WO2011073362A1 - Procédé de préparation de composés optiquement actifs par hydrogénation sous pression - Google Patents

Procédé de préparation de composés optiquement actifs par hydrogénation sous pression Download PDF

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Publication number
WO2011073362A1
WO2011073362A1 PCT/EP2010/070002 EP2010070002W WO2011073362A1 WO 2011073362 A1 WO2011073362 A1 WO 2011073362A1 EP 2010070002 W EP2010070002 W EP 2010070002W WO 2011073362 A1 WO2011073362 A1 WO 2011073362A1
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preparation
phenol
compound according
ethyl
compound
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PCT/EP2010/070002
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English (en)
Inventor
Michael Foulkes
Christian Mathes
Felix Spindler
Erhard Bappert
Martin Kesselgruber
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
    • C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • 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.
  • Ri C1-20 alkyl, C2-20 alkenyl, C 2- 2o alkynyl, C-i -2 o organohalide, an
  • 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;
  • the asymmetric catalytic reduction may produce an enantiomeric excess of the following optically active compound (III):
  • optically active compound (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):
  • the asymmetric catalytic reduction may result in an enantiomeric excess of compound (III) over compound (IV).
  • 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.
  • 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.
  • Ri may be a CMO alkyl, C 2- io alkenyl, C 2- io alkynyl or d.-io organohalide.
  • Ri may be any of methyl, ethyl, propyl or butyl.
  • R-i may be methyl.
  • 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.
  • a suitable catalyst is described in Zhang et al., Chem. Rev. 2003; 103(8); 3029-3070, which is incorporated herein by reference.
  • 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.
  • 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:
  • 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;
  • 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.
  • the transition metal M may be Ru, Rh or Ir.
  • the transition metal M may be Ru.
  • may be an organofluoride, an organochloride or a fluoroborate.
  • L-i may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato.
  • Li may be chloride.
  • l_2 may be an organofluoride, an organochloride or a fluoroborate.
  • L 2 may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato.
  • 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.
  • L 3 may be p- cymene, benzene, cyclooctadiene, triphenylphosphine, or norbornadiene.
  • L3 may be a mono-, bi- or poly-dentate ligand.
  • L3 may be a bi-dentate ligand.
  • L 3 may be a neutral or anionic ligand.
  • 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):
  • the pressure hydrogenation may be performed using (R)-4-lsopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline 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.
  • 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.
  • an ammonium salt such as triethylbenzylammonium chloride (TEBA) may also be present.
  • TEBA triethylbenzylammonium chloride
  • 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.
  • 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.
  • 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%.
  • a highly enantiomerically pure compound e.g. a polyol or a diol such as (R)-3-(1-Hydroxy-ethyl)-phenol
  • 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%.
  • 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.
  • a chiral amino alcohol such as (S)-3-(1-Dimethylamino- ethyl)-phenol.
  • the alcoholic hydroxy group is activated for nucleophiiic substitution.
  • the activation technique may be mentioned sulfonylation of the hydroxy group to form sulfonate esters.
  • the hydroxy group is derivatised to provide a leaving group. For example, the hydroxy!
  • 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).
  • sulfonic anhydride e.g. methanesulfonic anhydride
  • a sulfonyl chloride e.g. methanesulfonic anhydride
  • alkyl sulfonic acid e.g. methanesulfonic anhydride
  • ethyl sulfonic acid e.g. p-toluene sulfonates
  • tosylate e.g. p-toluene sulfonates.
  • Both hydroxy groups i.e. the phenolic hydroxy group and the
  • 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.
  • a base particularly a non-nucleophilic base, such as Hiinig's base (ethyldiisopropylamine), for example.
  • 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
  • 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.
  • a nucleophile e.g. an amine such as a dialkylamine, particularly dimethylamine
  • 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.
  • an aqueous alkali solution e.g. NaOH, KOH, etc.
  • 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.
  • the chiral amino alcohol may be directly acylated to form a free acylated compound.
  • (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.
  • transdermal delivery system for example a transdermal patch such as, for example, described in WO 2007/064407, which is incorporated herein by reference.
  • rivastigimine may be used in a transdermal patch and rivastigimine hydrogen tartrate may be used in capsules.
  • the asymmetric catalytic reduction may produce an enantiomeric excess of the following optically active compound (VI):
  • the asymmetric catalytic reduction may also produce a lesser amount of the following compound (XI):
  • the asymmetric catalytic reduction may result in an enantiomeric excess of compound (VI) over compound (XI).
  • 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 may then be converted to (S)-3-(1-Dimethylamino-ethyl)-phenol) via a series of steps.
  • the alcoholic hydroxy group is activated for nucleophilic substitution.
  • the activation technique may be mentioned sulfonylation of the hydroxy group to form a sulfonate ester.
  • the hydroxy group is derivatised to provide a leaving group.
  • 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
  • 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.
  • a base particularly a non-nucleophilic base, such as Hunig's base (ethyldiisopropylamine), for example.
  • 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.
  • (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.
  • a pharmaceutical composition comprising an active pharmaceutical compound formed according to the first and second aspects.
  • 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.
  • 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.
  • a capsule comprising a pharmaceutical composition according to the third aspect.
  • 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.
  • 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).
  • 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
  • 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
  • transition metal M may be a first, second or third row transition metal.
  • the transition metal may be Ru, Rh or Ir.
  • the transition metal M may be Ru.
  • may be an organofluoride, an organochloride or a fluoroborate.
  • L-i may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato.
  • BARF tripentafluorophenylborane
  • mesylate trifluoroacetate, triflate, methylallyl or acetylacetonato.
  • Li may be chloride.
  • I_2 may be an organofluoride, an organochloride or a fluoroborate.
  • L 2 may be chloride, bromide, iodide, tetrafluoroborate, tripentafluorophenylborane (i.e. BARF), mesylate, trifluoroacetate, triflate, methylallyl or acetylacetonato.
  • 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.
  • l_ 3 may be p- cymene, benzene, cyclooctadiene, triphenylphosphine, or norbornadiene.
  • L 3 may be a mono-, bi- or poly-dentate ligand.
  • L3 may be a bi-dentate ligand.
  • L3 may be a neutral or anionic ligand.
  • 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):
  • the pressure hydrogenation may be performed using (R)-4-lsopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline triphenylphosphino Ru(ll) dichloride.
  • the activation step may use an activating group, in particular by derivatisation of the hydroxyl groups to form a leaving group.
  • an activating 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
  • a base such as ⁇ , ⁇ -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.
  • Step (c) may comprise steps (d) and (c2):
  • 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.
  • 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.
  • 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.
  • 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.
  • the acylation may be an acylation/salt formation process.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • the present invention relates to a process which relies on utilising chiral catalysis to introduce stereochemical selectivity into a hydroxyphenone target molecule.
  • 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.
  • 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.
  • 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.
  • 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.
  • N,N- Diisopropylethylamine i.e. Hiinig's base
  • 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.
  • TEBA triethylbenzylammoniumchloride
  • 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.
  • (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).
  • the obtained (S)-3-(1-Dimethylamino-ethyl)-phenol may then be used as a starting material to make rivastigmine.
  • 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.
  • (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 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.
  • 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,
  • 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.
  • 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.
  • the reduced form of the hydroxyphenone may be converted to the required chiral aminophenol using any suitable known means.
  • 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.
  • the toluene phase was washed with 15 g water at 80°C. Ca. 100 g toluene was distilled off.
  • 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.
  • 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.
  • the toluene phase was washed with 15 g water at 80°C. Ca. 100 g toluene was distilled off.
  • 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.
  • 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.

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Abstract

La présente invention concerne un procédé catalytique de préparation de composés optiquement actifs et leur conversion en substances médicamenteuses souhaitées. Le procédé concerne notamment la préparation de (S)-3-(1-diméthylamino-éthyl)-phénol en utilisant une réduction catalytique asymétrique et l'hydrogénation sous pression, fournissant ainsi une voie de production améliorée de substances médicamenteuses telles que la rivastigimine et l'hydrogénotartrate de rivastigimine.
PCT/EP2010/070002 2009-12-18 2010-12-16 Procédé de préparation de composés optiquement actifs par hydrogénation sous pression WO2011073362A1 (fr)

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