COMPOUNDS USING PRESSURE HYDROGENATION

FIELD OF THE INVENTION

The present invention relates to a catalytic process for the preparation of optically active compounds and their conversion thereafter to desired drug substances. More particularly, the present invention relates to a catalytic process for the preparation of (S)-3-(1-Dimethylamino-ethyl)-phenol using asymmetric catalytic reduction and pressure hydrogenation, thereby providing an improved route to forming drug substances such as rivastigimine and rivastigimine hydrogen tartrate.

BACKGROUND OF THE INVENTION

Currently, there are no efficient large scale production methods for the formation of rivastigimine. Current processes rely on a kinetic resolution of a racemic mixture of 3-(1-Dimethylaminoethyl)-phenol that is time-consuming and labour-intensive when run in standard batch reactors. Prior art methods are thermodynamically inefficient.

Processes for manufacturing the drug substance rivastigmine (([3-[(1S)-1- dimethylaminoethyl]phenyl] N-ethyl-N-methylcarbamate marketed as Exelon®) and (S)-3-(1-Dimethylamino-ethyl)-phenol are known from WO 98/42643 and WO 2005/058804, which are incorporated herein by reference. However, as discussed above these processes are inefficient on larger scales. The drug substance rivastigimine is currently used for the treatment of Alzheimer's disease and there is a need to improve on existing inefficient production methods.

It is an object of at least one aspect of the present invention to obviate or at least mitigate one or more of the aforementioned problems.

It is a further object of at least one aspect of the present invention to provide an improved process for the manufacture of (S)-3-(1-Dimethylamino- ethyl)-phenol.

It is a yet further object of at least one aspect of the present invention to provide an improved process for the manufacture of rivastigimine and its salts.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided a process for the preparation of a compound according to the following general formula (I):

wherein

Ri = C1-20 alkyl, C2-20 alkenyl, C _2- 2o alkynyl, C-i _-2 o organohalide, an

, an amine or amide group; and n = 1 to 5;

said process comprising:

(a) performing an asymmetric catalytic reduction on a hydroxyphenone according to the following general formula

(II):

wherein

Ri = C-i-20 alkyl, C2-20 alkenyl, C _2- 2o alkynyl, C1-20 organohalide, an aryl, an amine or amide group;

n = 1 to 5; and

wherein said asymmetric catalytic reduction is performed using pressure hydrogenation.

Typically, the asymmetric catalytic reduction may produce an enantiomeric excess of the following optically active compound (III):

(III)

As well as forming optically active compound (III), the asymmetric catalytic reduction may also produce a lesser amount of the following optically active compound (IV):

As indicated above the asymmetric catalytic reduction may result in an enantiomeric excess of compound (III) over compound (IV). Typically, the asymmetric catalytic reduction as herein defined may result in an enantiomeric excess of compound (111) to compound (IV) of from about 96% : 4% or higher, about 98% : 2% or higher, about 99% : 1% or higher, prior to, for example, any form of purification process such as crystallization. A crystallization purification process may improve the enantiomeric excess. A crystallized product of the asymmetric catalytic reduction product may result in an enantiomeric excess of compound (III) to compound (IV) of from about 97% : 3% or higher, about 98% : 2% or higher, about 99% : 1% or higher, or about >99.5 % : about <0.5%. The present invention may therefore result in commercially useful enantiomeric ratios of the formed compounds (e.g. a high ratio of compound (III)). It has been found that the enantiomeric ratios of the formed compounds may be dependent on the amount of catalyst used. For example, by increasing the amount of catalyst may increase the amount of compound (III) formed. Enantiomeric excesses as herein defined were determined using chiral HPLC methods using chiral stationary phases (Daicel chemical industries) and suitable mixtures of heptane and isopropanol as mobile phase."

The present invention therefore relates to a process which relies on utilising chiral catalysis to introduce stereochemical selectivity on reduction of a hydroxyphenone. The reduced hydroxyphenone may be a chiral polyol or diol.

In general formulas (I) - (IV), n may equal 1 , meaning that general formulas (I), (III) and (IV) relate to a diol and that general formula (II) relates to a singly hydroxylated phenone.

The hydroxyl group on the aromatic ring in general formulas (I) - (IV) may occur at position 3 on the aromatic ring.

Conveniently, Ri may be a CMO alkyl, C _2- io alkenyl, C _2- io alkynyl or d.-io organohalide.

Typically, Ri may be any of methyl, ethyl, propyl or butyl. Preferably, R-i may be methyl. In particular embodiments, R-i may be methyl and n may equal 1 with the resulting structure of general formula (II) then being 1-(3-hydroxy-phenyl)- ethanone which is shown below as formula (V). The 1-(3-hydroxy-phenyl)- ethanone may be selectively reduced to the chiral diol of (R)-3-(1-Hydroxy-ethyl)- phenol which is shown as formula (VI) below:

The pressure hydrogenation may be performed using a chiral metal catalyst such as a transition metal based catalyst. For example, a suitable catalyst is described in Zhang et al., Chem. Rev. 2003; 103(8); 3029-3070, which is incorporated herein by reference. Typically, the chiral metal catalyst may comprise any suitable first, second or third row transition metal. The metal based catalyst may be a Ru, Rh or Ir based catalyst and may, for example, contain ligands such as mono-, bi- or poly-dentate ligands. Preferably, the metal based catalyst may be a Ru based catalyst.

The pressure hydrogenation may be performed using a chiral metal catalyst according to general formula (VII) shown below:

(VII)

wherein

M = a transition metal;

Li = a halide, an organohalide, a boron halide, a sulphonate, a carbonyl, an amine or amide group;

L ₂ = a halide, an organohalide, a boron halide, a sulphonate, nitriles, carbenes, carbon monoxide, phosphines, a carbonyl, an amine- or amide-containing group; and

l_3 = an aryl based group, a ferrocene based group, a carbonyl, C2- 30 alkenyl or C2-30 alkynyl.

The, transition metal may be a first, second or third row transition metal. Typically, the transition metal M may be Ru, Rh or Ir. Preferably, the transition metal M may be Ru.

L| may be an organofluoride, an organochloride or a fluoroborate. Typically, L-i may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato. Preferably, Li may be chloride. l_2 may be an organofluoride, an organochloride or a fluoroborate. Typically, L ₂ may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato. Preferably, l_2 may be chloride.

l_3 may be a substituted aryl group, a ferrocene based compound, a substituted phenyl group, C2-2D alkenyl or C2-20 alkynyl. Typically, L ₃ may be p- cymene, benzene, cyclooctadiene, triphenylphosphine, or norbornadiene. L3 may be a mono-, bi- or poly-dentate ligand. Typically, L3 may be a bi-dentate ligand. L ₃ may be a neutral or anionic ligand.

In particular, the metal based catalyst used for pressure hydrogenation may comprise a chiral ferrocene-based ligand in combination with a suitable metal precursor as shown below in structure (VIII):

(Vlll) In particular embodiments, the pressure hydrogenation may be performed using (R)-4-lsopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]ox azoline triphenylphosphino Ru(ll) dichloride.

The catalyst may be present in a range from about 0.001 mol % to about 5.0 mol %, about 0.003 mol % to about 1.0 mol % or from about 0.005 mol % to about 0.1 mol % based on the starting compound of formula I. Typically, the catalyst may be present in an amount of about 0.01 mol %.

The transfer hydrogenation reaction may be performed in an alcohol based solution such as a Ci to C ₁₀ alcohol. For example, methanol, ethanol, propanol, i-propanol, butanol or combinations thereof may be used as the reaction medium. An alkali may also be present such as a hydroxide. A metal hydroxide such as KOH may therefore be present. In addition, an ammonium salt such as triethylbenzylammonium chloride (TEBA) may also be present.

The hydrogenation reaction may be performed under hydrogen pressure of about 1 bar to about 100 bar or preferably about 5 to 40 bar. A typical operating pressure may be about 20 bar.

To improve the yield and rate of the catalytic reaction, the catalytic process may be heated up to about 30 - 100°C or about 50 ± 10°C for about 1 - 20 hours or typically about 9 hours.

The reaction product may then be purified by, for example, crystallization.

For example, the reaction product may be distilled and an organic solvent such as toluene added. An alcohol such as ethanol may then be added. The obtained product may be filtered and removed according to known processes. The pressure hydrogenation may result in a highly enantiomerically pure compound (e.g. a polyol or a diol such as (R)-3-(1-Hydroxy-ethyl)-phenol) with an enantiomeric excess of greater than about 70 %, 80 %, 90 %, 95 %, 99 %, 99.5 % or 99.9%.

The pressure hydrogenation may also result in a high conversion rate of greater than about 70 %, 80 %, 90 %, 95 %, 99 %, 99.5 % or 99.9%.

On formation of the enantiomerically pure polyol or diol referred to above, such as in formulas (III) and (VI), the polyol or diol may then be converted via a series of steps to a chiral amino alcohol such as (S)-3-(1-Dimethylamino- ethyl)-phenol. Firstly, in the series of steps, the alcoholic hydroxy group is activated for nucleophiiic substitution. As the activation technique may be mentioned sulfonylation of the hydroxy group to form sulfonate esters. Thus the hydroxy group is derivatised to provide a leaving group. For example, the hydroxy! groups may undergo sulfonylation using, for example, a sulfonylating agent such as sulfonic anhydride (e.g. methanesulfonic anhydride), a sulfonyl chloride, an alkyl sulfonic acid, an ethyl sulfonic acid or a tosylate (e.g. p-toluene sulfonates). Both hydroxy groups (i.e. the phenolic hydroxy group and the alcoholic hydroxy group) may therefore be mesylated using methanesulfonic anhydride or be otherwise sulfonated. The sulfonylating agent, e.g. methanesulfonic anhydride, may be contacted with the polyol or diol in the presence of a base, particularly a non-nucleophilic base, such as Hiinig's base (ethyldiisopropylamine), for example. In one procedure, methanesulfonic anhydride or another sulfonylating agent is combined with the polyol or diol, e.g. (R)-3-(1-hydroxyethyl)phenol, in the presence of an aprotic solvent, for example a dipolar aprotic solvent, e.g. ethyl acetate, and optionally a nucleophilic catalyst, for example 4-dimethylaminopyridine. Hiinig's base or another non-nucleophilic base is then added under cooling, for example maintaining the temperature at about 0°C or less until the resulting exothermic reaction is completed (heat generation is ceased).

The activated polyol or diol may then be contacted with a nucleophile, e.g. an amine such as a dialkylamine, particularly dimethylamine, to subject the activated (particularly mesylated) alcoholic hydroxy group to nucleophilic substitution with concomitant inversion of the chiral centre. The free phenolic hydroxy group is then regenerated; thus, mesylated or otherwise sulfonylated phenol groups may be cleaved in an aqueous alkali solution (e.g. NaOH, KOH, etc.) to form a chiral amino alcohol.

A preferred chiral amino alcohol to be formed may be (S)-3-(1- Dimethylamino-ethyl)-pnenol as shown below in structure (IX):

The formed chiral amino alcohol (e.g. (S)-3-(1-Dimethylamino-ethyl)- phenol) may then be used as a starting material for an active pharmaceutical ingredient by acylation, for example, via an acylation/salt formation to form, for example, rivastigimine hydrogen tartrate. The acylated/salt form (e.g. rivastigimine hydrogen tartrate) may then undergo, for example, a base liberation to form a free base form of rivastigimine. Alternatively, the chiral amino alcohol may be directly acylated to form a free acylated compound. In preferred embodiments, (S)-3-(1-Dimethylamino-ethyl)-phenol may therefore be used to form rivastigimine hydrogen tartrate or rivastigimine which may be used to treat Alzheimer's disease. The (S)-3-(1-Dimethylamino-ethyl)-phenol may therefore be formed into a salt, free base or prodrug from of rivastigimine. A free base, salt and/or a prodrug form of rivastigimine may also be formed into a pharmaceutical delivery product, for example a pharmaceutical composition, e.g. capsules or other oral formulation, or a transdermal delivery system, for example a transdermal patch such as, for example, described in WO 2007/064407, which is incorporated herein by reference. In preferred embodiments, rivastigimine may be used in a transdermal patch and rivastigimine hydrogen tartrate may be used in capsules.

According to a second aspect of the present invention there is provided a process for the preparation of 3-(1-Hydroxy-ethyl)-phenol according to the following formula (X):

(X)

said process comprising:

(a) performing an asymmetric catalytic reduction on 1-(3- Hydroxy-phenyl)-ethanone according to the following formula (V):

(V)

wherein said asymmetric catalytic reduction is performed using transfer hydrogenation.

Typically, the asymmetric catalytic reduction may produce an enantiomeric excess of the following optically active compound (VI):

As well as forming optically active compound (IV), the asymmetric catalytic reduction may also produce a lesser amount of the following compound (XI):

As indicated above the asymmetric catalytic reduction may result in an enantiomeric excess of compound (VI) over compound (XI). Typically, the asymmetric catalytic reduction as herein defined may result in an enantiomeric excess of compound (VI) to compound (XI) of from about 96% : 4% or higher, about 98% : 2% or higher, about 99% : 1% or higher, prior to, for example, any form of purification process such as crystallization. A crystallization purification process may improve the enantiomeric excess. A crystallized product of the asymmetric catalytic reduction may result in an enantiomeric excess of compound (IV) to compound (XI) of from about 97% : 3% or higher, about 98% : 2% or higher, about 99% : 1% or higher or about >99.5 % : about <0.5%. The present invention may therefore result in commercially useful enantiomeric ratios of the formed compounds. It has been found that the enantiomeric ratios of the formed compounds may be dependent on the amount of catalyst used. For example, by increasing the amount of catalyst may increase the amount of compound (IV) formed.

The (R)-3-(1-Hydroxy-ethyl)-phenol (i.e. compound (VI)) may then be converted to (S)-3-(1-Dimethylamino-ethyl)-phenol) via a series of steps. Firstly, in the series of steps, the alcoholic hydroxy group is activated for nucleophilic substitution. As the activation technique may be mentioned sulfonylation of the hydroxy group to form a sulfonate ester. Thus the hydroxy group is derivatised to provide a leaving group. For example, the hydroxy! groups may undergo sulfonylation using, for example, a sulfonylating agent such as sulfonic anhydride (e.g. methanesulfonic anhydride), a sulfonyl chloride, an alkyl sulfonic acid, an ethyl sulfonic acid or a tosylate (e.g. p-toluene sulfonates). Both hydroxy groups (i.e. the phenolic hydroxy group and the alcoholic hydroxy group) may therefore be mesylated using methanesulfonic anhydride or be otherwise sulfonylated. The sulfonylating agent, e.g. methanesulfonic anhydride, may be contacted with the polyol or diol in the presence of a base, particularly a non-nucleophilic base, such as Hunig's base (ethyldiisopropylamine), for example. In one procedure, methanesulfonic anhydride or another sulfonylating agent is combined with the (R)-3-(1-hydroxyethyl)phenol in the presence of an aprotic solvent, for example a dipolar aprotic solvent, e.g. ethyl acetate, and optionally a nucleophilic catalyst, for example 4-dimethylaminopyridine. Hiinig's base or another non-nucleophilic base is then added under cooling, for example maintaining the temperature at about 0°C or less until the resulting exothermic reaction is completed (e.g. heat generation is ceased). The activated (R)-3-(1-hydroxyethyl)phenol may then be contacted with a nucleophile, e.g. an amine such as a diaikylamine, particularly dimethylamine, to subject the activated (particularly mesylated) alcoholic hydroxy group to nucleophilic substitution. The mesylated or otherwise sulfonylated phenol groups may then be cleaved in an aqueous alkali solution (e.g. NaOH, KOH, etc.) to form (S)-3-(1-Dimethylamino-ethyl)-phenol which is shown below as structure (IX):

The formed chiral amino alcohol of (S)-3-(1-dimethylaminoethyl)phenol) may then be used as an active pharmaceutical ingredient starting material for the production of useful active pharmaceutical compounds via, for example, an acylation, particularly an acylation/salt formation and then, for example, a base liberation from the salt. In preferred embodiments, (S)-3-(1-Dimethylamino- ethyl)-phenol) may be used to form rivastigimine or rivastigimine hydrogen tartrate which may be used to treat Alzheimer's disease. According to a third aspect of the present invention there is provided a pharmaceutical composition comprising an active pharmaceutical compound formed according to the first and second aspects.

As indicated above, a preferred chiral amino alcohol is (S)-3-(1- Dimethylamino-ethyl)-phenol. The (S)-3-(1-Dimethylamino-ethyl)-phenol) can be used as a starting material which under acylation, particularly an acylation/salt formation, forms an active pharmaceutical compound such as rivastigmine or its salt form (e.g. rivastigimine hydrogen tartrate). Under base liberation, rivastigimine may then be formed from its salt and may then be used to form rivastigimine containing products which may be used to treat Alzheimer's disease.

According to a fourth aspect of the present invention there is provided a transdermal patch comprising an active pharmaceutical compound formed according to the first and second aspects, e.g. a pharmaceutical composition according to the third aspect.

According to a fifth aspect of the present invention there is provided a capsule comprising a pharmaceutical composition according to the third aspect.

According to a sixth aspect of the present invention there is provided use of a chiral alcohol obtainable, or obtained, according to the first and second aspects in the preparation of an active pharmaceutical ingredient for production of pharmaceutical compositions.

Typically, the chiral alcohol may be (R)-3-(1-Hydroxy-ethyl)-phenol which may be used to form (S)-3-(1-Dimethylamino-ethyl)-phenol. The (S)-3-(1- Dimethylamino-ethyl)-phenol may be used to manufacture pharmaceutical compositions comprising rivastigimine or its salt form (e.g. rivastigimine hydrogen tartrate).

According to a seventh aspect of the present invention there is provided use of a chiral metal catalyst in the formation of chiral alcohols in an asymmetric synthesis using pressure hydrogenation, said catalyst having a general formula (VII) shown below

(VII)

wherein

M = a transition metal;

Li = a halide, an organohalide, a boron halide, a sulphonate, a carbonyl, an amine or amide group;

l_ ₂ = a halide, an organohalide, a boron halide, a sulphonate, nitriles, carbenes, carbon monoxide, phosphines, a carbonyl, an amine- or amide-containing group; and

l_3 = an aryl based group, a ferrocene based group, a carbonyl, C2- 30 alkenyl or C2-30 alkynyl. Typically, transition metal M may be a first, second or third row transition metal. Typically, the transition metal may be Ru, Rh or Ir. Preferably, the transition metal M may be Ru.

L| may be an organofluoride, an organochloride or a fluoroborate. Typically, L-i may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato. Preferably, Li may be chloride.

I_2 may be an organofluoride, an organochloride or a fluoroborate. Typically, L ₂ may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato. Preferably, L ₂ may be chloride.

I_3 may be a substituted aryl group, a ferrocene based compound, a substituted phenyl group, C ₂ - ₂ o alkenyl or C ₂ - ₂₀ alkynyl. Typically, l_ ₃ may be p- cymene, benzene, cyclooctadiene, triphenylphosphine, or norbornadiene. L ₃ may be a mono-, bi- or poly-dentate ligand. Typically, L3 may be a bi-dentate ligand. L3 may be a neutral or anionic ligand.

In particular, the metal based catalyst used for pressure hydrogenation may comprise a chiral ferrocene-based ligand in combination with a suitable metal precursor as shown below in structure (VIII):

(VIII)

In particular embodiments, the pressure hydrogenation may be performed using (R)-4-lsopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]ox azoline triphenylphosphino Ru(ll) dichloride.

According to an eighth aspect of the present invention there is provided a process for the preparation of (S)-3-(1-Dimethylamino-ethyl)-phenol comprising:

(a) performing an asymmetric catalytic reduction using pressure hydrogenation on 1-(3-Hydroxy-phenyl)-ethanone (compound V) to form (R)-3-(1-Hydroxy-ethyl)-phenol (compound VI) as shown below :

(V) (VI) (b) performing an activation step on the hydroxyl groups of the formed (R)-3-(1-Hydroxy-ethyl)-phenol to form activated hydroxy alcoholic groups and activated hydroxy phenolic groups on the (R)-3-(1- Hydroxy-ethyl)-phenol;

(c) performing a nucleophilic substitution on the activated hydroxy alcoholic groups with dimethylamine; and

(d) cleaving the activated hydroxy phenolic groups;

wherein (S)-3-(1-Dimethylamino-ethyl)-phenol is formed.

Typically, the activation step may use an activating group, in particular by derivatisation of the hydroxyl groups to form a leaving group. For example, a sulfonyl group may be added to the hydroxyl groups of the (R)-3-(1-Hydroxy- ethyl)-phenol to form a sulfonate leaving group. The hydroxyl groups may undergo mesylation or other sulfonylation using a sulfonylating agent, for example, a sulfonic anhydride (e.g. methanesulfonic anhydride), a sulfonyl chloride, an alkyl sulfonic acid, an ethyl sulfonic acid or a tosylate (e.g. p-toluene sulfonates). Both hydroxy groups (i.e. the phenolic hydroxy group and the hydroxy alcoholic group) may therefore be sulfonylated, e.g. mesylated.

In the presence of an aprotic organic solvent (e.g. ethyl acetate), a base such as Ν,Ν-diisopropylethylamine (i.e. Hiinig's base) may be added at a lowered temperature. A nucleophilic substitution reaction may then be performed with, for example, an amine such as a dialkyi amine (e.g. dimethyl amine) which may be used to substitute the activatedalcoholic hydroxy groups. Mesylated or otherwise sulfonylated phenol groups may then be cleaved in an aqueous alkali solution (e.g. NaOH, KOH, etc.) to form the (S)-3-(1-Dimethylamino-ethyl)- phenol.

According to an ninth aspect of the present invention there is provided a process for the preparation of rivastigimine comprising:

(a) performing an asymmetric catalytic reduction using pressure hydrogenation on 1-(3-Hydroxy-phenyl)-ethanone (compound V) to form (R)-3-(1-Hydroxy-ethyl)-phenol (compound VI) as shown below :

(V) (VI)

(b) converting the (R)-3-(1-Hydroxy-ethyl)-phenol to (S)-3-(1- Dimethylamino-ethyl)-phenol;

(c) acylating the (S)-3-(1-Dimethylamino-ethyl)-phenol to form rivastigmine.

Step (c) may comprise steps (d) and (c2):

(c1) performing an acylation/salt formation on the formed (S)-3-(1- Dimethylamino-ethyl)-phenol ; and

(c2) performing a base liberation on the acylated/salt form of the (S)-3-

(l-Dimethylamino-ethyl)-phenol. The rivastigmine free base made by any method described herein may be contacted with a pharmaceutically acceptable acid to form an acid addition salt thereof. The free base or an acid addition salt thereof, or both, may be incorporated into a drug delivery product, e.g. a pharmaceutical composition (e.g. a capsule for oral administration) or a transdermal delivery system, for example a transdermal patch.

The (R)-3-(1-Hydroxy-ethyl)-phenol may be converted to (S)-3-(1- Dimethylamino-ethyl)-phenol by nucleophilic substitution with dimethylamine, and more particularly by forming activated hydroxy alcoholic groups and activated hydroxy phenolic groups on the (R)-3-(1-Hydroxy-ethyl)-phenol. A nucleophilic substitution reaction may then be performed on the activated hydroxy alcoholic groups by contacting the (R)-3-(1-Hydroxy-ethyl)-phenol with dimethylamine. The activated hydroxy phenolic groups may then be cleaved to form the (S)-3-(1- Dimethy lamino-ethy l)-phenol .

This latter compound may in turn by acylated with an acylating agent of the formula C2Hs(CH ₃ )NC(0)X, wherein X is OH or an activating group, e.g. halo such as chloro, for example, to form rivastigmine as the free base or an acid addition salt..

3-(1-Hydroxyethyl)-phenol itself forms an aspect of the invention, as do products (e.g. compositions of matter) containing a detectable amount of the compound. The 3-(1-hydroxyethyl)-phenol may be the (R)-enantiomer, the (S)- enantiomer, or a combination thereof. Racemic mixtures of 3-(1-hydroxyethyl)- phenol are therefore included within the invention, as are the isolated or enantiomerically pure (R)- and (S)-enantiomers. In particular embodiments, the compound is (R)-3-(1-hydroxyethyl)-phenol; the (R)-3-(1-hydroxyethyl)-phenol may be in enantiomeric excess over the (S)-isomer, e.g. an excess of 96% or more, as previously mentioned in the context of the synthesis of (R)-3-(1- hydroxyethyl)-phenol.

Also included in the invention is a process for preparing rivastigmine comprising effecting a nucleophilic substitution of the hydroxyethyl group of (R)- 3-(1-hydroxyethyl)-phenol with dimethylamine and acylating the phenolic hydroxy group of the resulting product with an acylating agent of the formula C ₂ H ₅ (CH ₃ )NC(0)X, wherein X is OH or an activating group, e.g. halo. The nucleophilic substitution may proceed by activating the hydroxy group of the hydroxyethyl radical and contacting the activated compound with dimethylamine. The starting compound (R)-3-(1-hydroxyethyl)-phenol is in one class of processes included in a racemate but in another class of processes is in an enantiomeric excess over its (S)-isomer, e.g. an excess of 96% or more, as previously mentioned. The (R)-3-(1-hydroxyethyl)-phenol may therefore be in isolated form. Where the (R)-3-(1-hydroxyethyl)-phenol is not of sufficient enantiomeric excess, or if enhanced enantiomeric excess is otherwise desired, the end product 3-[1-dimethylaminoethyl]phenyl] N-ethyl-N-methylcarbamate may be treated to select the desired (IS)-isomer (rivastigmine), for example by conventional procedures such as, e.g. HPLC or the use of a chiral resolving agent. As previously mentioned, the acylation may be an acylation/salt formation process. In any event, the rivastigmine may be converted to an acid addition salt thereof; similarly, the rivastigmine or its acid addition salt may be further processed into a pharmaceutical delivery product.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings in which:

Figure 1 represents of a prior art method for the production of (S)-3-(1- Dimethylamino-ethyl)-phenol which is used to form rivastigmine;

Figure 2 represents a process according to the present invention for the formation of (S)-3-(1-Dimethylamino-ethyl)-phenol using asymmetric catalytic reduction and pressure hydrogenation of 1-(3-Hydroxy-phenyl)-ethanone; and

Figure 3 represents a process according to the present invention using asymmetric catalytic reduction and pressure hydrogenation of 1-(3-hydroxy- phenyl)-ethanone to form (R)-3-(1-Hydroxy-ethyl)-phenol.

DETAILED DESCRIPTION

The current manufacturing process for rivastigimine uses a kinetic resolution to obtain active pharmaceutical ingredient starting material (S)-3-(1- Dimethylamino-ethyl)-phenol. Figure 1 represents this process.

As shown in Figure 1, a starting material of 1-(3-Hydroxy-phenyl)- ethanone undergoes a Schiff base formation to form an imino based compound. A Schiff base reduction is then performed to form an amine compound. The amine compound is then transformed under an Eschwei!er-Clarke N-methyiation reaction to a racemic mixture of 3-(1-Dimethylamino-ethyl)phenol. As shown in Figure 1 , there is a kinetic resolution bottleneck after the formation of the racemic mixture of 3-(1-Dimethylaminoethyl)phenol to the active pharmaceutical ingredient enantiomerically pure starting material of (S)-3-(1-Dimethylamino- ethyl)-phenol. Therefore, although the prior art method as shown in Figure 1 offers access to enantiomerically pure (S)-3-(1-Dimethylamino-ethyl)-phenol without the need for chiral auxiliaries or catalysts, productivity is limited in standard batch reactors due to a slow kinetic resolution. The current manufacturing process for (S)-3-(1-Dimethylamino-ethyl)-phenol is therefore time-consuming and labour intensive. This results in an inefficient process for manufacturing the drug compound rivastigimine on a larger scale.

The present invention relates to a process which relies on utilising chiral catalysis to introduce stereochemical selectivity into a hydroxyphenone target molecule. By using asymmetric pressure hydrogenation, a hydroxyphenone such as 1-(3-Hydroxy-phenyl)-ethanone is converted to a highly enantiomerically pure diol with high catalyst turnover rates and selectivities without the need to protect the free phenol functionality.

Figure 2 relates to the present invention and shows the chiral reduction of 1-(3-Hydroxy-phenyl)-ethanone to form (R)-3-(1-Hydroxy-ethyl)-phenol. With suitable further processing steps, the enantiomeric excess of (R)-3-(1-Hydroxy- ethyl)-phenol is carried over into the product (S)-3-(1-Dimethylamino-ethyl)- phenol which may be used to form rivastigimine or rivastigimine hydrogen tartrate on a large scale. Initially, the 1-(3-Hydroxy-phenyl)-ethanone as shown in Figure 2 undergoes a chiral reduction using asymmetric pressure hydrogenation to form (S)-3-(1-Hydroxy-ethyl)-phenol. The pressure hydrogenation therefore reduces the hydroxyphenone such as 1-(3-Hydroxy-phenyl)-ethanone in an enantioselective fashion.

As shown in Figure 2, the (S)-3-(1-Hydroxy-ethyl)-phenol undergoes a double mesylation of the hydroxy! groups in the presence of, for example, N,N- Diisopropylethylamine (i.e. Hiinig's base) to form a di-mesylated compound (R)- Methanesulfonic acid 3-(1-methanesulfonyloxy-ethyl)-phenyl ester. There is then a nucleophilic substitution of the benzylic mesylate with dimethylamine under inversion to form the compound (S)-Methanesulfonic acid 3-(1-dimethylamino- ethyl)-phenyl ester and then finally cleavage of the phenolic mesylate with aqueous sodium hydroxide to form (S)-3-(1-Dimethylamino-ethyl)-phenol. The (S)-3-(1-Dimethylaminoethyl)-phenol is produced in a very high enantiomerically pure form.

Figure 3 represents the pressure hydrogenation of 1-(3-Hydroxy-pheny))- ethanone. The reaction is carried out in about 20 bar H ₂ at about 50 ± 10°C, in about 1.2 eq. of KOH, about 0.05 eq. triethylbenzylammoniumchloride (TEBA), about 0.01 mol % catalyst in i-PrOH for about 9 hours. The catalyst used is as follows:

(VIII)

The chiral catalyst (VIII) results in over about 99 % conversion and over about 99 % selective reduction of 1-(3-Hydroxy-phenyl)-ethanone to the chiral (R)-3-(1-Hydroxy-ethyl)-phenol. Prior to the present invention, (R)-3-(1-Hydroxy- ethyl)-phenol was prepared by enzymatic means exhibiting mediocre activity and selectivity (e.g. Groger et al. Tetrahedron 2004, 60, 633-640; Goswami et al. Tetrahedron Lett. 2005, 46, 4411-4413, which are incorporated herein by reference).

It has been found that a pressure hydrogenation catalytic system such as herein described gives excellent results in the stereoselective reduction of hydroxyphenones such as 1-(3-Hydroxy-phenyl)-ethanone

The obtained (S)-3-(1-Dimethylamino-ethyl)-phenol may then be used as a starting material to make rivastigmine. Specifically, the starting material may be acylated with an acylating agent of the formula C ₂ H ₅ (CH ₃ )NC(0)X, wherein X is OH or an activating group, e.g. halo, particularly chloro, to form rivastigmine. The rivastigmine may be presented in the form of an acid addition salt. Thus (S)- 3-(1-Dimethylamino-ethyl)-phenol under acylation/salt formation may form rivastigmine hydrogen tartrate as shown in Figure 1. Under base liberation, rivastigimine is then formed.

Rivastigmine, therefore, may be administered as the free base or in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts can be synthesized from the parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of the rivastigmine with the appropriate acid, typically in a stoichiometric amount, in water or in an organic solvent, or in a mixture of the two. Examples of nonaqueous media are diethylether, ethyl acetate, ethanol, isopropanol and acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002, in particular Tables 1 , 2, 3 and 4, the disclosure of which publication is hereby incorporated by reference.

Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, hydrogen tartrate, tartrate, thiocyanate, tosylate, and undecanoate.

Irrespective of whether the rivastigmine is administered as the free base or a salt, it is typically delivered to the body from a drug delivery product, i.e. a product from which an active API may be delivered. Exemplary drug delivery products include pharmaceutical compositions comprising the active API and a pharmaceutically acceptable diluents, excipient or carrier and, optionally, at least one additional active compound. Such compositions may by way of example be oral or parenteral. Another type of drug delivery product is a transdermal patchlt will be clear to those of skill in the art, that the above described embodiments of the present invention are merely exemplary and that various modifications and improvements thereto may be made without departing from the scope of the present invention. For example, a range of chiral metal catalysts may be used in the chiral reduction of a hydroxy phenone such as 1-(3-Hydroxy-phenyl)-ethanone using pressure hydrogenation. Moreover, the reduced form of the hydroxyphenone may be converted to the required chiral aminophenol using any suitable known means. EXAMPLES

The following procedures are only exemplary. The mentioned temperatures may be varied by about ± 10°C and the amount of reactant and solvent may also be varied from the mentioned amount and may therefore be about the stated values.

Example 1 : (R)-3-(1-Hvdroxy-ethyl)-phenol via pressure hydrogenation

2.5 g 1-(3-Hydroxy-phenyl)-ethanone and 208 mg triethylbenzyl ammonium chloride were placed in a 50 ml autoclave with a mechanical stirrer under argon. A solution of 1.44 g KOH in dry, degassed isopropanol (20 ml) was added via cannula and the mixture was stirred in the closed autoclave for 15 min under an argon atmosphere.

A solution of 1.69 mg (R)-4-lsopropyl-2-[(R)-2-

(diphenylphosphino)ferrocen-1-yl]oxazoline triphenylphosphino Ru(ll) dichloride in dry, degassed isopropanol (5 ml) was added via cannula into the autoclave under argon. The autoclave was purged with argon (3x, 10 bar), with hydrogen (3x, 10 bar) and the pressure was set to 20 bar. The reaction mixture was heated to 50°C. After 22 h the pressure was released. The mixture was treated with 200 ml tert-butyl methyl ether and 70 ml 1M aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted twice with tert-butyl methyl ether (100 ml). The combined organic layers were dried using sodium sulfate and filtered. The solvent was removed and the crude product was crystallized from toluene:ethanol (9:1 , 20 ml) at 20°C. After stirring at about 0 °C for 3 h the product was collected by filtration and washed with toluene (about 3x5 ml) to give 2.2 g (85% yield, enantiomeric ratio 99:1) (R)-3-(1-Hydroxy-ethyl)- phenol as a nearly white crystalline solid. ¹ H NMR (400 MHz, DMSO-d ⁶ , ppm): 1.25 (s, 3H); 4.60 (m, 1 H); 5.08 (s, 1 H); 6.58 (d, 1 H); 6.73 (m, 2H); 7.08 (t, 1 H); 9.27 (s, 1 H).

]R (ATR, cm ^"1 ): 3382, 1617, 1590, 1481 , 1407, 1372, 1294, 1269, 1168, 1085, 1070, 1009, 997, 939, 868, 787, 736, 699, 626.

Example 2: (S)-3-(1-Dimethylamino-ethyl)-phenol via dimesylate and amine-mesylate

In a 0.75 L round-bottomed flask with mechanical stirring were placed 96.5 g methanesulfonic anhydride, 30.0 g of (R)-3-(1-Hydroxy-ethyl)-phenol, 0.27 g 4- dimethylaminopyridine and 270 g ethyl acetate under nitrogen. Stirring was continued at 20°C for15 min before cooling down to 0°C. 74.4 g N,N- Diisopropylethylamine (i.e. Hiinig's base) was added at 0°C (exothermic) within 3 h and stirring was continued for 30 min at about -5°C before heating to 20°C and further 30 min stirring of the resulting suspension.

Sample of (R)-methanesulfonic acid 3-(1-mathanesulfonyloxy-ethyl)-phenyl ester) drawn at this point: H NMR (400 MHz, CDCI ₃ , ppm): 1.70 (d, 3H); 2.84 (s, 3H); 3.18 (s, 3H); 5. 75 (q, 1 H); 7.30 (d, 1 H); 7.38 (m, 2H); 7.49 (t, 1 H).

79.1 g gaseous dimethyl amine was added within >4 h at 15-25°C into the gas phase from a laboratory lecture bottle. The reaction was moderately exothermic. The suspension was stirred for >10 h at 20°C before conversion was checked. 60 g water was added dissolving the salts and ca. 100 g of the aqueous phase of the resulting Diphasic solution was removed.

00 g water was added. After stirring for 5 min ca. 100 g of the aqueous phase was removed.

3 g Cellflock 40 PL filter aid was added, the solution was filtered and transferred to a second 0.75 L round-bottomed flask. Phases were separated and the aqueous phase was discarded.

391 g ethyl acetate was removed by distillation.

Sample of (S)-methanesulfonic acid 3-(1-dimethylamino-ethyl)-phenyl ester drawn at this point:

¹ H NMR (400 MHz, CDCI ₃ , ppm): 1.37 (d, 3H); 2.21 (s, 3H); 3.15 (s, 3H); 3.31 (q, 1H); 7.18 (d, 1 H); 7.26 (m, 2H); 7.37 (t, 1 H).

IR (ATR, cm ^"1 ): 3631 , 2979, 2941 , 2820, 2773, 1607, 1584, 1484, 1443, 1369, 1179, 1128, 967, 917, 823, 804, 700. MS (ESI, m/z): 244 (100%, MH ⁺ ), 199.

80 g water was added and distillation was continued until water started to distill over. 87 g 30% aqueous NaOH was added and the resulting biphasic solution was heated to 90°C with rapid stirring for 2 h. A clear, dark monophasic solution was obtained. Temperature was lowered to about 80°C. 174 g toluene was added and the pH was adjusted to 8.7 with 24 g orthophosphoric acid at about 80°C. The biphasic mixture was heated to a temperature of about 80°C and phases were separated. The aqueous phase was discarded.

The toluene phase was washed with 15 g water at 80°C. Ca. 100 g toluene was distilled off.

3 g silica gel 60 was added and the suspension was filtered at 80°C into a 0.25 L round-bottomed flask. The filter cake was washed with 17 g hot toluene. 20 mg and then the (S)-3-(1-dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70°C resulting in crystallization. The suspension was held at 70°C for 30 min, then the temperature was lowered to a temperature of about 0°C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 44 g toluene each. The wet filter cake (29.5 g) was transferred to a 0.25 L round-bottomed flask. 78 g toluene was added. The suspension was heated to 100°C to dissolve the (S)-3-(1-Dimethylamino- ethyl)-phenol and filtered hot over a plate filter into a preheated 0.25 L round- bottomed flask. Temperature was lowered to about 70°C and 20 mg of (S)-3-(1- Dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70°C resulting in crystallization. The suspension was held at 70°C for 30 min, then the temperature was lowered to 0°C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 25 g toluene each. The wet product (29.2 g) was dried at 45°C/50 mbar for at least 8 hours to give 28.5 g (79% yield of (R)-3-(1-Hydroxy-ethyl)-phenol and an, enantiomeric ratio >99.9:0.1 of (S)-3-(1-Dimethylamino-ethyl)-phenol as colorless crystals. H NMR (400 MHz, CDCI ₃ , ppm): 1.42 (d, 3H); 2.24 (s, 3H); 3.37 (q, 1H); 6.75 (m, 3H); 7.14 (m, 1H).

IR (ATR, cm ^"1 ): 3004, 2974, 2874, 2839, 2795, 2672, 2552, 1595, 1465, 1454, 1465, 1454, 1373, 1335, 1270, 1206, 1163, 1082, 1059, 1019, 957, 911 , 871, 810, 792, 706.

MS (ESI, m/z): 166 (100%, MH ⁺ ), 121, 79, 60, 46.

Example 3: (S)-3-(1-Dimethylamino-ethyl)-phenol via dimesylate and aminomesylate

In a 0.75 L round-bottomed flask with mechanical stirring were placed 96.5 g methanesulfonic anhydride, 30.0 g of (R)-3-(1-Hydroxy-ethyl)-phenol, 0.27 g 4- dimethylaminopyridine and 270 g ethyl acetate under nitrogen. Stirring was continued at 20°C fori 5 min before cooling down to 0°C. 74.4 g N,N- Diisopropylethylamine (i.e. Htinig's base) was added at 0°C (exothermic) within 3 h and stirring was continued for 30 min at about -5°C before heating to 20°C and further 30 min stirring of the resulting suspension. Sample of (R)-methanesulfonic acid 3-(1-mathanesulfonyloxy-ethyl)-phenyl ester) drawn at this point: H NMR (400 MHz, CDCI ₃₎ ppm): 1.70 (d, 3H); 2.84 (s, 3H); 3.18 (s, 3H); 5. 75 (q, 1H); 7.30 (d, 1 H); 7.38 (m, 2H); 7.49 (t, 1 H).

79.1 g gaseous dimethyl amine was added within >4 h at 15-25°C into the gas phase from a laboratory lecture bottle. The reaction was moderately exothermic. The suspension was stirred for >10 h at 20°C before conversion was checked. 60 g water was added dissolving the salts and ca. 100 g of the aqueous phase of the resulting biphasic solution was removed.

100 g water was added. After stirring for 5 min ca. 100 g of the aqueous phase was removed.

3 g Cellflock 40 PL filter aid was added, the solution was filtered and transferred to a second 0.75 L round-bottomed flask. Phases were separated and the aqueous phase was discarded.

391 g ethyl acetate was removed by distillation.

Sample of (S)-methanesulfonic acid 3-(1-dimethylamino-ethyl)-phenyl ester drawn at this point:

¹ H NMR (400 MHz, CDCI _3> ppm): 1.37 (d, 3H); 2.21 (s, 3H); 3.15 (s, 3H); 3.31 (q, 1H); 7.18 (d, 1 H); 7.26 (m, 2H); 7.37 (t, 1 H). IR (ATR, cm ^"1 ): 3631 , 2979, 2941 , 2820, 2773, 1607, 1584, 1484, 1443, 1369, 1 79, 1128, 967, 917, 823, 804, 700. MS (ESI, m/z): 244 (100%, MH ⁺ ), 199.

100 g water was added and pH was adjusted to 3.8 with ca. 27 g orthophosphoric acid at 80°C. Phases were separated and the organic phase was discarded. 174 g fresh toluene was added and the pH was adjusted to 8.7 at a temperature of 80 ± 10°C with ca. 62 g 30% aqueous NaOH. Phases were separated and the aqueous phase was discarded.

The toluene phase was washed with 15 g water at 80°C. Ca. 100 g toluene was distilled off.

3 g silica gel 60 was added and the suspension was filtered at 80°C into a 0.25 L round-bottomed flask. The filter cake was washed with 17 g hot toluene. 20 mg and then the (S)-3-(1-dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70°C resulting in crystallization. The suspension was held at 70°C for 30 min, then the temperature was lowered to a temperature of about 0°C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 44 g toluene each. The wet filter cake (29.5 g) was transferred to a 0.25 L round-bottomed flask. 78 g toluene was added. The suspension was heated to 100°C to dissolve the (S)-3-(1-Dimethylamino- ethyl)-phenol and filtered hot over a plate filter into a preheated 0.25 L round- bottomed flask. Temperature was lowered to about 70°C and 20 mg of (S)-3-(1- Dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70°C resulting in crystallization. The suspension was held at 70°C for 30 min, then the temperature was lowered to 0°C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 25 g toluene each. The wet product (29.2 g) was dried at 45°C/50 mbar for at least 8 hours to give 28.5 g (79% yield of (R)-3-(1-Hydroxy-ethyl)-phenol and an, enantiomeric ratio >99.9:0.1 of (S)-3-(1-Dimethylamino-ethyl)-phenol as colorless crystals. ¹ H NMR (400 MHz, CDCI ₃ , ppm): 1.42 (d, 3H); 2.24 (s, 3H); 3.37 (q, 1H); 6.75 (m, 3H); 7.14 (m, 1H).

IR (ATR, cm- ¹ ): 3004, 2974, 2874, 2839, 2795, 2672, 2552, 1595, 1465, 1454, 1465, 1454, 1373, 1335, 1270, 1206, 1163, 1082, 1059, 1019, 957, 911, 871, 810, 792, 706.

MS (ESI, m/z): 166 (100%, MH ⁺ ) ₍ 121, 79, 60, 46.