WO2008077560A1 - Procédé de préparation de 2-amino-1-phényléthanols optiquement actifs - Google Patents

Procédé de préparation de 2-amino-1-phényléthanols optiquement actifs Download PDF

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Publication number
WO2008077560A1
WO2008077560A1 PCT/EP2007/011180 EP2007011180W WO2008077560A1 WO 2008077560 A1 WO2008077560 A1 WO 2008077560A1 EP 2007011180 W EP2007011180 W EP 2007011180W WO 2008077560 A1 WO2008077560 A1 WO 2008077560A1
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alkyl
phenyl
formula
hydrogen
alkoxy
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PCT/EP2007/011180
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English (en)
Inventor
John Mcgarrity
Antonio Zanotti-Gerosa
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Lonza 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
    • 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 refers to a process for the preparation of optically active 2-amino-l- phenylethanols of formula (I)
  • R 1 is hydrogen, C 1 - O alkyl or aryl-substituted C 1 ⁇ alkyl and R 2 through R 6 are independently hydrogen, hydroxy or C ⁇ alkoxy, or a salt thereof, particularly of (/?)-(-)- 1 -(3 '-hydroxyphenyl)-2-methylaminoethanol hydrochloride, which can be obtained by asymmetrically hydrogenating corresponding aminoketones or its salts in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.
  • Compounds of the formula I belong to the group of sympathomimetic drugs. They generally act by binding to or activating ⁇ - and ⁇ -adrenergic receptors, resulting in numerous physiological effects like vascular constriction, reduced blood flow or decrease in mucus secreted into nasal passages. This broad scope of physiological effect make compounds of formula I important as drugs.
  • sympathomimetic drugs were often commercialized as racemic mixtures because purification of one stereoisomer is expensive and time-consuming. During the past few years the demand on the more selective stereoisomer has increased as thus the required dosage and unwanted side-effects might be reduced.
  • the most difficult step in synthesizing the amino alcohols of formula I is hydrogenation of the corresponding ketones in a way that the amino alcohols obtained are optically enriched or pure. In large quantities, this used to be carried out by hydrogenation with a Pd-catalyst followed by fractional crystallization. More recently, it has been found out that stereoisomers can easily be achieved by transition metal-catalyzed asymmetric hydrogenation.
  • All compounds of formula I are characterized by an unprotected primary or secondary amino group. During hydrogenation, these unprotected amino groups are expected to lead to undesired side-reactions like self-condensation or even polymerization, especially in a large-scale process.
  • Noyori et al. report successful asymmetric hydrogenation by use of the [(xylbinap)RuCl 2 (daipen)] complex but only with classically protected aminoacetophenones like iV-acetyl-, N-benzoyl- or N-Boc-aminoacetophenone (Noyori J. Am. Chem. Soc. 2000, 122, 6510-6511).
  • EP 1 254 885 which also discloses such protected compounds.
  • rhodium catalysts are described to be effective for the unprotected substrates of formula I.
  • these asymmetric hydrogenations are characterized by relatively low catalyst activities and moderate stereoselectivity.
  • Knorr et al. produced the sympathomimetic drug etilefrine by means of Rh-catalysts having a substrate to catalyst (S/C) ratio of 100:1 or 200:1 respectively (Knorr Arzneim.-Forsch./Drug Res. 1984, 34 (II), No. 12, 1709-1713).
  • the N-benzyl protected aminoketone is used as substrate as disclosed in EP 1 147 075.
  • An object of the present invention is to provide such an economical asymmetrical hydrogenation process.
  • R 1 is hydrogen, Ci- ⁇ alkyl or aryl-substituted Ci- ⁇ alkyl and R 2 through R 6 are independently hydrogen, hydroxy or C 1- ⁇ alkoxy, or salts thereof, by asymmetric hydrogenation of unprotected 2-aminoacetophenones of formula or salts thereof, wherein R 1 through R 6 are as defined above, in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.
  • C 1 -,, alkyl is to be understood to mean any linear or branched alkyl group containing 1 to n carbon atoms.
  • the term “Ci_ 6 alkyl” comprises groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter/-butyl, pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, isohexyl (4-methylpentyl) and the like.
  • Ci_ n alkoxy means a group composed of a C 1 -,, alkyl group as defined above and an oxygen atom linked by a single covalent bond.
  • R 7 at each occurrence is selected from the group consisting of phenyl, 4-methylphenyl and 3,5-dimethylphenyl; R at each occurrence is alkoxy, or both R 8 groups together form a moiety of formula
  • n is an integer from 1 to 6; and R 9 is hydrogen, Ci_ 4 alkyl or alkoxy.
  • halogen fluorine, chlorine, bromine and iodine can be used, most preferably chlorine.
  • Examples of such chiral diphosphines of formula (III), in (R) or (S) configuration, are: "P-Phos", wherein Q is nitrogen, R 7 is phenyl and R 8 and R 9 are methoxy, i.e. 2,2',6,6'- tetramethyoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine, or
  • Xyl-P-Phos wherein Q is nitrogen, R is 3,5-dimethylphenyl and R and R are methoxy, i.e. 2,2',6,6'-tetramethoxy-4,4'-bis[di(3,5-dimethylphenyl)phosphino]-3,3'-bipyridine, or "ToI-P -Phos", wherein Q is nitrogen, R 7 is 4-methylphenyl and R 8 and R 9 are methoxy, i.e.
  • the use of chiral compounds selected from the group consisting of P-Phos and Xyl-P-Phos has proved particularly advantageous.
  • diphosphines of formula III wherein Q is CH- or
  • n is an integer from 1 to 6 like Cl-TunePhos, C2-TunePhos, C3-TunePhos, C4-TunePhos, C5-TunePhos and C6-TunePhos. Most preferably is n 3, i.e. C3-TunePhos.
  • R 10 is phenyl, optionally substituted with one or more C 1 - 4 alkyl or Ci_ 4 alkoxy groups, and R 11 is cycloalkyl or branched C 3 _ 6 alkyl.
  • cycloalkyl is to be understood to mean mono- or bicyclic saturated groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, norcaryl, norpinanyl, and related groups, such as the above-mentioned groups being further substituted with lower alkyl substituents.
  • R 10 is 4-methoxyphenyl and R 11 is isopropyl ("DAIPEN").
  • R 12 is Ci_ 8 alkyl, C 7- . ⁇ aralkyl, phenyl or substituted phenyl
  • R 13 is phenyl, substituted phenyl, naphthyl or C 1 - 4 alkyl and R 15 and R 16 together with the adjacent carbon atoms form a 6 ⁇ - or 10 ⁇ -electron aromatic or heteroaromatic system, optionally substituted by linear or branched C 1-8 alkyl or C 1-8 alkoxy, and possible heteroatoms are S, N or O.
  • R 15 and R 16 together with the adjacent carbon atoms form a benzene ring, optionally substituted by linear or branched C 1-8 alkyl or Ci -8 alkoxy, thus forming a compound of formula
  • R 12 and R 13 are defined as in formula V and R 14 is Ci_ 8 alkyl or Ci_ 8 alkoxy.
  • Examples of such chiral phosphine-oxazolines of formula VI, in (R) or (S) configuration, are: "i-Pr-Phox", wherein R 12 is isopropyl, R 13 is phenyl and R 14 is hydrogen, or
  • R 13 is phenyl and R 14 is hydrogen like i-Pr-Phox.
  • R 15 and R 16 together with the adjacent carbon atoms form a cyclopentadienyl ring of a ferrocene system, thus forming a compound of formula
  • R 12 and R 13 are defined as in formula V.
  • Examples of such chiral phosphine-oxazolines of formula VII, in (R) or (S) configuration, are: VII-a, wherein R 12 is isopropyl and R 13 is phenyl, or
  • VII-e wherein R 12 is isopropyl and R 13 is 4-trifluoromethylphenyl
  • VII-f wherein R 12 is isopropyl and R 13 is 3,5-trifluoromethylphenyl, or
  • R 1 is methyl, ethyl or isopropyl and at least one of R 2 to R is hydroxy.
  • Corresponding products are compounds such as oxedrine, epinephrine, phenylephrine, etilefrine, orciprenaline and isoprenaline.
  • R 1 is methyl
  • R 3 is hydroxy
  • R 2 , R 4 , R 5 and R 6 are hydrogen, i.e., the product is phenylephrine.
  • Bases applicable in the present invention include inorganic and organic bases.
  • the bases may be expressed by the general formula MY, wherein M is an alkali metal or an alkaline earth metal, and Y is a hydroxy group, alkoxy group or naphthyl group. More specifically, applicable bases include KOH, KOCH 3 , KOCH(CH 3 ) 2 , KOC(CH 3 ) 3 , NaOH, NaOCH 3 , NaOCH(CH 3 ) 2 as well as quaternary ammonium salts. Most preferably KOH is used as base.
  • the catalyst may be added as such to the reaction mixture or alternatively the catalyst may be prepared in situ from chiral ligands and suitable precursor complexes like (PPh 3 ) 3 RuCl 2 .
  • suitable precursor complexes like (PPh 3 ) 3 RuCl 2 .
  • solvent any liquid solvent which can dissolve the reactants and catalyst components may be used. Two-phase systems with water may also be used.
  • Applicable solvents include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as pentane and hexane, halogenated hydrocarbons such as methylene chloride, ethers such as diethyl ether and tetrahydrofuran, alcohols such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, dimethylformamide and dimethyl sulfoxide. More preferably, 2-propanol and methanol may be used. Also solvent mixtures comprising the above-mentioned solvents may be used.
  • the amount of 2-aminoacetophenone of formula II (substrate) varies with the reactor volume and can be at a molar ratio relative to the ruthenium complex catalyst (S/C) from 50:1 to 100,000:1, or more preferably from 500:1 to 50,000:1.
  • the hydrogenation process according to the invention may be carried out at typical pressures from 1 to 100 bar.
  • 10 to 85 bar, in particular 20 to 40 bar are used.
  • the hydrogenation reactions may be carried out in a temperature range from 0 °C to 120 °C. Preferred is a temperature between 40 0 C and 90 °C, and most preferred is a range from 65 °C to 85 °C.
  • the reaction time depends on different factors like the catalyst loading, the temperature and the hydrogen pressure. Therefore, the reaction might be completed in a period of time within a range from a few minutes to several hours or even days.
  • Example 1 Synthesis of 2-bromo-3'-hydroxyacetophenone a) 1,4-Dioxane dibromide was prepared following a literature procedure (J. D. Billimoria, N. F. Maclagan, J. Chem. Soc. 1954, 3257-3262). Bromine (320 g, 2 mol) was added with vigorous stirring to 1,4-dioxane (180 g, 2 mol). The warm solution (ca. 60 °C) was poured into light petroleum (2 L, b.p. 30-60 °C). The yellow precipitate was filtered off and washed with light petroleum as rapidly as possible. The compound (m.p. 60-61 °C) was used without further purification and could be stored at 0 °C.
  • the title compound was synthesized following a modified literature procedure (JP-A 63-192744). The whole procedure was performed under nitrogen atmosphere. A solution of methylamine (85 mL, 0.70 mol) in 250 mL tetrahydrofuran (THF) was cooled in an ice-salt bath. A solution of 2-bromo-3'-hydroxyacetophenone (42.5 g, 0.23 mol) in 750 mL of THF was added dropwise into the above solution within a period of 30 minutes. The temperature was kept below 5 °C, and after complete addition stirring was continued for 2 hours. At the beginning of addition, the solution became light yellow.
  • JP-A 63-192744 The whole procedure was performed under nitrogen atmosphere. A solution of methylamine (85 mL, 0.70 mol) in 250 mL tetrahydrofuran (THF) was cooled in an ice-salt bath. A solution of 2-bromo-3'-hydroxyacetophenone (42.5 g, 0.23 mol) in
  • the mixture was then concentrated under vacuum to remove excess of methylamine and some solvent (about 800 mL).
  • the resulting solution (ca. 200 mL) was filtered in order to remove the CH 3 NH 2 HBr deposit, and then 30 mL of concentrated HCl was added dropwise within 30 minutes while cooling in an ice bath. Then, the mixture was evaporated under vacuum. 30 mL Ethanol and 15 mL methanol were added to the dark brown residue and the mixture was refluxed for 30 to 60 minutes. After cooling to room temperature, the mixture was filtered.
  • the reaction were then purged with hydrogen five times, then heated to the temperature reported, pressurised to 28 bar and run for the time reported in the table.
  • the catalyst of example 7 was introduced as 0.005 M catalyst stock solution prepared as from 0.1 mmol (5)-i-
  • MeOH methanol
  • acac acetylacetonate
  • dmf ⁇ VV-dimethylformamide
  • the reaction was then pressurised to 25 bar hydrogen, stirred at around 1000 rpm and heated to 80 °C over 30 minutes. The temperature was then slowly increased to 85 °C over 30 minutes and the pressure adjusted to 30 bar. The reaction was stirred for 20 hours while the hydrogen pressure was maintained between 28 bar and 31 bar. About 90% of the total hydrogen uptake took place in about 4 hours. The reaction was then allowed to cool to room temperature, the pressure released and the solvent evaporated to give a solid residue of 2.32 g (115% mass recovery). HPLC analysis indicated full conversion and 1 H NMR analysis of the crude material indicated that the material was >95% pure. The solid residue was dissolved in 3 mL methanol.

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

Abstract

La présente invention concerne des 2-amino-1-phényléthanols optiquement actifs de formule (I) ou son image miroir, dans laquelle R1 est hydrogène, alkyle C1-C6 ou alkyle C1-C6 à substitution aryle et R2 à R6 sont indépendamment hydrogène, hydroxy ou alcoxy C1-C6, ou leurs sels préparés par l'hydrogénation asymétrique de 2-aminoacétophénones correspondants en présence d'un catalyseur à base de complexe de ruthénium comprenant un ligand de type phosphine chirale.
PCT/EP2007/011180 2006-12-22 2007-12-19 Procédé de préparation de 2-amino-1-phényléthanols optiquement actifs WO2008077560A1 (fr)

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EP06026754 2006-12-22

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455692B2 (en) 2010-11-01 2013-06-04 Divi's Laboratories, Ltd. Process for resolution of 1-(3-hydroxyphenyl)-2-methylamino ethanol
JP2013536853A (ja) * 2010-09-01 2013-09-26 アムビト ビオスシエンセス コルポラチオン 光学活性のあるピラゾリルアミノキナゾリン及びその医薬組成物及び使用方法
CN103889958A (zh) * 2011-10-07 2014-06-25 阿尔米雷尔有限公司 通过新的中间体制备5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(r)-羟基乙基)-8-羟基喹啉-2(1h)-酮的方法
CN104876828A (zh) * 2015-03-23 2015-09-02 李玉山 一种辛弗林及其盐酸盐、酒石酸盐的合成方法
US9334266B2 (en) 2009-09-04 2016-05-10 The University Of Toledo Catalysts and related processes for producing optically pure beta-lactones from aldehydes and compositions produced thereby
CN107021884A (zh) * 2017-04-27 2017-08-08 武汉凯特立斯科技有限公司 通过Ir/f‑amphox催化α‑氨基酮高效合成手性1,2‑氨基醇的方法
CN107417562A (zh) * 2017-08-14 2017-12-01 凯特立斯（深圳）科技有限公司 催化前手性α‑酮酰胺合成手性α‑羟基酰胺的方法
WO2018029102A1 (fr) 2016-08-10 2018-02-15 Bayer Cropscience Aktiengesellschaft 2-hétérocyclyle-imidazolyle-carboxamides substitués utilisés en tant que pesticides

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US5801261A (en) * 1995-06-20 1998-09-01 Bayer Aktiengesellschaft Bisphosphines as catalysts for asymmetric reactions
WO2000043345A1 (fr) * 1999-01-21 2000-07-27 Boehringer Ingelheim Pharma Kg Procede de preparation d'hydrochlorure de l-phenylephrine
US20060122431A1 (en) * 2002-10-24 2006-06-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing (R) salbutamol

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Publication number Priority date Publication date Assignee Title
US5801261A (en) * 1995-06-20 1998-09-01 Bayer Aktiengesellschaft Bisphosphines as catalysts for asymmetric reactions
WO2000043345A1 (fr) * 1999-01-21 2000-07-27 Boehringer Ingelheim Pharma Kg Procede de preparation d'hydrochlorure de l-phenylephrine
US20060122431A1 (en) * 2002-10-24 2006-06-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing (R) salbutamol

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Title
SAKURABA S ET AL: "EFFICIENT ASYMMETRIC HYDROGENATION OF ALPHA-AMINO KETONE DERIVATIVES A HIGHLY ENANTIOSELECTIVE SYNTHESIS OF PHENYLEPHRINE, LEVAMISOLE, CARNITINE AND PROPRANOLOL", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 43, no. 5, 1 May 1995 (1995-05-01), pages 738 - 747, XP000571426, ISSN: 0009-2363 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9334266B2 (en) 2009-09-04 2016-05-10 The University Of Toledo Catalysts and related processes for producing optically pure beta-lactones from aldehydes and compositions produced thereby
JP2013536853A (ja) * 2010-09-01 2013-09-26 アムビト ビオスシエンセス コルポラチオン 光学活性のあるピラゾリルアミノキナゾリン及びその医薬組成物及び使用方法
JP2013536854A (ja) * 2010-09-01 2013-09-26 アムビト ビオスシエンセス コルポラチオン 光学活性のあるピラゾリルアミノキナゾリン及びその医薬組成物及び使用方法
US8455692B2 (en) 2010-11-01 2013-06-04 Divi's Laboratories, Ltd. Process for resolution of 1-(3-hydroxyphenyl)-2-methylamino ethanol
CN103889958A (zh) * 2011-10-07 2014-06-25 阿尔米雷尔有限公司 通过新的中间体制备5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(r)-羟基乙基)-8-羟基喹啉-2(1h)-酮的方法
JP2014532059A (ja) * 2011-10-07 2014-12-04 アルミラル・ソシエダッド・アノニマＡｌｍｉｒａｌｌ， Ｓ．Ａ． 新規中間体を介する５−（２−｛［６−（２，２−ジフルオロ−２−フェニルエトキシ）ヘキシル］アミノ｝−１（ｒ）−ヒドロキシエチル）−８−ヒドロキシキノリン−２（１ｈ）−オンの製造方法
CN104876828A (zh) * 2015-03-23 2015-09-02 李玉山 一种辛弗林及其盐酸盐、酒石酸盐的合成方法
WO2018029102A1 (fr) 2016-08-10 2018-02-15 Bayer Cropscience Aktiengesellschaft 2-hétérocyclyle-imidazolyle-carboxamides substitués utilisés en tant que pesticides
CN107021884A (zh) * 2017-04-27 2017-08-08 武汉凯特立斯科技有限公司 通过Ir/f‑amphox催化α‑氨基酮高效合成手性1,2‑氨基醇的方法
CN107021884B (zh) * 2017-04-27 2019-12-24 武汉凯特立斯科技有限公司 通过Ir/f-amphox催化α-氨基酮高效合成手性1,2-氨基醇的方法
CN107417562A (zh) * 2017-08-14 2017-12-01 凯特立斯（深圳）科技有限公司 催化前手性α‑酮酰胺合成手性α‑羟基酰胺的方法

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