be recovered easily and economically. It is a further aim to provide an efficient process in which catalyst can be recycled without the need for further treatment. It is a further aim to provide a process that can be operated continuously or semi-continuously.

The present invention satisfies some or all of the above aims and overcomes the prior art problems.

We have thus found that a limited number of iridium pentamethyl cylopentadenyl catalysts such as iridium pentamethylcyclopentadienylduodide, SCRAM', can be used for the efficient racemisation of primary, secondary and tertiary amines such as those used as pharmaceuticaUy active drugs or as drug intermediates. We have also found that they can be used in dynamic kinetic resolution (DKR) of amines, and n particular for the resolution of secondary amines.

The present invention therefore concerns the development of a dynamic thermodynamic crystal resolution process potentiaUy applicable to a broad range of chiral amines by virtue io of the fact that the racemisation does not rely on a low pKa proton at the chiral centre.

The process retains the simpcity and robustness diastereomeric crystaHisation, and enables low yielding crystallisation process to be considered and might be preferred over asymmetric processes to make amines.

is The practical difficulty with carrying out a crystalsation DIR process is the need to operate under condillons that aHow selective crystalsation of the least soluble diastereomer whilst permitting the racemsaton to take place. It is known that a catalyst such as SCRAMTM s more active at higher temperatures which runs counter to the conditions required for crystallsaton.

In the case of sertraline, we have found racemisation of the chiral amine centre can be achieved using the iridium pentamethyl cyclopentadienyl catalysts and the tertiary carbon centre using an alkoxide base. Ideally both racemisation steps and the diastereomeric crystallisaton of the present invention would be operated in the same solvent using a chiral agent such as mandelic acid as the resolvng reagent. Other important benefits of the process of the nvention include: the removal and possible recycle of the catalyst, as this has a significant impact on cost and product purity and the order of racemisation ie catalyst then base, or base then catalyst, or both together.

Thus, the invention provides a process in which a primary or secondary amine in optically pure form, or in the form of a mixture of isomers, can be subject to racemisation at its amine chiral centre and the catalyst recovered after use. The invention also provides recovered catalyst compounds which can be used to regenerate catalyst material or which can be used directly n the reaction without further transformation. The invention also relates to certain intermediate compounds which can be used as precursors of optically pure amine isomers and from which re-usable catalyst can be recovered.

According to one aspect, the present invention provides a dynamic thermodynamic resolution process for a primary, secondary or tertiary amine, the process comprising the steps: (a) providing a solution comprising two or more amine isomers; (b) reacting the solution with IrX2Cp and/or IrX2CpNH3 wherein each X is independently chloro, bromo or iodo and Op is a cydopentadienyl group which may be optionay substituted by from 1 to 5 independently selected hydrocarbyl substituents; (c) passing NH3 though the solution obtained in step (b) to generate IrX2CpNH3 and recovering it as a solid from the solution; is (d) recovering preferentially a sing'e desired amine isomer from the solution of step (c).

(e) recovering the unwanted isomer or isomers from the solution of step (d) and returning said unwanted isomer or isomers to step (a) of the process and optionally adding a further quantity of the two or more amine isomers to the solution.

(f) optionally, repeating steps (b) to (e) for a desired time period or number of cycles.

In an embodiment, the solution of two or more amines is provided in a non-polar aprotic solvent.

In the above formulae in steps (b) and (c), each X is independendy chloro, bromo or iodo.

Afternatively, each X may independently be halo (i.e. chloro, bromo or iodo), CO or OH.

In another embodiment, the step of recovering the single desired amine isomer (step (d)) is accomplished by the addition of a chiral resolving agent and preferential crystallisation of the desired diastereoisomer. In this case, the desired amine is recovered subsequently from the diastereoisomer after crystallisation by conventiona' methods.

Afternative methods for treating the solution of step (d) to obtain a desired amine isomer include: the use of a chiral resolving agent, seeding crystalisation, enzymatic resolution and chromatography.

In an embodiment, the Ir-ammonia complex formed in step (c) can be returned to step (b) in addition to or in place of the IrX2Cp. This means that a reduced charge of lrX2Cp can be used when fresh amine isomers are added. The ft-ammonia complex has the formula IrX2CpNH3 where X and Cp are as previously defined.

In a further embodiment, the solvent used in steps (a) to (f) is the same solvent.

Preferab'y this solvent is a non-polar aprotic solvent. The solvent is preferably an ether, an aromatic or a halogenated solvent, preferab'y an halogenated aliphatic so'vent. More preferably, this solvent is selected from the group comprising: toluene, mesityene, cumene, tertbutylmethylether, tertbutylacetate, cyclopentylmethylether or 1,4-dioxane.

According to one aspect of the present invention, there is provided a process for recovery is of a metal catalyst from a dynamic thermodynamic resolution process, the process comprising the following steps: (a) providing a solution comprising an iridium cyclopentadienyl catalyst of formula lr2X4Cp2 or lrX2Cp wherein each X is independently selected from chloro, bromo or odo; and Cp is a cyclopentadienyl group which may be optiona'ly substituted by from 1 to 5 independently selected hydrocarbyl substituents in a non-polar aprotic solvent; the solution also comprising one or more isomers of an optically active amine; (b) passing gaseous ammonia through the reaction mixture to produce solid material; and (c) recovering the solid material.

In the above formulae in step (a), each X is independently chloro, bromo or odo.

Aiternatively, each X may independently be halo (i.e. chloro, bromo or iodo), CO or OH.

The resulting complex has the formula: IrX2CpNH3, where X and Cp are as previously defined. Preferably X is iodo. Afternatively, X may be CO or OH. These are novel compounds and form part of the invention.

In an embodiment, the solid material is suspended in a non-polar aprotic solvent and heated to a temperature of from 35°C to 150°C. Alternatively, the solid material may be added to an amine racemisation process directly without further chemical treatment. This process may be operated as a discrete step, or as part of a continuous process.

According to another aspect of the present invention, there is provided an amine-iridium complex of Formula (I) amine -IrX2Cp (I) wherein the amine is a primary, secondary or tertiary amine; each X is independently chloro, bromo or odo; and Cp is a cyclopentadienyl group which may be optionally substituted by from 1 to 5 independently selected hydrocarbyl substituents.

i5 In another aspect of the present invention, there is provided an mine-iridium complex of Formula (II) [imine -IrHXCp]HX (il) wherein the mine is formed from a primary, secondary or tertiary amine and wherein each X is independently chloro, bromo or odo and Cp is a cyclopentadienyl group which may be optionally substituted by from 1 to 5 independently selected hydrocarbyl substituents.

In the above aspects relating to the amine-iridium complex and mine-iridium complex of Formulae (I) and (II) respectively, X iS ndependenty chloro, bromo or iodo. Alternatively, each X may independently be halo (i.e. chloro, bromo or odo), CO or OH.

The mine-iridium complex can be formed from the amine-iridium complex by remova' of a proton. Alternative'y, the mine complex can be prepared by addition of a suitable mine to a suitab'e solution of the cat&yst itself.

Thus, in an embodiment, the compound of Formu'a (I) is: H3C -lrX2Cp Cl (0 wherein each X is independently selected from halo, CO and OH; preferably each X is independently chloro, bromo or odo; and more preferably each X is odo; and Cp is a cyclopentadienyl group which may optionally be substituted by from 1 to 5 independently selected hydrocarbyl substituents.

Compounds of the Formula (I) may be obtained by reacting any of the individual isomers of the primary, secondary or tertiary amine with the iridium catalyst. Thus, in the case of sertraline for example, the compound of Formula (I) can be obtained by reacting any of the four stereolsomers of sertraline with an iridium catalyst of the formula lr2X4Cp2.

Hence, in this examp'e, the compound of Formula (I) includes compounds of the following formulae: H3CL lrX2Cp H3CN X2Cp H3CL lrX2Cp H3CN lrX2Cp 0CCQLD Cl Cl Cl Cl both in indwdual form and n the form of mixtures of any of these.

The compounds of Formula (I) may be bound to a suitable support or may be provided as free compounds. Suitable inorganic and organic supports are described below.

The catalyst recovery process of the present invention ensures that the racemisation process can be effected efficiently with the required amount of catalyst and that the catalyst can ultimately be separated from the end drug product such that only very low levels of metal remain in the final drug product. Thus, utilisation of the process of the invention results in a quantity of iridium of less than 100 ppm and preferably less than 10 ppm, and more preferably less than 5 ppm in the final amine product. The presence or absence of material derived from the catalyst in a final drug product which is the amine or is devised from the amine is a continuing problem in the prior art.

One of the advantages of the process of the present invention is that the separation and recovery of the catalyst is achieved at very high efficiency. Separation is achieved by passing ammonia through the reaction to precipitate the iridium ammonia complex. A C14 alkyl primary amine could be used in place of or in addition to ammonia. However, the use of ammonia is preferred. The resulting complex is insoluble in non-polar aprotic solvents such as toluene. We have also found that the complex formation is reversible.

This means that the catalyst can easily be recovered by heating a suspension of the catalyst. Alternatively, the recovered insoluble complex may simply be returned to the reaction mixture and heated in situ in order to regenerate active catalyst. Otherwise, the active catalyst can be regenerated separately from the reaction system.

In an embodiment, the compound of Formula (II) is:

N X

Me LY,I:N. Cp

wherein X is chloro, bromo or odo. Preferab'y X is iodo.

We also found that a single solvent could be used to conduct a continuous process. Non polar aprotic solvents, such as toluene and tert-butylmethy ether are suitable solvents.

Halides which may be represented by X include chloro, bromo and iodo. Thus where more than one halo is present each X can be independently selected from: fluoro, chloro, io bromo and iodo. Preferab'y, each X is the same. More preferably, each X is odo.

A'ternatively, each X may independently be halo (Le. chloro, bromo or iodo), CO or OH.

Cyclopentadienyl groups represented by Cp may be unsubstituted or substituted with 1 2, 3, 4 or 5 substituents. Exemplary substituents include hydrocarbyl groups, for example is selected from C120 aikyl (e.g. C1, C2, C3 or C4 alkyl), terpenes (e.g. menthyl, neomenthyl or imonenyl) and aryl (incIudng C6, e.g. phenyl, naphthyl) groups, any of which hydrocarbyl groups may themselves be optionally substituted with from 1 to 5 substtuents independently selected from C18 akyl, C28 alkenyl, C28 alkynyl, C1 alkoxy, halo, cyano and hydroxy. In one embodiment, R1 s cyclopentadienyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from methy, ethyl and phenyl. In another embodiment, R1 is cyclopentadienyl optionally substituted with 1, 2, 3, 4 or 5 methyl groups. The cyclopentadienyl group may be present in the form of one or more structural isomers, each of which is encompassed by the present invention. The cyclopentadienyl group may be in the form of a deprotonated anion and therefore may comprise a cationic counterion. Exampes of optionally substituted cyclopentadienyl complexing groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadenyl, ethyltetramethylpentad ienyl, menthyltetraphenyicyclopenta- thenyl, neomenthyl-tetraphenylcyclopentadenyl, menthyl-cyclopentadenyl, neomenthyl- cydopentadienyl, tetrahydroindenyl, menthyltetra-hydroindenyl and neomenthy-tetrahydrokldenyl groups. Pentamethylcyclopentadienyl i5 especially preferred.

A'though compounds of the invention are beeved to be substantiay as represented in the above formulae, n some circumstances the compounds may also exist as a dmer, trimer or some other polymeric species.

io The ntermediate compounds and the iridum-ammona complex may be solated and obtained in substantially pure form. The term substantially pure" as used herein includes reference to crystalline forms of greater than 70%, more preferably 90%, more preferably 95%, more preferably 96%, more preferably 97%, more preferably 98%, more preferably 99% purity as determined.

One aspect of the invention thus re'ates to a process for the manufacture of a complex of iridium with a primary, secondary or tertiary amine, such as sertraline, which process comprises reacting a catalyst of formula rX2Cp with the amine to form a compound of formula (I). The process may be carried out by reaction of the amine in a suitab'e solvent.

Upon completion of the reaction, the meta' catalyst wou'd conventionally be separated from the reaction mixture using standard procedures known in the art. For purity reasons, the amount of catalyst present is preferably minimised and one or more extractions are normal'y performed in the presence of charcoal. The process of the present invention obviates the need for such extraction steps. Thus by passing ammonia through the reaction mixture, in accordance with the invention an insoluble iridium-ammonia complex can be formed. Once this complex has been separated, the catalyst can be regenerated by heating at a temperature from 40 to 150°C, e.g. to a temperature of approximately 110°C.

The amine iridium complex may also be immobilised, at least in part, on a solid support or in an encapsulated system. Thus, the invention provides compounds of the formula (I) in which Cp is a cyclopentadienyl group bound to a support via a linker. Where present on a solid support or as an encapsulated system, such supported catalyst systems may be of assistance in performing subsequent separation operations which may be required, and may faci'itate the ease of cycling of materials between steps, especially when repetitions are envisaged. Exposure of the supported catalyst to ammonia forms the same complex as in free solution but in this case the resulting complex is now bound to a support.

Heating in a suitable solvent releases the original supported catalyst.

Supports include inorganic supports and organic supports, particularly po'ymer supports.

In some embodiments, the support is a solid support. The support is soluble in the reaction mixture and the supported catalyst therefore participates in the reaction.

Suitable polymer supports may be derived from the polymerisation of a composition comprising one or more monomers, and are preferably derived from the polymerisation a composition comprising of two or more monomers. The monomers may contain one or more poymerisable double bonds. In one embodiment, the polymer support is derived from the polymerisation of a composition comprising one or more monomers containing only one polymerisable double bond, and one or more monomers containing two or more polymerisabe double bonds. In another embodiment, the polymer support is derived from the polymerisation of a composition comprising one or two monomers containing only one polymerisable double bond, and one monomer containing two or three polymerisabe double bonds. Examples of monomers containing on'y one polymerisable double bond include styrene and substituted styrenes such as a-methyl styrene, methyl styrene, t-butyl styrene, bromo styrene and acetoxy styrene; alkyl esters of mono-olefinically unsaturated dicarboxylic acids such as di-n-butyl maeate and di-n-butyl fumarate; vinyl esters of carboxylic acids such as vinyl acetate, vinyl propionate, vinyl laurate and vinyl esters of versatic acid such as VeoVa 9 and VeoVa 10 (VeoVa is a trademark of Shell); acrylamides such as methyl acrylamide and ethyl acrylamide; methacrylamides such as methyl methacrylamide and ethyl methacrylamide; nitrile monomers such as acrylonitrile and methacryonitrUe; and esters of acrylic and methacrylic acid, preferably optionally substituted C120 alkyl and C120 cycIoalky esters of acrylic and methacrylic acid, such as methyl acrylate, ethyl acrylate, n-butyl acrylate, 2-ethylhexyl acrylate, i-propyl acrylate, and n-propyl acrylate, methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, 2-ethylhexyl methacrylate, i-propyl methacrylate, n-propyl acrylate, hydroxyethyl acryate, hydroxyethyl methacrylate, N, N-dimethylam inoethyl acrylate and N,N-dimethylaminoethyl methacrylate. Functional derivatives of the foregoing monomers containing on'y one polymerisable double bond can also be employed.

Examples of monomers containing two or more poymerisabIe double bonds include divinylbenzene (DVB), trivinylbenzene, and multifunctional acrylates and methacrylates such as ethy'ene gIyco diacrylate, ethylene glycol dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, ethylene bisacrylamide, pentaerythritol triacrylate, pentaerythritol tetraacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate and N, N-bis-acryloyl ethylene diam ne.

The support may comprise a poly(ethylene glycol). The use of a poly(ethylene glycol)-s based support may advantageously allow compounds of the invention and metal complexes thereof to be separated from the reaction mixture, e.g. using membrane separation techniques. In embodiments, the support compnses a poly(ethylene glyco) having a number average molecular weight Mn of from about 100 to about 10000 Daltons, e.g. from about 200 to about 5000 Daltons, in particular from about 200 to about 2000 Daftons. In a particu'ar embodiment, Z comprises a poly(ethylene glycol) and -X-Y-s an ether or polyether chain.

Other suitable solub'e supports, linkers and methods of attachment wil' be evident to those skilled in the art in light of the above. For examp'e, where a linker comprises is pendant oxo or thioxo groups, a support comprising one or more pendant amine functionalities may be employed. Where a linker comprises a pendant hydroxy group, a support comprising one or more pendant carboxylic acid or halogen groups may advantageously be used. Typically, binding will take place on an outer surface of the support, e.g. the surface of a polymer bead.

The invention will now be illustrated by Figure I which is a schematc flow diagram for a dynamic thermodynamic resolution (DTR) process according to the present invention for sertrali ne.

Starting with the resolution process, the resolving reagent is charged to a warmed non-polar organic solution of the sertraline diastereomers; upon cooling the desired sertraline enantiomer crystalises, is separated and can be further treated to form sertraline hydrochlonde. In the Pre-SCIRAM preparation stage the waste isomers contained in the mother liquors are treated with aqueous base to generate sertraline free-base and extract the resolving reagent for potential re-use. Further sertraline free-base isomers are charged the non-polar organic solution to replace the product sertraline removed at the previous stage. In the SCRAM racemisation stage the catalyst is charged and the mixture heated to racemise the 1-position. The catalyst charge can be a combination of ammonio-catalyst comp'ex and fresh SCRAM catalyst. The partially racemised sertraline solution is 3s cooled. At the Catalyst Separation stage ammonia is passed through the so'ution to precipitate part or al the catalyst which is then screened and may be recycled. At the Base racemisation stage the base is charged to the non-polar organic solution, the mixture heated to racemise the 4-position, then cooled. At the Base Separation stage dilute acid is charged to remove the base, water soluble materials and residual catalyst.

The non-polar organic solution of racemised sertraline isomers is then ready for the next Resolution Process stage.

The process of the invention can be further appreciated from the following example of the DIR process app'ied to sertraine.

Resolution The seectve crystallisation of the 1S,4S isomer of sertraline from the mixture of all four diastereomers was achieved using (R)-mandeic acid in toluene or tert-butyl methyl ether in >99%ee and 90-98%de. Whilst the isolated yield of 35% is quite reasonable, it is a feature of the technology that the resolution yield is not-critical as the waste isomers are being recycled and in theory all can be transformed into the product Using 1 OOg (0.327mo1) of a racemic 90:10 cis:trans mixture n 500mltoluene with 0.35mole equv of (R)-mandelic acid, the mixture was strred at 85°C with a coolingIhod reaction profile and seeding with the (1S,4S) sertraline (R)-mandelate salt. We iso'ated 52.lg (0.ll4moles) (of the desired (1 S,4R) sertraline (R)-mandeate salt by filtration, which is quantitative with respect to the mandelic acid. The product was analysed and found to be 99% ee and 95%de. Using TBME solvent the results were similar.

Resolving Agent Recycle Taking the mother liquors we charged an equal volume of 1 M sodium hydroxide base and quantitatively extracted the sodium mandelate, which could be recycled and used in the next resolution. The mixture of waste sertraline isomers in toluene were washed with water and topped up with a fresh 35g of the racemic 90:10 sertraline mixture.

Amine Racemisation As with other amine substrates it was found that bis diiodopentamethyl-cycopentadienyliridium, SCRAMIM catalyst (1) had the highest turnover frequency.

Indeed using O,lmoI% catalyst the IS chiral centre was racemised with at1of 15 minutes. In contrast, the chloro-, bromo-and rhodium an&ogues were poorly active, as was the ShvO catalyst. When the reaction was left for an extended period we noticed a slow accumulation of sertraline imine which forms as molecular hydrogen is lost from the system. The imine hydrogenation is reversbe. If reactions were carried out under a hydrogen atmosphere the racemisation rate was slowed, demonstrating microscopic reversibility and that the reaction is an equilibrium. Sparging nitrogen or air mixtures through the reaction had little effect on the rate of racemisation, rather increased the formation of imine.

Initially we carried out racemisation studies on pure (1 S,4S) sertraline. A number of solvents were evaluated and the results are shown in Table 1.

Table I Racemsation of 1 S,4S sertraline to 1 R,4S sertraline with 0.1 mol% catalyst (1)* entry solvent d.e. (%)** 1 Toluene 15 2 Mesitylene 14 3 Cumene 16 4 Cyclohexene 65 Anisoe 43 6 Nitrobenzene 97 7 Tetrachloroethane 95 8 1,4-Dioxane 20 9 Cyclopentylmethylether 18 t-Butylmethylether 15 11 t-Butylacetate 19 12 Toluene-Water 40 *Reactions 0.5M at 80°C; **diastereomeric excess at 240 mins.

It can be seen that the solvents give different racemisation endpoints and the diastereomeric excess does not reach zero as the benzylic chiral centre induces diastereoselective imine reduction depending upon the system thermodynamics ie catalyst, solvent and temperature. The aromatic solvents toluene, cumene and mesitylene gave consistent rates and thermodynamic endpoints of +15% d.e. The endpoint might be a result of thermodynamic equi'ibrium or cata'yst decomposition. To confirm this was a true equilibrium position, we carried out the same experiment with a racemic mixture of -50% d.e. sertraline (e an excess of trans). The kinetics followed a similar profile with endpoint at +13% d.e. confirming that under these conditions this was indeed the thermodynamic endpoint resulting from the 4S stereo-control. With anisole the d.e. fal's to 40%, this solvent apparently affecting the thermodynamc equilibrium. With nitrobenzene and 1.1,2,2-tetrachloroethane minor falls in the d.e were observed and it is possible that the catalyst is inactive in these solvents. Each of the ether solvents are effective as is tertiary butyl acetate. Cyclohexene was used as a potential hydrogen donor/acceptor and interestingly seems to slow the rate of racemisation giving 65 %de.

at 4h and 58% d.e. at lOh. A surprising observation is seen when an equal volume of water is added to the toluene when the racemisation endpoint is 40% d.e. rather than 15% d.e. The other factor affecting the racemisation endpoint is temperature, it was found that the effect of temperatures on catalyst activity out-weighs the benefit in a lower d.e.

Other additives such as base, acid, ligands, or salts had little effect on reaction rate or racemisation endpoint. Toluene was the solvent selected for further studies as it is a good general process solvent and could be integrated with the other parts of the process.

A critical part of the process for preparing sertraline isomers resides in separation of the catalyst from product. We found that catalyst removal after the amine racemisation is provided the greatest potential for its recycle. Other options considered induded the known methods of adsorption or extraction of the soluble catalyst and use of an immobilised form of the catalyst. The catalyst was found to bind poorly to adsorption media such as charcoal, silica, ion exchange resins, and the like. Extraction into water using reagents such as cysteine, thiourea and methylamine were only partially effective, removing about 50% of the available iridium. These were intended to displace sertraline ligand from the catalyst, however further investigation showed the techniques failed to give complete Ir removal.

We found that significantly better results than those obtained in prior art processes for removal of the catalyst were achieved by generating an insoluble ammonio-complex.

This can be formed by bubbling gaseous ammonia through the racemised reaction solution. The identity of this solid was confirmed by x-ray crystallography, and 13C NMR. The recovery of Ir was greater than 50%, in contrast to the prior art methods which do not allow any recovery of the iridium catalyst. This is a significant advantage both from the perspective of purity of the resulting amine product and from an economic perspective. An important advantage of this method over extraction was that subsequent heating of the complex reformed active catalyst for use in the next reaction. Conveniently the ammonio-complex was introduced directly in the amine acemisation stage, upon heating the catalyst re-entering the catalytic cycle.

Experi mental Sertraline Resolution 1 OOg (0.34mo) of racemc 90:10 cis:trans sertrane was dissolved in 500m1 touene at 85°C. 53g (0.35mo1) of (R)-mandec acid was charged and the mixture stirred untU homogenous then cooled slowly whilst seeding with crystals of the (1 S,4S) sertraline (R)-mandeate salt. The reaction mass was filtered, the cake washed with toluene and dried yielding 52g (0.l2mol) 35%. The product was analysed and found to be (1S,4R) sertraline (R)-mandelate of 99% ee and 95%de.

Catalytic racemisation of 1-position of sertraline The filtrates from the resolution stage were washed with an equal volume of 1 M sodium hydroxide, the aqueous layer was separated and set aside for recovery of the resolving reagent. The toluene layer was further washed and azeotropically dried. 35g of racemic 90:10 cis:trans sertr&ine was charged along with 0.lg (85imol) bis diiodoiridiumpentamethylcycopentadiene. The solution was heated to 80°C for 8h then cooled to ambient. In-situ monitoring showed (1S,4S) 32.9%, (1R,4R) 24.1%, (1R,4S) 16.4%, 1S,4R 19.4%.

Ammonium complex formation Gaseous ammonia was bubbled through the solution for 6h during which a fine precipitate formed.

More specifically, ammonia gas was bubbled through a toluene solution of sertraline isomers with a cyclopentadienyl iridium iodo catalyst A fine yellow precipitate gradually settled and the iquid was decanted. The solid was washed with toluene and dried. The product was characterised by: 1HNMR(CD2CI2) CpMe5 i.84(s,15H);NH3 3.00(b,3H); 13CNMR (CD2CI2) GpMe5 54.2, 54.0, 53.8, 53.6, 53.4; MS 605, 472; Microanalysis %theory(%actual):G 20.08(20.1 7);H 3.03(2.97); N 2.34(2.23); Other 74.55(7463); IR (cm-i): 2923(m), 2959(m), 2904(m),1 459(l), 1412(m), 1 380(l),1356(m), 1155(m), 1076(m), 1022(l), 951 (m), 609(m), 533(m), 422(m) Single crystal x-ray diffraction: li-li 2.717A, lr-12 2.27iA, li-N 2.i33A, Cp(cent)-lr i.783A, l1-lr-12 91.5degrees, N-li-li 85.4degrees, N-lr-12 83.5-degrees The sod was screened and the toluene sohjtion containing sertraline isomers was used in the next stage.

Base racemisation of 4-position 3.8g (O.034mo1) potassium tert-butoxide was charged to the toluene solution and heated to ref lux for I h. The solution turns dark and was cooled to ambient. Charcoal was added and the solution screened before adding an equal volume of water stirring, settling and separating. After a further wash the solution was azeotropically dried. Analysis of the isomer composition showed (1S,4S) 32.9%, (1R,4R) 24.1%, (1R,4S) 16.4%, 1S,4R 19.4%, imine 5.6%.

Repeat and recycling in a continuous process is Fresh sertraline isomers were added to the solution and the resolution and racemisation stages were repeated. In this case the recovered catalyst ammonia complex was charged in addition to a reduced fresh catalyst charge. In other words, part of the active catalyst used was replaced with the ammonia complex recovered from the reaction.

A continuous reactor may be used in the process of racemisation which comprises one or several vessels, for example arranged vertically, horizontally or inclined. The reactants may be fed directly to the reactor or via a separate mixing device. Suitably the reactor is a preferably substantially tubular through-flow vessel or pipe, most preferably comprisrng means for mixing the reactants in a substantially uniform manner. Such means for mixing are described in eg US6790427.

The purification and recovery steps may be conducted continuously, such that the fluid stream is fed continuously to each isomerisation vessel n a sequential manner. Each vessel contains the relevant isomerisation reactant(s), maintained at the preferred temperature and pressure. The stream is allowed to continuously react to form a mixture of all four isomers. The resulting mixture of isomers is continuously withdrawn from the vessel. One of the advantages of the process of the present invention is the fact that the same solvent may be used throughout the resolution, racemisation and catalyst recovery steps, thereby facilitating operation in a continuous process and awarding unwanted solvent contamination. The mixture of isomers of sertraline are separated in the conventional manner as described in W020051023752. Similarly, catalyst recovery and isolation may be performed in a continuous manner.

Advantageously, the processes descnbed herein may find use in recycling unwanted isomers obtained from chiral processes, such as chiral separations, chemical and enzymic chiral resolutions and the likes. Typically, in chiral separations or resolutions, racemic mixtures are subjected to physicaL chemica' or biochemic& treatments which result in the separation of a desired enantiomer or enatiomeric product while often leaving behind an unreacted or unwanted enatiomers or enatiomeric bi-products. The processes described herein permit convenient recycling of both the catalyst and the unwanted steroisomers of the active amine compound on a commercial scale as the entire process is simple and requires inexpensive raw materials.

Claims (6)

1. CLAIMS1. A dynamic thermodynamic resolution process for a primary, secondary or tertiary amine, the process comprising the steps: (a) providing a solution comprising two or more amine isomers; (b) reacting the solution with lrX2Cp and/or IrX2CpNH3 wherein each X is independently chloro, bromo or iodo and Cp is a cyclopentadienyl group which may be io optionally substituted by from 1 to 5 independently selected hydrocarbyl substituents; (c) passing NH3 though the solution obtained in step (b) to generate IrX2CpNH3 and recovering it as a solid from the solution; is (d) recovering preferentially a sing'e desired amine isomer from the solution of step (c); (e) recovering the unwanted isomer or isomers from the solution of step (d) and returning said unwanted isomer or isomers to step (a) of the process and optionally adding a further quantity of the two or more amine isomers to the solution.(f) optionally, repeating steps (b) to (e) for a desired time period or number of cycles.
2. 2. The process according to claim 1 wherein the Ir-ammonia complex formed in step (c) is returned to step (b) in addition to or in place of the lrX2Cp.
3. 3. A process for recovery of a metal catalyst from a dynamic thermodynamic resolution process, the process comprising the following steps: (a) providing a solution comprising an iridium cyclopentadienyl catalyst of formula lr2X4Cp2 or lrX2Gp wherein each X is independently selected from chloro, bromo or odo; and Cp is a cyclopentadienyl group which may be optiona'ly substituted by from 1 to 5 independently selected hydrocarbyl substituents in a non-polar aprotic solvent; the solution also comprising one or more isomers of an optically active amine; (b) passing gaseous ammonia through the reaction mbcture to produce solid matedai; and (c) recovering the solid material.
4. 4. A complex of Formula: IrX2CpNH3 whereIn each X Is Independently selected from chioro, bromo or lodo; and Cp Is a cyclopentadienyl group which may be optionally substituted by from 1 to 5 independently
5. 5. An amine-iridium complex of Formula (I): amlne-IrXCp (I) wherein the amine Is a primary, secondary or tertiary amine; each X is Independently chioro, bromo or lode; and Cp is a cyclcpentadlenyi group whkh may be optionally substItuted by from 1 to 5 Independently selected hydrocarbyl substituents.
6. 6. The complex of claimS wherein the complex is: i4,eir;cpCI7. A complex accordIng to claIm 6 wherein the complex Is: H3C -lrX2Cp Cl 8. An imine-iridium complex of Formula (II): [imine -frHXCp]HX () wherein the mine is formed from a primary, secondary or tertiary amine and wherein each X is independently chloro, bromo or iodo and Cp is a cyclopentadienyl group which may be optionally substituted by from 1 to 5 independently selected hydrocarbyl substituents.9. The complex according to claim 8 wheren the complex is:HX ,X ivie Op10. The process or complex accordng to any preceding claim, wherein each X is iodo.11. The process or comp'ex according to any preceding claim, wherein Cp is pentamethylcyclopentadienyl.12. The process or complex according to any of claims 1 to 10, wherein Cp is a cydopentadienyl group bound to a support.13. The complex according to any of claims 4 to 12 in substantially pure form.14. A composition comprising sertralne, i.e. (1S,4S) N-methyl-4-(3,4-dichlorophenyl)- 1,2,34-tetrahydro-1 -naphthaleneamine, and less than about 100 ppm of a complex of any of claims 4 to 11.