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WO2009086283A1 - Synthèse de 2-hydroxy-2-aryl-éthylamines énantiomériquement pures - Google Patents

Synthèse de 2-hydroxy-2-aryl-éthylamines énantiomériquement pures Download PDF

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Publication number
WO2009086283A1
WO2009086283A1 PCT/US2008/087975 US2008087975W WO2009086283A1 WO 2009086283 A1 WO2009086283 A1 WO 2009086283A1 US 2008087975 W US2008087975 W US 2008087975W WO 2009086283 A1 WO2009086283 A1 WO 2009086283A1
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Prior art keywords
alkyl
aryl
chiral
optionally substituted
hydroxy
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PCT/US2008/087975
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English (en)
Inventor
Hossein Saeedi
Erik Michaelson
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Cambrex Charles City Inc
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Cambrex Charles City Inc
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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

Definitions

  • the present invention relates to an improved process for preparing enantiomerically pure 2-hydroxy-2-aryl-ethylamines, and accordingly their pharmaceutically acceptable salts, by transition metal catalyzed asymmetric hydrogenation.
  • a representative list includes such compounds as (R)- phenylephrine, (R)-epinephrine, (R)-salbutamol, (R)-denopamine, clenbuterol, tulobuterol and many others.
  • Such compounds can be used for a variety of pharmaceutical uses including as adrenergics, as bronchodilators, as tocolytics, as cardiotonics, for weight loss and for many other uses.
  • Such compounds are of great commercial interest.
  • the chemical structures of (R)- phenylephrine, (R)-epinephrine, and (R)-salbutamol are shown below in formulae II- IV:
  • the present invention provides a simple method by which 2-hydroxy-2-aryl- ethylamines of formula (I) can be prepared with high optical and chemical purity. As a consequence, the risk of contaminating the pharmaceutical composition with unwanted enantiomers is substantially avoided.
  • the present invention relates to a process for preparing chiral, optically pure 2- hydroxy-2-aryl-ethylamines of formula (I) and their pharmaceutically acceptable salts (generally an acid addition salt thereof):
  • R 1 denotes H, an optionally substituted C 1-6 -alkyl, an optionally substituted C 1-6 -alkoxy, an optionally substituted C 7-18 -aralkyl or an optionally substituted C 7-18 -aralkoxy.
  • R 1 is selected from H, methyl, ethyl, iso-propyl, tert-butyl or benzyl, and more preferably is selected from H, methyl, or benzyl.
  • R 2 denotes H, an optionally substituted C 1-6 - alkyl, an optionally substituted C 1-6 -alkoxy, an optionally substituted C 7-18 -aralkyl or an optionally substituted C 7-18 -aralkoxy.
  • R 2 is selected from H, methyl, ethyl, iso-propyl, tert-butyl or benzyl, more preferably is selected from H, methyl or benzyl.
  • Each R 3 independently denotes an optionally substituted C 1-6 -alkyl, -OH, amino, amido, triflurormethyl, -O-C 1-6 -alkyl, C 1-6 -alkyl -OH; -O-C 7-18 -aralkyl, -OOC- Ci- 6 -alkyl, -OOC-aryl, or halogen.
  • each R 3 independently denotes methyl, iso-propyl, tert-butyl, hydroxy, hydroxymethyl, methoxy, propoxy, butoxy, benzyloxy, acetyloxy, benzoyloxy, amino, amido, F, Cl or Br; and more preferably each R 3 independently denotes hydroxy, hydroxymethyl, amino, amido, trifluoromethyl. methoxy, benzyloxy, acetyloxy or benzoyloxy. Also, n is 0, 1, 2 or 3.
  • the compound of formula (I) is prepared by asymmetric hydrogenation of an optionally substituted 2-aminoacetophenone (l-amino-2-(aryl)-ethan-2-one) of formula (V) (or one of its acid addition salts):
  • the asymmetric hydrogenation of the compound of formula (V) is conducted in the presence of (1) a transition metal catalyst system or complex consisting of a transition metal, such as ruthenium, rhodium or indium, (preferably ruthenium), generally supplied as an organo-metallic compound and a chiral, bidentate phosphine ligand, such as ((R)-l-diphenylphosphino-2-[(S)- (dimethylamino-diphenylphosphonophenyl) methyl] ferrocene) (also known as ((R)- l-diphenylphosphino-2-[(S)- ⁇ -(N,N-dimethylamino)-o-diphenylphosphinophenyl) methyl] ferrocene)), (2) a weak base, preferably comprising the desired 2-hydroxy-2- aryl-ethylamine of formula (I), and (3) optionally an
  • Optionally susbstituted 2- aminoacetophenone compounds of formula (V) (or their acid addition salts) used as the starting material product are generally commercially available or can be obtained either by reacting the R 3 -substituted benzaldhyde with a correspondingly substituted amine and formaldehyde in a Mannich reaction, or by converting an R 3 -substituted acteophenone to the corresponding R 3 -substituted-l- haloacetophenone with primary or secondary amines to obtain the 2- aminoacetophenone compounds of formula (V).
  • a Mannich reaction or by converting an R 3 -substituted acteophenone to the corresponding R 3 -substituted-l- haloacetophenone with primary or secondary amines to obtain the 2- aminoacetophenone compounds of formula (V).
  • the present invention is directed to a process for making chiral, optically pure 2-hydroxy-2-aryl-ethylamines of formula (I) and acid addition salts thereof: wherein * denotes a chiral carbon having an absolute configuration of (R) or (S); R 1 is an optionally substituted C 1-6 -alkyl, an optionally substituted C 1-6 -alkoxy, an optionally substituted C 7-18 -aralkyl or an optionally substituted C 7-18 -aralkoxy; R 2 is an optionally substituted C 1-6 -alkyl, an optionally substituted C 1-6 -alkoxy, an optionally substituted C 7-18 -aralkyl or an optionally substituted C 7-18 -aralkoxy; each R 3 independently is C 1-6 -alkyl, -OH, amino, amido, triflurormethyl, -O-C 1-6 -alkyl, C 1- 6 -alkyl -OH; -O-C 7-18
  • R 1 , R 2 , R 3 and n are as hereinbefore defined, in the presence of (1) a transition metal catalyst system having a chiral, bidentate phosphine ligand; (2) a weak base and (3) optionally an inert diluent.
  • C 1-6 -alkyl denotes branched and unbranched alkyl groups with 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. Preferred are alkyl groups with 1 to 4 carbon atoms. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question.
  • propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl.
  • C 1-6 -alkyl moieties can be optionally substituted. Suitable substituents include aryl, C 1-6 -alkoxy, amino, amido, halogen and hydroxy.
  • aryl generally denotes aromatic ring systems (optionally substituted) with the ring system itself having from 6 or 10 carbon atoms.
  • suitable aryls include phenyl or naphthyl; the preferred aryl group is phenyl.
  • the aromatic groups, and particularly a phenyl group optionally may be substituted by one or more groups (usually no more than three groups) independently selected from among methyl, ethyl, iso-propyl, tert-butyl, amino, amido, hydroxy, C 1-6 -alkoxy, such as methoxy, fluorine, chlorine, bromine and iodine.
  • C 7-18 -aralkyl denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms which are substituted by an aromatic ring system (aryl) with 6 or 10 carbon atoms (optionally substituted as defined above). Examples include: benzyl, 1- or 2-phenylethyl. As noted earlier, unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, amino, amido, hydroxy, C 1-6 -alkoxy, such as methoxy, fluorine, chlorine, bromine and iodine.
  • the transition metal in the catalyst complex usually is supplied as an organometallic-derivative of a salt.
  • chiral-selective reactions are carried out in the presence of a weak base, preferably comprising the desired chiral 2-hydroxy-2-aryl-ethylamine. While the chiral base is preferably used, it may be replaced, or alternatively may be supplemented with another organic base or inorganic base, either in solid form or in the form of solutions, such as aqueous solutions.
  • Suitable inorganic bases are basically reacting alkali metal salts or alkali metal hydroxides. Preferably, alkali metal hydrogen carbonates or alkali metal carbonates are used in addition to alkali metal hydroxides. If any additional inorganic base is used, it is preferably one of Na 2 CO 3 , K 2 CO 3 , LiOH, NaOH, KOH or NaHCO 3 .
  • Suitable organic bases are tertiary amines, particularly tertiary alkylamines, tertiary alkyl-arylamines, pyridine alkali metal alkoxides, or the free base of formula (V) which is present in excess.
  • the desired chiral 2-hydroxy-2-aryl-ethylamine is the only added base.
  • the hydrogenation reaction can be conducted with another base as suggested above to produce a sufficient amount of the desired chiral 2-hydroxy-2-aryl-ethylamine for use as the base.
  • the asymmetric hydrogenation is carried out in a temperature range of from 0° C to 100° C, preferably from 0° C to 90° C, and particularly from 40° C. to 75° C.
  • a temperature range of from 0° C to 100° C, preferably from 0° C to 90° C, and particularly from 40° C. to 75° C.
  • asymmetric hydrogenation is carried out under a pressure of 100 to 450 psi, preferably at about 300 to 450 psi.
  • the upper limit on pressure is generally dictated by considerations of safety and the capabilities of the reactor.
  • Inert diluents that may be used include both protic solvents—such as alcohols and/or water; or aprotic polar solvents such as ethers and/or amides or lactams and/or mixtures thereof. Water may optionally be added to any solvent that is used.
  • Preferred protic solvents include branched or unbranched C 1-8 -alcohols. Particularly preferred are lower alcohols such as methanol, ethanol, n-propanol and iso-propanol or mixtures thereof. Methanol is particularly preferred as the reaction medium. As noted, the methanol or other alcohol or other solvent may optionally contain water.
  • Suitable aprotic solvents are polar ethers such as for example tetrahydrofuran or dimethoxyethylether or amides such as for example dimethylformamide, or lactams such as for example N-methylpyrrolidone.
  • polar ethers such as for example tetrahydrofuran or dimethoxyethylether
  • amides such as for example dimethylformamide
  • lactams such as for example N-methylpyrrolidone.
  • solvents which have low flammability tendency.
  • acetophenone of formula (V) or the acid addition salt thereof is used in a molar ratio to the transition metal catalyst, and preferably a ruthenium catalyst, of 500:1 to 100,000:1, preferably from 750:1 to 20,000:1, during the asymmetrical hydrogenation.
  • a preferred catalyst is commercially available from Umicore AG & Co., KG as
  • Chiralyst LM 1010 RS (((R)-l-Diphenylphosphino-2-[(S)- ⁇ -(N,N-dimethylamino)-o- diphenylphosphinophenyl)methyl]ferrocene)-hapto 5-2,4-dimethylpentadienyl) ruthenium(II)iodide).
  • Other catalysts potentially suitable for use in the present invention are known from the prior art, e.g., see U.S. 6,191,284; U.S. 6,573,389 and U.S. 7,294,744 (where pyrrolidine based chiral ligands are used in combination with organorhodiium compounds as a metal catalyst).
  • catalysts described in U.S. 6,191,284 which is incorporated herein by reference.
  • the catalyst may also be present in polymer-bound form, e.g. with the chiral ligand bound to a polymer e.g. by covalent attachment through an un-substituted ring carbon of a phenyl group.
  • polymer-bound ligands of this kind does not necessarily rule out the use of non-polymer-bound ligands at the same time.
  • Polymer-bound catalysts of this kind may be advantageous for easy purification of the product.
  • the catalyst is used either as a pre-prepared, oxygen-free solution of the transition metal (preferably ruthenium) source and chiral ligand or the catalyst complex is prepared in situ from a transition metal (preferably ruthenium) source and chiral ligand in the presence of l-amino-2-aryl-ethan-2-one under oxygen-free conditions and under a protective gas atmosphere or hydrogen atmosphere.
  • the transition metal preferably ruthenium
  • the catalyst complex is prepared in situ from a transition metal (preferably ruthenium) source and chiral ligand in the presence of l-amino-2-aryl-ethan-2-one under oxygen-free conditions and under a protective gas atmosphere or hydrogen atmosphere.
  • the hydrogenation is carried out in oxygen-free conditions, conveniently under inert gas, but preferably under a hydrogen atmosphere and conventional steps are taken to eliminate oxygen from all of the starting materials.
  • reaction time for the asymmetric hydrogenation is generally between 24 and 64 hours up to its end, preferably between about 36 and 56 hours.
  • reaction product may be worked up in the conventional manner, e.g. by optionally deactivating the catalyst and removing it, eliminating the solvent from the residue and isolating the pure end product by crystallisation, distillation, extraction or chromatography.
  • the following steps are carried out in order to work up and isolate the product: (i) evaporating a portion of any inert solvent, (ii) dividing the reaction mixture obtained in the asymmetrical hydrogenation between water and an organic solvent, (ii) adjusting a pH value of the aqueous phase in the acid range, (iii) separating off the aqueous phase, (iv) optionally repeating steps (i) to (iii) (v) adjusting the pH value of the aqueous phase in the basic range; (vi) dividing the reaction mixture between water and an organic solvent, (vii) optionally repeating steps (v) to (vi) (vii) separating off the organic phase formed and concentrating it.
  • the adjustment of the pH value of the aqueous phase in the acidic range in step (ii) serves to form the salt of the hydrogenated product, so as to increase the solubility of the product in the aqueous phase.
  • the pH selected for this purpose depends on the product, and is preferably from 1-2, particularly preferably from 1.2-1.8.
  • the adjustment of the pH of the aqueous phase in the basic range in step (v) serves to bring the hydrogenated product out of its salt form, so as to increase the solubility of the product in the organic phase.
  • the pH selected for this purpose again depends on the product and is preferably 6-10, particularly 7-9.
  • the reaction mixture obtained is evaporated and the solid or syrupy oil residue so-obtained is divided between water and a suitable organic solvent such as toluene, ethyl or isopropyl acetate, diethyl or isopropyl ether, tetrahydrofuran or dichloromethane.
  • a suitable organic solvent such as toluene, ethyl or isopropyl acetate, diethyl or isopropyl ether, tetrahydrofuran or dichloromethane.
  • the pH of the aqueous phase is adjusted to a value of 1 to 2, preferably 1.2 to 1.8, and then the aqueous phase is separated off.
  • the organic phase is preferably again combined with water, acidified and separated off again.
  • the combined aqueous phases then are adjusted to a pH of 8 to 10, preferably 8.5 to 9.5, combined with solvent and extracted.
  • the corresponding 2-hydroxy-2- arylethylamine (free base) of formula I is obtained, after elimination of the solvent, with a high chemical purity (generally >95%) and optical purity (generally >95% ee).
  • the product of the catalytic hydrogenation into a salt.
  • the purpose of this may be to stabilize or make it easier to isolate the 2-hydroxy-2-arylethylamine and further increase the enantiomeric purity of the product, preferably to levels >99%.
  • this produces the product in the form of a solid which can be more easily transported and stored. Indeed, in the vast majority of cases, the active pharmaceutical compound is used in the salt form.
  • salts with inorganic acids such as hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, sulphonic acid or organic acids, such as oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, methanesulfonic acid, tartaric acid, or acetic acid, can be formed. It is also possible to use mixtures of the above-mentioned acids. To increase the enantiomeric purity, however, chiral salt- forming agents such as chiral mandelic acid, lactic acid or tartaric acid may also be used, although this is not essential.
  • the compounds of formula (I) and (V) may optionally be converted into the acid addition salts thereof with the same inorganic or organic acids identified above.
  • a 200 mL SS Buchi Miniclave reactor charge is charged with the following materials (1) ⁇ -methylamino-m-hydroxy acetophenone sulfate ((MAHAP) 2 sulfate) (17.14 g, 0.04 mol ⁇ 0.08 mol free base MAHAP); (2) (R)-phenylephrine free base (155 mg; 0.9 mmol); Umicore Chiralyst ML 1010 RS chiral catalyst complex (14.2-14.4 mg; 0.011 mmol).
  • MAHAP ⁇ -methylamino-m-hydroxy acetophenone sulfate
  • the reactor is set to a temperature of 70 °C ( ⁇ 1 0 C) and the level of agitation is increased to 2000 RPM and the ensuing hydrogenation reaction is allowed to proceed for 48 hours.
  • the reactor contents are cooled to 20-30 °C and the level of agitation is reduced to 100-200 RPM.
  • a small sample is obtained to check (using a phenylephrine chiral column) whether the reaction has been completed.
  • the reaction mixture should contain ⁇ 2.5% of (S)-phenylephrine and no residual starting material.
  • the product is filtered through a PP filter cloth.
  • the filtrate should be recycled in order to ensure transfer of the entire product on the filter cake.
  • the filter cake is washed in 2 portions using cold water that has been chilled in ice.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé amélioré pour préparer des 2-hydroxy-2-aryl-éthylamines énantiomériquement pures, et leurs sels pharmaceutiquement acceptables, par hydrogénation asymétrique catalysée par métal de transition, en utilisant de préférence un système de catalyseur de métal de transition ruthénium ayant comme ligand phosphine bidentate chiral, du ((R)-1-diphénylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphénylphosphinophenyl)méthyl]ferrocène), tel que Chiralyst LM 1010 RS disponible auprès de Umicore AG & Co., R-U.
PCT/US2008/087975 2007-12-21 2008-12-22 Synthèse de 2-hydroxy-2-aryl-éthylamines énantiomériquement pures Ceased WO2009086283A1 (fr)

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US61/015,958 2007-12-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011128370A1 (fr) 2010-04-13 2011-10-20 Krka, D.D., Novo Mesto Synthèse de duloxétine et/ou de ses sels pharmaceutiquement acceptables de celle-ci
US8455692B2 (en) 2010-11-01 2013-06-04 Divi's Laboratories, Ltd. Process for resolution of 1-(3-hydroxyphenyl)-2-methylamino ethanol
US9102959B2 (en) 2009-08-19 2015-08-11 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3968147A (en) * 1972-02-09 1976-07-06 Monsanto Company Asymmetric reduction of ketones to form optically active alcohols
US6187956B1 (en) * 1999-01-21 2001-02-13 Boehringer Ingelheim Pharma Kg Method for preparing of L-phenylephrine hydrochloride
US6191284B1 (en) * 1998-12-19 2001-02-20 Degussa-Huels Aktiengesellschaft Ligands and complexes for enantioselective hydrogenation
JP2004115437A (ja) * 2002-09-26 2004-04-15 Iwaki Seiyaku Co Ltd Ｌ−フェニレフリンを製造する方法
US7247750B2 (en) * 2002-10-24 2007-07-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing (R)-salbutamol
US7294744B2 (en) * 2004-07-08 2007-11-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for manufacturing of enantiomerically pure 3-hydroxy-3-phenyl-propylamin

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3968147A (en) * 1972-02-09 1976-07-06 Monsanto Company Asymmetric reduction of ketones to form optically active alcohols
US6191284B1 (en) * 1998-12-19 2001-02-20 Degussa-Huels Aktiengesellschaft Ligands and complexes for enantioselective hydrogenation
US6187956B1 (en) * 1999-01-21 2001-02-13 Boehringer Ingelheim Pharma Kg Method for preparing of L-phenylephrine hydrochloride
JP2004115437A (ja) * 2002-09-26 2004-04-15 Iwaki Seiyaku Co Ltd Ｌ−フェニレフリンを製造する方法
US7247750B2 (en) * 2002-10-24 2007-07-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing (R)-salbutamol
US7294744B2 (en) * 2004-07-08 2007-11-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for manufacturing of enantiomerically pure 3-hydroxy-3-phenyl-propylamin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 27 August 2007, Columbus, Ohio, US; abstract no. 849925-15-1 *
SPINDLER ET AL., TETRAHEDRON: ASYMMETRY, vol. 15, 2004, pages 2299 - 2306 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9102959B2 (en) 2009-08-19 2015-08-11 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US9834758B2 (en) 2009-08-19 2017-12-05 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US10358631B2 (en) 2009-08-19 2019-07-23 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US10590396B2 (en) 2009-08-19 2020-03-17 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US10870835B2 (en) 2009-08-19 2020-12-22 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US11345898B2 (en) 2009-08-19 2022-05-31 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US12031159B2 (en) 2009-08-19 2024-07-09 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
US12480100B2 (en) 2009-08-19 2025-11-25 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
WO2011128370A1 (fr) 2010-04-13 2011-10-20 Krka, D.D., Novo Mesto Synthèse de duloxétine et/ou de ses sels pharmaceutiquement acceptables de celle-ci
US8455692B2 (en) 2010-11-01 2013-06-04 Divi's Laboratories, Ltd. Process for resolution of 1-(3-hydroxyphenyl)-2-methylamino ethanol

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