WO2010004278A1 - Procédé pour augmenter l'excès énantiomérique des oxydes, des sulfures, et des imides de phosphine ainsi que des phosphine-boranes chiraux - Google Patents

Procédé pour augmenter l'excès énantiomérique des oxydes, des sulfures, et des imides de phosphine ainsi que des phosphine-boranes chiraux Download PDF

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WO2010004278A1
WO2010004278A1 PCT/GB2009/001696 GB2009001696W WO2010004278A1 WO 2010004278 A1 WO2010004278 A1 WO 2010004278A1 GB 2009001696 W GB2009001696 W GB 2009001696W WO 2010004278 A1 WO2010004278 A1 WO 2010004278A1
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aryl
phenyl
bis
alkyl
methyl
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PCT/GB2009/001696
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Gary King
Declan G. Gilheany
Graham R. Cumming
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Celtic Catalysts Limited
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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
    • C07F9/025—Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/06—Hydrogen phosphides
    • 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
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • 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
    • C07F9/535—Organo-phosphoranes
    • C07F9/5355—Phosphoranes containing the structure P=N-

Definitions

  • the present invention relates to a method for increasing the enantiomeric excess of neutral four-coordinated chiral phosphorus compounds, the use of said method and the phosphorus-containing compounds obtainable by said method.
  • Asymmetric reactions making use of metal catalysts with chiral phosphine ligands include alkene hydrogenations, hydroformylations and hydrosilylations, allylamine isomerisations, allylic substitutions and a number of cross coupling procedures. Some of these processes have gained industrial significance, e.g. Monsanto L-dopa process
  • Reduction of chiral four coordinated phosphorus compounds such as phosphine oxides is perhaps the most common route to chiral phosphines and can be achieved by a number of reagents including hydrides, boranes and silanes, the choice of which is determined by the sensitivity of the compound to reduction and the stereochemistry required in the product phosphine.
  • the preferred reductants for phosphine oxides are silanes.
  • the use of such reduction methods has merely pushed the stereoselectivity problem back to an earlier stage in the synthesis, i.e. a source of a chiral four-co-ordinated phosphorus compound is now required, such as a chiral phosphine oxide.
  • WO2005118603 (University College Dublin), the disclosure of which is incorporated herein by reference, relates to the preparation of stereoisomerically enriched phosphorus containing compounds. P-chiral- three- and four-coordinated phosphorus compounds are generated by the disclosed process.
  • phosphine oxides such as phosphine oxides, phosphine sulfides, phosphine imides and phosphine-boranes.
  • such compounds can be converted to the corresponding P-chiral three-coordinated phosphorus compounds by reduction or coupled to form, for example, bis-phosphine oxides that may be subsequently reduced to the bis-phosphines; phosphine sulfides and phosphine-boranes may be similarly coupled to form alternative bis-phosphine precursors.
  • the phosphine oxides have important uses in pharmaceutical and agrochemical applications in their own right.
  • One aspect of the present invention relates to a method for increasing the enantiomeric excess of a neutral four-coordinated phosphorus compound selected from a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide and a chiral phosphine-borane, said method comprising the steps of: (a) contacting said chiral phosphine oxide, sulfide, imide or borane with a solvent to form a heterogeneous mixture (i.e. a slurry);
  • Another aspect relates to use of the method according to the present invention for increasing the enantiomeric excess of a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide or a chiral phosphine borane.
  • Yet another aspect relates to the phosphine oxides, phosphine sulfides, phosphine imides, phosphine-boranes, phosphines, bis-phosphine oxides, bis-phosphine sulfides, bis(phosphine-boranes), or bis-phosphines obtainable by the method of the present invention.
  • one aspect of the present invention relates to a method for increasing the enantiomeric excess of a neutral four-coordinated phosphorus compound selected from a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide and a chiral phosphine-borane, said method comprising the steps of: (a) contacting said chiral phosphine oxide, sulfide, imide or borane with a solvent to form a heterogeneous mixture (i.e.
  • partitioning refers to increasing the enantiomeric purity of a chiral phosphine oxide, sulfide, imide or borane. Increasing the enantiomeric purity of a chiral phosphine oxide is also known as increasing the enantiomeric excess (ee) of the compound. Percent enantiomeric excess can be represented by the following formula (J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4 th Edition, Wiley-Interscience, 1992):
  • the enantiomeric excess of the chiral phosphine oxide, sulfide, imide or borane may be increased as follows: (a) the chiral phosphine oxide, sulfide, imide or borane is partitioned into the solvent. This means that some or all of the desired enantiomer of the phosphine oxide, sulfide, imide or borane is preferentially dissolved in the solvent and some or all of the other enantiomer preferentially remains as a solid. (b) the chiral phosphine oxide, sulfide, imide or borane is partitioned as an insoluble product. This means that some or all of . the desired enantiomer preferentially remains as a solid while some or all of the other enantiomer is preferentially dissolved in the solvent.
  • the chiral phosphine oxide, sulfide, imide or borane is contacted with a solvent to form a heterogeneous mixture (i.e. a slurry) in which some or all of one of the enantiomers dissolves in the solvent and some or all of the other enantiomer remains as a solid.
  • a heterogeneous mixture i.e. a slurry
  • the phosphine oxide, sulfide, imide or borane completely dissolved in the solvent.
  • phosphine oxide and "phosphinoyl”
  • phosphine sulfide and “thiophosphinoyl”
  • phosphinimine phosphine imine
  • phosphine imide phosphine imide
  • the chiral phosphine oxide is a compound of formula (Ia):
  • the chiral phosphine sulfide is a compound of formula (Ib):
  • the chiral phosphine imide is a compound of formula (Ic):
  • the chiral phosphine-borane is a compound of formula (Id):
  • Rj and R 2 are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl) r , where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group;
  • R 3 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl) r , where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-PPQR 1 R 2 , wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)
  • R 4 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl) r , where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, NR a R b , SO 2 R 0 , SO 2 NR d R e , P(0)R f R ⁇ R b , wherein R a"h axe each independently selected from H, alkyl and alkylaryl.
  • the star (*) as illustrated in the structural formulae above represents a chiral centre.
  • alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
  • the alkyl group is a C 1-2O alkyl group.
  • the alkyl group is a Ci -15 .
  • the alkyl group is a Gi -12 alkyl group.
  • the. alkyl group is-a Ci -6 aikyl group.
  • Preferred alkyl groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • the alkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R ⁇ , COR h , SO 3 H, SO 2 R', SO 2 NR j R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR n ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a" ⁇
  • heteroalkyl refers to an alkyl group as defined above containing one or more heteroatoms selected from Si, O, N and S.
  • the heteroatom is S, N or O.
  • the heteroatom is Si or O.
  • the heteroalkyl group is a C 1-2O heteroalkyl.
  • the heteroalkyl group is a C l -i 5 heteroalkyl group, hi yet another embodiment, the heteroalkyl group is a C 1-12 heteroalkyl group.
  • the heteroalkyl group contains one to three heteroatoms preferably one herteroatom.
  • the term "carbocycle” refers to a mono- or multi-ringed carbocyclic ring system which may be substituted (mono- or poly-) or unsubstituted.
  • the multi-ringed carbocycle is bi- or tri-cyclic.
  • the carbocycle is a C 3-2O carbocyclic group. More preferably, the carbocycle is a C 3-12 carbocyclic group. More preferably the carbocycle group is a C 3-7 carbocyclic group.
  • the carbocycle may be optionally substituted with one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R g , COR h , SO 3 H, SO 2 R*, SO 2 NR J R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR ⁇ ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a"n are each
  • the substituents are selected from halogeno, (CH 2 ) m OR a , where m is 0, 1, 2 or 3, NR c R d , COOR e , CONR f R g , COR h .
  • the carbocycle is a carbocycle ring.
  • the carbocycle is a cycloalkyl.
  • cycloalkyl refers to a mono- or multi-ringed cyclic alkyl group which may be substituted (mono- or poly-) or unsubstituted.
  • the multi-ringed cyclic alkyl group is bi- or tri-ringed.
  • the cycloalkyl group is a C 3-20 cycloalkyl group. More preferably, the cycloalkyl group is a C 3-12 cycloalkyl group. More preferably, the cycloalkyl group is a C 3-7 cycloalkyl group.
  • the cycloalkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, F), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R g , COR h , SO 3 H, SO 2 R*, SO 2 NR*R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a"n
  • heterocycloalkyl refers to a cycloalkyl group containing one or more heteroatoms selected from O, N and S.
  • heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, pyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, l,3-oxazolidin-3
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • connection of said heterocycloalkyl rings is through a carbon or a sp hybridized nitrogen heteroatom.
  • Preferred heterocycloalkyl groups include piperazine, morpholine, piperidine and pyrrolidine.
  • the heterocycloalkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably ,F, Cl, Br, F), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , C0NR f R ⁇ , COR h , SO 3 H, SO 2 R 1 , SO 2 NR 1 R*, -alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR n ; wherein m is 0, 1, 2, or 3; n is
  • alkenyl refers to a group containing one or more carbon- carbon double bonds, which may be branched or unbranched, substituted (mono- or poly-) or unsubstituted.
  • the alkenyl group is a C 2-20 alkenyl group.
  • the alkenyl group is a C 2-I5 alkenyl group.
  • the alkenyl group is a C 2-12 alkenyl group, hi another embodiment, the alkenyl group is a C 2-6 alkenyl group.
  • the alkenyl group may be optionally substituted by one or more substituents selected from selected from halogeno (preferably, F, Cl, Br, I), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , C0NR f R ⁇ , COR h , SO 3 H, SO 2 R*, SO 2 NR j R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR n ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R
  • aryl refers to a mono- or multi- ringed aromatic group which may be substituted (mono- or poly-) or unsubstituted.
  • the multi- ringed aromatic group is bi- or tri-ringed.
  • the aromatic group is a C 5-20 aryl group. More preferably, the aryl group is a C 6- I 2 aromatic group. Typical examples include phenyl and naphthyl etc.
  • the aryl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 )nOR b , (CH ⁇ aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R g , COR h , SO 3 H, SO 2 R 1 , SO 2 NR j R k , alkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a"n are each independently selected from H, alky
  • alkylaryl is used as a conjunction of the terms “alkyl” and “aryl” as given above.
  • the alkylaryl group is -CH 2 Ph.
  • heteroalkylaryl is used as a conjunction of the terms “heteroalkyl” and “aryl” as given above.
  • the heteroalkylaryl group is -OCH 2 Ph.
  • heteroaryl refers to a C 4-I2 aromatic, substituted (mono- or poly-) or unsubstituted group, which comprises one or more heteroatoms independently selected from N, O and S.
  • the heteroatom is N or S.
  • Preferred heteroaryl groups include pyrrole, pyrazole, pyrimidine, pyrazine, pyridine, quinoline, triazole, tetrazole, thiophene, furan imidazole and oxazolidine.
  • the heteroaryl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R g , COR h , SO 3 H, SO 2 R*, SO 2 NR*R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH2) ra OR a , R m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a n are each independently selected
  • the heteroaryl group is optionally substituted by one or more substituents selected from phenyl, phenyloxy, benzyloxy, methyl, iso-propyl, hydroxy and methoxy.
  • hetero-(hetero)-(aryl) r refers to a groups wherein one or two aryl groups (as defined above) are covalently bonded to a heteroatom.
  • the heteroatom is N, O or S. More preferably, the heteroatom is N (in which case two aryl groups are covalently bonded) or O (where one aryl group is covalently bonded).
  • the group is -O-aryl and even more preferably, -OPh.
  • Ri and R 2 are independently selected from aryl, alkyl, heteroalkylaryl, -(hetero)-(aryl) r , where r is 1 or 2 and heteroalkyl.
  • R 3 is selected-from alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl) r , where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-P(X)RiR 2 , wherein A is selected from Ci-3alkyl, Cijheteroalkyl, C 3-7 aryl, -CH 2 -aryl, -(hetero)-(phenyl), maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH 3 or NR 4 , and Ri , R 2 and R 4 are as herein described.
  • X is selected from absent (lone pair), O, S, BH 3 and NR 4 , preferably X is selected from absent, O, S and BH 3 , more preferably X is absent, O or S, most preferably X is absent or O.
  • X is selected from absent (lone pair), O, S, BH 3 and NR 4 , preferably X is absent, O, S or BH 3 , more preferably X is absent, O or S, most preferably X is absent or S.
  • X is selected from absent (lone pair), O, S, BH 3 and NR 4 , preferably X is absent, O, S or BH 3 , more preferably X is absent, O or BH 3 , most preferably X is absent or BH 3 .
  • X is selected from absent (lone pair), O, S, BH 3 and NR4, preferably X is absent, O, S or NR4, more preferably X is absent, O or NR 4 , most preferably X is absent or NR 4 .
  • Ri and R 2 are independently selected from C 5-20 aryl, C 4-I2 heteroalkylaryl, Ci -20 alkyl, C 1-20 heteroalkyl and -(hetero)-(Cs -2 o aryl) r , wherein the C 5-2O aryl, C 4-12 heteroalkylaryl, Ci -20 alkyl, Ci -20 heteroalkyl and -(hetero)-(Cs -2 o aryl) r groups are optionally substituted by one or more substituents selected from halogeno, NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , C0NR f R ⁇ , COR h , SO 3 H, SO 2 R 1 , SO 2 NR j R k ,
  • R 1 and R 2 are independently selected from C 5-20 aryl, G ⁇ 12 heteroalkylaryl, Ci -20 alkyl, Ci -20 heteroalkyl and -(hetero)-(Cs -2 o aryl) r , wherein the C5-20 aryl, C 4-12 heteroalkylaryl, Ci -20 alkyl, C] -20 heteroalkyl and -(hetero)-(C 5 -2o aryl) r , groups are optionally substituted by one or more substituents selected from (CH 2 ) m OR a , COOR e , O(CH 2 ) n aryl, alkyl, aryl and alkylaryl; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3; r is 1 or 2 and R a and R e are independently selected from H, alkyl and alkylaryl.
  • Ri and R 2 are independently selected from phenyl, phenyloxy, naphthyl and tert-butyl wherein each group is optionally substituted by one or more methoxy, benzyloxy, hydroxy, phenyl, wo-propyl and methyl groups.
  • R 3 is a C 1-20 alkyl group which is optionally substituted by one or more substituents selected from halogeno, NO 2 , CN, (CH 2 ) m OR a , O(CH 2 ) n OR b , (CH 2 ) n aryl, O(CH 2 ) n aryl, NR c R d , CF 3 , COOR e , CONR f R g , COR h , SO 3 H, SO 2 R*, SO 2 NR J R k , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl may be optionally further substituted by one or more substituents selected from (CH 2 ) m OR a , R m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R a n are each independently selected
  • R 3 is selected from alkyl, aryl, heteroalkylaryl, heteroalkyl, -(hetero)-(aryl) r , where r is 1 or 2.
  • R 3 is -A-P(X)RiR 2 , wherein A is selected from Ci- 3 alkyl, Ci-sheteroalkyl, phenyl, -O-phenyl, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH 3 or NR 4 , and R 1 , R 2 and R 4 are as herein described.
  • R 3 is -A-P(X)R 1 R 2 , wherein A is selected from C 1-3 alkyl, C 1-3 heteroalkyl, phenyl, -O-phenyl, X is absent (lone pair), O, S, BH 3 or NR 4 , and R 1 , R 2 and R 4 are as herein described.
  • R 4 is selected from alkyl, aryl, suifonyl-(SO 2 R c ) and phosphoryl (P(O)R f R g R h ).
  • R 4 is alkyl.
  • R 4 is selected from alkyl, aryl, sulfonyl (SO 2 R C ) and phosphoryl (P(O)R f R 8 R h ).
  • the compound of formula (Ia) to (Id) is selected from: l-methoxy-2-(methyl-phenyl-phosphinoyl)-benzene; 1 ,4-dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene; l,3-dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene; l-(methyl-phenyl-phosphinoyl)-naphthalene;
  • the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a non-racemic mixture.
  • the non-racemic mixture has an enantiomeric excess of greater than about 1%; more preferably, greater than about 25%; yet more preferably, greater than about 50% and most preferably, greater than about 75%.
  • the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a racemate.
  • a “racemate” or “racemic mixture” relates to enantiomers of compounds present in equal amounts.
  • the partitioned phosphine oxide, sulfide, imide or borane has an enantiomeric excess from about 1% to greater than about 99%; preferably, from about 60% to greater than about 99%; more preferably, from about 75% to greater than about 99% and most preferably, from about 95% to greater than about 99%.
  • the solvent is selected from at least one of alkanes, cycloalkanes, heteroalkanes, heterocycloalkanes, alkyl esters, aromatics, heteroaromatics, alcohols or mixtures thereof.
  • alkanes "cycloalkanes”, “heteroalkanes”, “heterocycloalkanes” and the “alkyl” groups of “alkyl esters” should be construed in line with the definitions for “alkyl”, “cycloalkyl”, “heteroalkyl” and “heterocycloaJkyl” given above providing that the resulting substance acts as a solvent.
  • a “solvent” is a substance capable of dissolving or dispersing one or both of the enantiomers of the chiral phosphine oxide, sulfide, imide or borane.
  • the heteroalkane is an ether i.e. the heteroatom is O.
  • the solvent is selected from at least one of C 1-2 O alkanes, C 3-20 cycloalkanes, C 1-20 heteroalkanes, C 3-2 O heterocycloalkanes, C 1-2 O alkyl esters, C 6-20 aromatics, C 4-2O heteroaromatics and Ci -2O alcohols, or mixtures thereof.
  • the. solvent is selected from at least one of C 1-I5 alkanes,. C 3-H cycloalkanes, C M5 heteroalkanes, C 3-12 heterocycloalkanes, C 1-15 alkyl esters, C ⁇ -io aromatics, C 4-I0 heteroaromatics and Ci -15 alcohols, or mixtures thereof.
  • the solvent is selected from at least one of C 1-6 alkanes, C 3-7 cycloalkanes, Q- ⁇ heteroalkanes, C 3-7 heterocycloalkanes, Ci -6 alkyl esters, C 6-S aromatics, C 4-5 heteroaromatics and C 1- I 0 alcohols, or mixtures thereof.
  • Suitable aromatic solvents include benzene, xylene, chlorobenzene, dichlorobenzne, toluene.
  • Suitable heteroaromatic solvents or co-solvents include furan, pyrrole and pyridine.
  • the solvent is selected from at least one of hexane, heptane, cyclohexane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate, toluene and methanol, or mixtures thereof.
  • the solvent is diethyl ether.
  • the solvent is a mixture of a C 1-2 O heteroalkane, preferably diethyl ether, with a second solvent.
  • the second solvent is selected from tetrahydrofuran, cyclohexane, heptane and a C 1-3 alcohol, preferably methanol.
  • the solvent is a mixture of a C 1-6 alkyl ester, preferably ethyl acetate, with a second solvent.
  • the second solvent is selected from tetrahydrofuran, cyclohexane, heptane and a C 1-3 alcohol, preferably methanol.
  • the alcohol solvent or co-solvent employed may contain a chiral centre.
  • the enantiomeric excess of the alcohol is greater than 10%, more preferably greater than 50%, yet more preferably, greater than 90%.
  • Preferred chiral alcohols include (-)-menthol, (-)-trans-2-tertbutylcyclohexanol, (+)-neomenthol, cholesterol, (+)-fenchyl alcohol, (-)-(l,2)-cyclohexanediol, (-)-trans-2- phenylcyclohexanol, diacetone-D-glucose, and the corresponding enantiomers thereof.
  • the ratio of diethyl ether or ethyl acetate to the second solvent is from about 1:100 to about 100:1 v/v; preferably, from about 1:50 to about 50:1 v/v; more preferablyrfrom ab ⁇ ut-l:10 ⁇ to-about-10:l v/v; yet more preferably, from about _L:2 to about 2:1 v/v and most preferably about 1 : 1 v/v.
  • the ratio of solvent to the chiral phosphine oxide, sulfide, imide or borane of step (a) is from about 1 ml/g to about 1000 ml/g.
  • the ratio is from about 1 ml/g to about 500 ml/g; more preferably, from about 1 ml/g to about 100 ml/g and most preferably, from about 1 ml/g to about 50 ml/g.
  • the present method further comprises reducing the partitioned phosphine oxide or sulfide to the corresponding phosphine.
  • Suitable reducing agents include trichlorosilane, trichlorosilane/amine combinations, hexachlorodsilane or phenylsilane (Edmundson, 1992).
  • the phosphine may optionally be protected as a borane complex for example using BH 3 .THF or BH 3 -Me 2 S, such phosphine-boranes being suitable for conversion to a protected bisphosphine.
  • the present method further comprises converting the partitioned phosphine oxide to the bis-phosphine oxide. Suitable methods are described in Edmundson, 1992.
  • the bis-phosphine oxide is selected from:
  • the present method further comprises converting the partitioned phosphine sulfide to the bis-phosphine sulfide. This may be carried out according to methods described for the coupling of phosphine oxides (Edmundson,
  • the bis-phosphine sulfide is selected from:
  • the present method further comprises reducing the bis- phosphine oxide or sulfide to the corresponding bis-phosphine, using similar methods to those described above for the corresponding monophosphine oxides and sulfides (Edmundson 1992).
  • the bis-phosphine is selected from:
  • the present method further comprises converting the partitioned phosphine borane to the bis(phosphine-borane), such bis(phosphine- boranes) being readily deboronated to afford bis-phosphines. Suitable methods are described in Wada, 2004.
  • the phosphine borane is selected from:
  • the present method further comprises converting the partitioned phosphine imide to the phosphine oxide. This transformation may generally be accomplished by hydrolysis under acidic conditions. The phosphine oxide may be further converted to the phosphine or the bis-phosphine oxide.
  • Another aspect relates to use of the method according to the present invention for enhancing the enantiomeric excess of a chiral phosphine oxide, sulfide, imide or borane.
  • Yet- another aspect relates to the phosphine oxides, phosphine sulfides, phosphine imides, phosphine-boranes, phosphines, bis-phosphine oxides, bis-phosphine sulfides, bis(phosphine-boranes), or bis-phosphines obtainable by the method of the present invention.
  • phosphine oxides used as starting material in the following examples may be prepared according to the methods described in WO2005/118603 or according to the methods described in (Juge, S., Genet, J. P., Tetrahedron letters. 1989, 30, 2783- 2786).
  • Step 1 Enhancement of ee with scalemic phenyl-methyl-(2.,5- dimethoxyphenvDphosphine oxide
  • Step 4 Synthesis of (Tl,R)-1.2-BisPx)ranatof2.5-dimemQX ⁇ henyl)(phen.v-l * ) phosphinoiethane
  • Table 1 Enhancement of ee of enantioenriched tolyl-PAMPO in various solvents.
  • PrBMP-BH 3 of 50% ee was stirred with pentane for 1 h min, affording a heterogeneous mixture whose supernatant contained P/BMP-BH 3 of 62% ee.
  • Spectral data consistent with literature values (Stankevic, M.; Pietmsiewicz, K. M. J. Org. Chem., 2007, 72, 816).
  • HPLC Daicel Chiralcel OJ-H (250 x 4.6 mm) + Daicel OJ-H guard cartridge, heptane/EtOH 70/30, 1.0 mL/min, UV detection (254, 230, 210 nm); retention times 8.5 (major), 11.6 min (minor).
  • Example 5 Partitioning of 2-fr(di-fer/-butyl-phosphanyI)-methvH-methyl- phosphanyl ⁇ -2-methyl-propane ('trichickenfootphos-bisborane'. 'TCFP-BHs')
  • HPLC Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 97/03, 1.0 mL/min, UV detection (210 nm); retention times 5.77 (R),

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Abstract

La présente invention concerne un procédé pour augmenter l'excès énantiomérique d'un oxyde de phosphine chiral, un sulfure de phosphine chiral, un phosphine-borane chiral et un imide de phosphine chiral, ledit procédé comprenant les étapes consistant à : (a) mettre en contact ledit oxyde, sulphide, imide de phosphine ou phosphine-borane chiral avec un solvant afin de former une boue ; (b) diviser l'oxyde, le sulphide, l'imide de phosphine ou le phosphine-borane dans le solvant ou comme produit insoluble ; et (c) éventuellement, isoler l'oxyde, le sulphide, l'imide de phosphine ou le phosphine-borane divisé.
PCT/GB2009/001696 2008-07-08 2009-07-08 Procédé pour augmenter l'excès énantiomérique des oxydes, des sulfures, et des imides de phosphine ainsi que des phosphine-boranes chiraux WO2010004278A1 (fr)

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GB0812497.6 2008-07-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114181252A (zh) * 2021-12-13 2022-03-15 中国科学技术大学 一种chiralphos衍生物的合成方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PERLIKOWSKA W ET AL: "Kinetic resolution of P-chiral tertiary phosphines and chlorophosphines: a new approach to optically active phosphoryl and thiophosphoryl compounds", TETRAHEDRON LETTERS, vol. 42, no. 44, 29 October 2001 (2001-10-29), pages 7841 - 7845, XP004308017, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(01)01694-X *
SERREQI A N ET AL: "Kinetic resolution of phosphines and phosphine oxides with phosphorus stereocenters by hydrolases", JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 25, 1 December 1994 (1994-12-01), pages 7609 - 7615, XP009124231, ISSN: 0022-3263, DOI: 10.1021/jo00104a015 *
STANKEVIC M ET AL: "Resolution and stereochemistry of tert-butylphenylphosphinous acid-borane", JOURNAL OF ORGANIC CHEMISTRY, vol. 72, no. 3, 2 February 2007 (2007-02-02), pages 816 - 822, XP009124230, ISSN: 0022-3263, DOI: 10.1021/jo061896e *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114181252A (zh) * 2021-12-13 2022-03-15 中国科学技术大学 一种chiralphos衍生物的合成方法

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