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WO2006002730A1 - Procede de preparation de biaryldiphosphines a substitution asymetrique - Google Patents

Procede de preparation de biaryldiphosphines a substitution asymetrique Download PDF

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Publication number
WO2006002730A1
WO2006002730A1 PCT/EP2005/006064 EP2005006064W WO2006002730A1 WO 2006002730 A1 WO2006002730 A1 WO 2006002730A1 EP 2005006064 W EP2005006064 W EP 2005006064W WO 2006002730 A1 WO2006002730 A1 WO 2006002730A1
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alkyl
group
cycloalkyl
halogen atoms
formula
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Hanspeter Mettler
Frédéric LEROUX
Manfred Schlosser
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Lonza AG
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Lonza AG
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Priority to EP05751951A priority Critical patent/EP1761549A1/fr
Priority to BRPI0512571-5A priority patent/BRPI0512571A/pt
Priority to JP2007517124A priority patent/JP4519912B2/ja
Publication of WO2006002730A1 publication Critical patent/WO2006002730A1/fr
Priority to IL179980A priority patent/IL179980A0/en
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5027—Polyphosphines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • 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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • 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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0046—Ruthenium compounds
    • C07F15/0053—Ruthenium compounds without a metal-carbon linkage
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/505—Preparation; Separation; Purification; Stabilisation
    • C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
    • C07F9/5068—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure >P-Hal
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group

Definitions

  • the invention relates to a process for the preparation of asymmetrically substituted biaryldiphosphine ligands and transition metal complexes thereof for the hydrogenation of unsaturated prochiral compounds using said complexes.
  • Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds. Providing methods for the precise control of molecular chirality of pharmaceutical active compounds and compounds thereof tends to play an increasingly important role in synthetic chemistry.
  • diphosphine ligand families are commonly known with their trade names, for example BINAP, CHIRAPHOS, DIOP, DUPHOS, SEGPHOS and TUNAPHOS.
  • Biaryl diphosphine ligands consist of three different moieties, a rigid biaryl core, substi- tuents to hinder biaryl rotation and usually two phosphine groups with voluminous substituents to complex a transition metal.
  • ligand systems have symmetric substitution patterns of the core and identical phosphine groups.
  • WO-A-02/40492 discloses asymmetric hydrogenation of ethyl 4-chloro- 3-oxobutyrate, using a catalyst containing the ligand (S)-6-methoxy-5',6'-benzo- 2,2'-bis(diphenylphosphino)-biphenyl.
  • the (5)-alcohol is obtained with an enantiomeric excess (ee) of 83%.
  • EP-A-O 647648 and WO-A-02/40492 claim diphosphines with asymmetrically substituted biaryl core, but the disclosed synthetic principles are not suitable to produce a broad variety of different asymmetrically substituted biaryldiphosphine ligands.
  • enantiomerically pure compound comprises optically active compounds with an enantiomeric excess (ee) of at least 90 %.
  • C 1-n -alkyl represents a linear or branched alkyl group having 1 to n carbon atoms.
  • C 1-6 -alkyl represents for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, fer/-butyl, pentyl and hexyl.
  • C -n -alkoxy represents a linear or branched alkoxy group having 1 to n carbon atoms.
  • C 1-6 -alkoxy represents for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, fert-butoxy, pentyloxy and hexyloxy.
  • C 3-n -cycloalkyl represents a cycloaliphatic group having 3 to n carbon atoms.
  • Cs-io-cycloalkyl represents mono- and polycyclic ring systems such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norborayl.
  • C 3-n -cycloalkoxy represents a cycloalkoxy group having 3 to n carbon atoms.
  • C 5-10 -cycloalkyl represents for example cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy or cyclodecyloxy.
  • di-Ci-6-alkylamino represents a dialkylamino group comprising two alkyl moieties independently having 1 to 6 carbon atoms.
  • Di-C 1-6 -alkyl- amino represents for example N,iV-dimethylamino, N,N-diethylamino, iV-ethyl- JV-methylamino, N-methyl-iV-propylamino, N-ethyl-N-hexylamino or iV,N-dihexylamino.
  • aryl represents an aromatic group, preferably phenyl or naphthyl optionally being further substituted with one or more halogen atoms, nitro and/or amino groups, and/or optionally substituted C 1-6 -alkyl, C 1-6 -alkoxy or di-C 1-6 -alkylamino groups.
  • C 1-3 -alcohols represents methanol, ethanol, propanol and isopropanol.
  • C 1-3 -alkanoic acids represents formic acid, acetic acid and propanoic acid.
  • the technical problem to be solved by the present invention was to provide a method for the tailored synthesis of a series of biaryldiphosphines.
  • a further problem to be solved was to establish said process in a robust manner to provide suitable amounts of ligands for the pharmaceutical industry.
  • the general concept should start with an easily available compound and should contain few reaction steps, allowing the synthesis of a wide variety of ligands, only depending on the reaction sequence.
  • R 1 is C 1-6 -alkyl or C 3-10 -cycloalkyl optionally being substituted with one or more halogen atoms
  • R 2 and R 3 are equal and are selected from the group consisting of aryl, C 5-1 o-cycloalkyl and Q-6-alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino groups, or
  • R 2 is d- 6 -alkyl or Cs-io-cycloalkyl
  • R 3 is aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C t - 6 -alkoxy and di-C 1-6 -alkylamino groups, and each C 1-6 -alkyl, Ci -6 -alkoxy, di-C ⁇ - 6 -alkylamino and C 5-1 o-cycloalkyl group in R 2 and R 3 optionally being substituted with one or more halogen atoms,
  • each reaction sequence comprises at least one bromine-metal exchange and subsequent metal-substituent exchange with the respective substituent, thereby exchanging the respective bromine atoms with substituents selected from the group consisting of hydrogen, diarylphosphino, di-C ⁇ -6 -alkyl ⁇ hosphino and di-Cs-io-cycloalkylphosphino.
  • the bromine-metal exchanges mentioned in the instant invention may be carried out with the required amount of the respective organometallic compound at a temperature below -40 °C ("low temperature bromine-metal exchange") or at a temperature of at last 0 °C ("high temperature bromine-metal exchange").
  • Chiral biaryldiphosphine ligands comprising a biaryl skeleton which is permanently twisted around the central carbon-carbon bond have two atropisomers.
  • Asymmetric hydrogenation with transition metal complexes are preferably performed with one of the atropisomeres and optionally further chiral auxiliaries. Therefore, it should be appreciated that any reference to ligands of formula
  • R 1 , R 2 and R 3 are as defined above, implicitly includes its atropisomers
  • I"-S, and V-R if not otherwise specified, e.g. by indicating their positive (+) or negative (-) optical rotation.
  • [a-1] 1 eq. low temperature bromine-metal exchange
  • [a-2] 2 eq. low temperature bromine-metal exchange
  • [a-3] 1 to 2 eq. high temperature bromine-metal exchange
  • the first bromine-metal exchange of the compound of formula III is carried out with one equivalent of n-butyllithium at a temperature below -40 °C ("1 eq. low temperature bromine-metal exchange") in a polar solvent to afford a metallated intermediate.
  • the following metal-hydroxy exchange is carried out by reacting the metallated intermediate with a borane or organoborate, and followed by reaction with a peroxy compound in the presence of an alkali and/or earth alkali hydroxide, and the alkylation is carried out with an alkylating agent in the presence of a base.
  • the borane or organoborate is fluorodimethoxyborane diethyl ether adduct, triisopropylborate or trimethylborate, preferably in ethereal solution.
  • the peroxy compound is selected from the group consisting of hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid and tert-bntyl hydroperoxide.
  • the alkali and/or earth alkali hydroxide in the reaction with the peroxy compound is selected from the group consisting of LiOH, NaOH, KOH, Ca(OH) 2 and Mg(OH) 2 .
  • the base of the alkylation reaction is an alkali and/or earth alkali hydroxide, selected from the group consisting of LiOH, NaOH, KOH, Ca(OH) 2 and Mg(OH) 2 .
  • the alkylating agent is a C 1-6 -alkyl halide, a C 5-10 -cycloalkyl halide or dimethyl sulfate.
  • the C 1-6 -alkyl halide is a C 1-6 -alkyl bromide or d- 6 -alkyl iodide.
  • the alkylating agent is iodomethane or dimethyl sulfate.
  • R 1 is as defined above, and
  • R 2 and R 3 are equal and are aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino groups, and each C 1-6 -alkyl, C 5-10 -cycloalkyl, C ⁇ -alkoxy and di- C 1-6 -alkylamino group in R 2 and R 3 optionally being substituted with one or more halogen atoms, and the remaining bromine atom of the compound of formula V is replaced with hydrogen by high temperature bromine-metal exchange and subsequent reaction with a proton donor, to afford ligands of formula
  • R 1 , R 2 and R 3 are as defined in compound V above.
  • a further reaction sequence is carried out starting from compounds of formula IV above, comprising a low temperature bromine-metal exchange of one bromine atom of the aryl moiety containing two bromine atoms and subsequent metal-hydrogen exchange by reaction with a proton donor, to afford a compound of formula wherein R 1 is as defined above, and a further low temperature bromine-metal exchange of the remaining bromine atoms and subsequent metal-phosphine exchange, affording ligands of formula I, wherein R 1 is as defined above, and R and R are equal and are selected from the group consisting of aryl, C 5 -io-cycloalkyl and C 1-6 -alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, Ci- 6 -alkyl, C 1-6 -alkoxy and di-Ct-6-alkylamino groups, and each d
  • R 1 is defined above, and R 2 is C 5-10 -cycloalkyl or C 1-6 -alkyl, the C 1-6 -alkyl or
  • C 5-10 -cycloalkyl group optionally being substituted with one or more halogen atoms, and a high temperature bromine-metal exchange of the remaining bromine atom and subsequent metal-phosphine exchange, affording ligands of formula I, wherein R 1 and R 2 are as defined above, and R 3 is aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-Ci- 6 -alkylamino groups, and each C 1-6 -alkyl, Cs.io-cycloalkyl, C 1-6 -alkoxy and di- Ci- 6 -alkylamino group in R 3 optionally being substituted with one or more halogen atoms.
  • each low temperature bromine-metal exchange is carried out with an organometallic compound such as n-butyllithium, isopropylmagnesium chloride or lithium tributylmagnesate at a temperature below —40 °C, preferably in the range of -60 to -90 °C.
  • each low temperature bromine-metal exchange is carried out in a polar solvent, preferably containing tetrahydrofuran.
  • the halogen-metal exchange is carried out with an organometallic compound such as n-butyllithium, tert- butyllithium, isopropylmagnesium chloride or lithium tributylmagnesate, at a temperature of at least 0 °C, preferably in the range of 0 to +40 0 C.
  • organometallic compound such as n-butyllithium, tert- butyllithium, isopropylmagnesium chloride or lithium tributylmagnesate
  • the high temperature bromine-metal exchange is carried out in a solution containing toluene and/or tetrahydrofuran.
  • the hydrogen donor is selected from the group consisting of Q- 3 -alcohols, water, non-oxidizing inorganic proton acids, and C 1-3 -alkanoic acids.
  • the non-oxidizing inorganic proton acid is HCl.
  • the reaction with the hydrogen donor is carried out at a temperature in the range of -60 to -90 0 C.
  • the metal-phosphine exchange is carried out using a halo- phosphine of the formula ⁇ VIII,
  • X is chlorine, bromine or iodine and both substituents R are equal and are R 2 or R 3 , wherein R 2 and R 3 are as defined above.
  • the halophosphine of the formula VIII is selected from the group consisting of halodiarylphosphines, halodi-(C 5-10 -cycloalkyl)phosphines and halodi-(C 1-6 -alkyl) ⁇ hosphines.
  • Each aryl substituent of the halodiarylphosphine moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, d- 6 -alkyl, C ⁇ -alkoxy and di-d- 6 -alkylamino groups.
  • substituents selected from the group consisting of halogen atoms, nitro, amino, d- 6 -alkyl, C ⁇ -alkoxy and di-d- 6 -alkylamino groups.
  • each C 1-6 -alkyl, C 1-6 -alk- oxy, di-C ⁇ -6 -alkylamino and Cs-io-cycloalkyl group of the halophosphine of the formula VIII is substituted with one or more halogen atoms.
  • the halo ⁇ phosphine of the formula VIII is selected from the group consisting of halodiarylphos ⁇ phines and halodi-(C 5-10 -cycloalkyl) ⁇ hosphines, more preferably is chlorodicyclohexyl- phosphine, bromodicyclohexylphosphine, chlorodiphenylphosphine or bromodiphenyl- phosphine.
  • R 1 is d- 6 -alkyl or C 3-10 -cycloalkyl optionally substituted with one or more halogen atoms
  • R 2 and R 3 are equal and are selected from the group consisting of aryl, Cs-io-cycloalkyl and d- 6 -alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, d- 6 -alkyl, C 1-6 -alkoxy and di-d- 6 -alkylamino groups, or
  • R 2 is C 5-1 o-cycloalkyl or C 1-6 -alkyl
  • R 3 is aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino groups, and each C 1-6 -alkyl, C 5-10 -cycloalkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino group in R 2 and R 3 optionally being substituted with one or more halogen atoms.
  • R 1 is C 1-6 -alkyl or C 3-10 -cycloalkyl optionally substituted with one or more halogen atoms.
  • R 1 is C 1-6 -alkyl or C 3- i 0 -cycloalkyl optionally substituted with one or more halogen atoms
  • R 2 and R 3 are equal and are selected from the group consisting of aryl, Cs ⁇ o-cycloalkyl and Ci- 6 -alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, Q ⁇ -alkyl, Ct- 6 -alkoxy and di-C 1-6 -alkylamino groups, or
  • R 2 is C 5-10 -cycloalkyl or C 1-6 -alkyl
  • R 3 is aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino groups, and each C 1-6 -alkyl, Cs- t o-cycloalkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino group in R 2 and
  • R 3 optionally being substituted with one or more halogen atoms.
  • the invention provides compounds of formula
  • R 1 is C 1-6 -alkyl or Ca- t o-cycloalkyl optionally substituted with one or more halogen atoms, and
  • R 2 is selected from the group consisting of aryl, C 5-10 -cycloalkyl and Ci -6 -alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkyl- amino groups, and each C 1-6 -alkyl, Cs-io-cycloalkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino group in R 2 optionally being substituted with one or more halogen atoms.
  • R 1 is Ci -6 -alkyl or C 3-10 -cycloalkyl optionally substituted with one or more halogen atoms
  • R 2 and R 3 are equal and are selected from the group consisting of aryl, C 5-10 -cycloalkyl and Q- 6 -alkyl, wherein each aryl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C 1-6 -alkyl, C 1-6 -alkoxy and di-Ci -6 -alkylamino groups, or R 2 is C5 -10 -cycloalkyl or C 1-6 -alkyl, and R 3 is aryl optionally substituted with one or more substituents selected from the group consisting of halogen atoms, nitro, amino, C ⁇ -alkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino groups, and each Ci -6 -alkyl, C 5-1 o-cycloalkyl, C 1-6 -alkoxy and di-C 1-6 -alkylamino group in R 2 and R
  • Said catalytic active complexes of transition metals can be used for hydrogenating, preferably asymmetrically hydrogenating, of a compound containing at least one unsaturated prochiral system.
  • the products obtained by said asymmetrically hydrogenating are enantiomerically pure compounds.
  • the hydrogen pressure during hydrogenating is in the range of 1 to 60 bar, particularly preferred in the range of 2 to 35 bar.
  • hydrogenating is carried out at a temperature in the range of O to 150 °C.
  • the compounds containing at least one unsaturated prochiral system are selected from the group consisting of compounds containing a prochiral carbonyl group, a prochiral alkene group or a prochiral imine group.
  • the compound containing at least one unsaturated prochiral carbonyl, alkene or imine group is selected from the group consisting of ⁇ - and ⁇ -ketoesters, ⁇ - and ⁇ -ketoamines, ⁇ - and ⁇ -ketoalcohols, acrylic acid derivatives, acylated enamines or N-substituted imines of aromatic ketones and aldehydes.
  • the hydrogenation reactions are carried out with a catalyst solution in a polar solvent like C ⁇ -alcohols, water, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile (MeCN), ethers or mixtures thereof.
  • the polar solvent contains methanol, ethanol or isopropyl alcohol or a mixture thereof.
  • the solution may contain further additives.
  • the present invention is illustrated by the following non-limiting examples.
  • Example 1 l,3-Dibromo-2-iodobenzene (II) Diisopropylamine (0.14 L, 0.10 kg, 1.0 mol) and 1,3-dibromobenzene (0.12 L, 0.24 kg, 1.0 mol) were consecutively added to a solution of n-butyllithium (1.0 mol) in tetrahydro- furan (2.0 L) and hexanes (0.64 L) at -75 °C. After 2 h at -75 °C, a solution of iodine (0.26 kg, 1.0 mol) in tetrahydrofuran (0.5 L) was added.
  • the reaction mixture was neutralized at 25 °C with 2.0 M hydrochloric acid (0.10 L) and extracted with diethyl ether (3x0.10 L). The combined organic layers were washed with a 10% aqueous solution of sodium sulfite (0.10 L), dried over sodium sulfate and evaporated. The oily residue was dissolved in dimethyl sulfoxide (0.20 L) before iodomethane (7.5 mL, 17 g, 0.12 mol) and potassium hydroxide powder (6.7 g, 0.12 mol) were consecutively added. After 1 h, water (0.50 L) was added and the product was extracted with diethyl ether (3x0.10 L). The organic layers were dried over sodium sulfate and evaporated. Crystallization form ethanol (0.10 L) afforded 35 g (82%) product as colorless cubes; m.p. 184 to 185 0 C;
  • n-butyllithium (50 mmol) in hexanes (30 mL) was added to a solution of com ⁇ pound Va (16 g, 25 mmol) in toluene (0.1 L).
  • methanol (2 mL) was added followed by water (25 mL) and the organic layer was separated.
  • the aqueous phase was extracted with dichloromethane (2x25 mL) and the combined organic layers were dried over sodium sulfate before being evaporated. Crystallization from dichloromethane (50 mL) afforded 7.9 g (57%) colorless prisms; m.p.
  • n-butyllithium 25 mmol
  • hexanes 13 mL
  • methanol 2.0 mL
  • ethyl acetate 3x30 mL
  • the combined organic layers were dried over sodium sulfate before being evaporated.
  • n-butyllithium (0.10 mol) in hexanes 63 mL was added to a solution of com ⁇ pound Vila (17 g, 50 mmol) in tetrahydrofuran (0.25 L).
  • the mixture was treated with a 2.0 M solution of chlorodicyclohexylphosphine (22 mL, 24 g, 0.10 mol) in tetrahydrofaran (50 mL).
  • the mixture was allowed to reach 25 °C and treated with a saturated aqueous solution of ammonium chloride (0.10 L).
  • the mixture was extracted with ethyl acetate (3x50 mL), and the combined organic layers were dried over sodium sulfate.
  • the diphosphine 43 g (74%) was obtained after evaporation of the solvents and crystallization form methanol (0.10 L) as colorless cubes; m.p. 220 to 221 °C (decomposition);
  • Vila 2'-Bromo-6-methoxy-l,l'-biphenyl-2-yl
  • n-butyllithium (0.10 mol) in hexanes (63 mL) was added to a solution of com ⁇ pound Via (34 g, 0.10 mol) in tetrahydrofuran (0.50 L).
  • racemic diphosphine Ic was separated into its enantiomers by preparative chromato- graphy using a chiral stationary phase.
  • the column used was CHIRALCEL ® OD 20 ⁇ m, the mobile phase was n-Heptane / EtOH 2000:1. From 360 mg racemic material 142 mg of (+)-6-dicyclohexylphosphanyl-2'-diphenylphosphanyl-2-methoxy-l,l'-biphenyl and 123 mg of (-)-6-dicyclohexylphos ⁇ hanyl-2'-diphenylphosphanyl-2-methoxy-l,l '-biphenyl were isolated.
  • the separation was performed as described in example 10.
  • reaction solution After cooling to room temperature the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and, after derivatization with trifluoroacetic acid anhydride, enantiomeric excess (column: Lipodex-E 25 m / 0.25 mm). Conversion is 99.7% at an ee of 99.0%.
  • Example 15 (if)-Ethyl 4-chloro-3-hydroxybutyrate In a 150 mL autoclave in an argon atmosphere bis(l-isopro ⁇ yl-4-methylbenzene)dichloro- ruthenium (7.6 mg, 0.012 mmol), (+)-ligand Ia (14.0 mg, 0.025 mmol) and ethyl 4-chloro- 3-oxobutyrate 98.4% (0.83 g, 5.0 mmol) is dissolved in degassed ethanol (30 mL). After flushing the autoclave with argon hydrogenation is carried out during 4 h at 80 °C and at 4 bar hydrogen pressure.
  • reaction solution After cooling to room temperature the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and ee (column: Lipodex-E 25 m / 0.25 mm). Conversion is 99.9% at an ee of 88%.
  • reaction solution After cooling to room temperature the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and ee (column: Lipodex-E 25 m / 0.25 mm). Conversion is 100% at an ee of 80%.
  • Example 17 iV-Acetyl-D-phenylalanine In a 15 mL autoclave in an argon atmosphere bis(benzene)dichlor-ruthenium (2.6 mg,
  • (+)-ligand Ia (6.0 mg, 0.011 mmol) and N-acetylaminocinnamic acid (0.53 g, 2.5 mmol) is dissolved in degassed methanol (5 mL). After flushing the autoclave with argon hydrogenation is carried out during 16 h at 40 °C and at 50 bar hydrogen pressure. After cooling to room temperature the reaction solution is evaporated and the residue analysed by HPLC for conversion (column: Bischoff Kromasil 100 C8) and enantiomeric excess (column: ⁇ ucleodex Beta-PM). Conversion is 100% at an ee of 43%.
  • reaction solution is directly analysed by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey- ⁇ agel, ⁇ ucleodex Beta-PM CC200/4). Conversion is 100% at an ee of 29%.
  • Example 21 (S)-iV-Benzyl-l-phenylethylamine
  • (+)-ligand Ic (5.7 mg, 0.010 mmol)
  • benzylamine (5.6 mg, 0.052 mmol)
  • N-benzyl-iV-(l-phenylethylidene)amine (0.21 g, 1.0 mmol) is dissolved in degassed methanol (5 mL) and stirred for Ih at room temperature.
  • Example 22 (R)-Dimethyl methylsuccinate Bis(l,5-cyclooctadiene)-rhodium(I) tetrafluoroborate (2.1 mg, 0.005 mmol) and ligand (+)-Ic (3.1 mg, 0.005 mmol) are dissolved in 5 mL degassed methanol in a 15 mL auto ⁇ clave under argon atmosphere. Dimethyl itaconate (97%, 0.15 g, 0.9 mmol) is added via syringe. After flushing the autoclave with argon, hydrogenation is carried out during 15 h at 23 °C and at 2 bar hydrogen pressure. The reaction solution is directly analysed by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column:
  • reaction solution is directly analysed by GC for conversion (column: HP-IOl 25 m / 0.2 mm) and enantiomeric excess (column: Macherey- Nagel, Nucleodex Beta-PM CC200/4). Conversion is 60% at an ee of 24%.

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Abstract

La présente invention concerne un procédé de préparation de ligands biaryldiphosphine à substitution asymétrique représentés par la formule (I), dans laquelle R1 représente alkyle C1-6 ou cycloalkyle C3-10 éventuellement substitué par un ou plusieurs atomes d'halogène, R2 et R3 sont égaux et sont sélectionnés dans le groupe formé par: aryle, cycloalkyle C5-10 et alkyle C1-6, ou bien R2 représente cycloalkyle C5-10 ou alkyle C1-6, et R3 représente aryle éventuellement remplacé par un ou plusieurs substituants sélectionnés dans le groupe formé par: des atomes d'halogène, nitro, amino, alkyle C1-6, alcoxy C1-6 et des groupes alkylamino di-C1-6, chaque alkyle C1-6, cycloalkyle C5-10, alcoxy C1-6 et groupe alkylamino di-C1-6 présent dans R2 et R3 étant facultativement remplacé par un ou plusieurs atomes d'halogène, à partir du 2,2',6,6'-tétrabromobiphényle par une séquence d'échanges bromine-métal et les réactions qui suivent. Formule (I)
PCT/EP2005/006064 2004-06-25 2005-06-06 Procede de preparation de biaryldiphosphines a substitution asymetrique Ceased WO2006002730A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP05751951A EP1761549A1 (fr) 2004-06-25 2005-06-06 Procede de preparation de biaryldiphosphines a substitution asymetrique
BRPI0512571-5A BRPI0512571A (pt) 2004-06-25 2005-06-06 processo para a preparação de biarildifosfinas assimetricamente substituìdas
JP2007517124A JP4519912B2 (ja) 2004-06-25 2005-06-06 非対称的に置換されたビアリールジホスフィンの調製方法
IL179980A IL179980A0 (en) 2004-06-25 2006-12-11 Asymmetrically substituted biaryldiphosphine ligands 1

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04014909.8 2004-06-25
EP04014909 2004-06-25

Publications (1)

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WO2006002730A1 true WO2006002730A1 (fr) 2006-01-12

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EP (1) EP1761549A1 (fr)
JP (1) JP4519912B2 (fr)
KR (1) KR20070029263A (fr)
CN (1) CN1972953A (fr)
BR (1) BRPI0512571A (fr)
IL (1) IL179980A0 (fr)
WO (1) WO2006002730A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1761548A1 (fr) * 2004-06-25 2007-03-14 Lonza Ag Procede de preparation de biaryldiphosphines a substitution asymetrique
FR2952638A1 (fr) * 2009-11-17 2011-05-20 Univ Strasbourg Procede de phosphination catalytique double ou triple de composes di, tri ou tetrahalobiaryles, intermediaires employes, composes obtenus et leurs utilisations
CN111349114A (zh) * 2020-03-20 2020-06-30 河南省科学院化学研究所有限公司 一种合成2-二环己基膦-2’,4’,6’-三异丙基联苯的方法
CN112321639A (zh) * 2020-11-10 2021-02-05 河南省科学院化学研究所有限公司 一种芳基二苯基膦衍生物的制备方法

Citations (2)

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EP0955303A2 (fr) * 1998-05-08 1999-11-10 Takasago International Corporation Complexe ruthénium-iodo-phosphine optiquement actif
WO2002040492A1 (fr) * 2000-11-17 2002-05-23 Ppg-Sipsy Diphosphines chirales et leurs complexes metalliques

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Publication number Priority date Publication date Assignee Title
EP0647648B1 (fr) * 1993-10-08 1999-03-10 F. Hoffmann-La Roche Ag Composés de phosphore optiquement actifs
JPH11322734A (ja) * 1998-05-08 1999-11-24 Takasago Internatl Corp ルテニウム−光学活性ホスフィン錯体、その製法およびこれを用いた光学活性４−メチル−２−オキセタノンの製造方法
EP1609795A1 (fr) * 2004-06-25 2005-12-28 Lonza AG Procédé de préparation de Biaryldiphosphines asymétriquement substituées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0955303A2 (fr) * 1998-05-08 1999-11-10 Takasago International Corporation Complexe ruthénium-iodo-phosphine optiquement actif
WO2002040492A1 (fr) * 2000-11-17 2002-05-23 Ppg-Sipsy Diphosphines chirales et leurs complexes metalliques

Non-Patent Citations (2)

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Title
MARCO CEREGHETTI ET AL: "(R)- and (S)-6,6'-Dimethyl- and 6,6'-Dimethoxy-2,2'-diiodo-1,1'-biphenyls: Versatile Intermediates for the Synthesis of Atropisomeric Diphosphine Ligands", TETRAHEDRON LETTERS, vol. 37, no. 30, 1996, pages 5347 - 5350, XP002311142 *
See also references of EP1761549A1 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1761548A1 (fr) * 2004-06-25 2007-03-14 Lonza Ag Procede de preparation de biaryldiphosphines a substitution asymetrique
FR2952638A1 (fr) * 2009-11-17 2011-05-20 Univ Strasbourg Procede de phosphination catalytique double ou triple de composes di, tri ou tetrahalobiaryles, intermediaires employes, composes obtenus et leurs utilisations
WO2011061439A1 (fr) 2009-11-17 2011-05-26 Universite De Strasbourg Procede de phosphination catalytique
CN111349114A (zh) * 2020-03-20 2020-06-30 河南省科学院化学研究所有限公司 一种合成2-二环己基膦-2’,4’,6’-三异丙基联苯的方法
CN112321639A (zh) * 2020-11-10 2021-02-05 河南省科学院化学研究所有限公司 一种芳基二苯基膦衍生物的制备方法

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CN1972953A (zh) 2007-05-30
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IL179980A0 (en) 2007-05-15
BRPI0512571A (pt) 2008-03-25
KR20070029263A (ko) 2007-03-13
JP2008503507A (ja) 2008-02-07

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