WO2011056737A1 - Novel chiral phosphorus ligands - Google Patents

Novel chiral phosphorus ligands Download PDF

Info

Publication number
WO2011056737A1
WO2011056737A1 PCT/US2010/054912 US2010054912W WO2011056737A1 WO 2011056737 A1 WO2011056737 A1 WO 2011056737A1 US 2010054912 W US2010054912 W US 2010054912W WO 2011056737 A1 WO2011056737 A1 WO 2011056737A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
membered
alkyl
compound
ieri
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2010/054912
Other languages
English (en)
French (fr)
Inventor
Bo QU
Chris Hugh Senanayake
Wenjun Tang
Xudong Wei
Nathan K. Yee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to US13/504,146 priority Critical patent/US8552212B2/en
Priority to EP10774398.1A priority patent/EP2496589B1/en
Priority to JP2012537924A priority patent/JP5750449B2/ja
Publication of WO2011056737A1 publication Critical patent/WO2011056737A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • C07F15/0073—Rhodium compounds
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to a series of novel chiral phosphorus ligands and their metal complexes as catalysts for applications in asymmetric hydro genation. More particularly, the present invention relates to the transition metal complexes of these novel phosphine ligands and their use as catalysts in asymmetric hydro genation.
  • Asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines has become one of most efficient methods for constructing chiral compounds. It also accounts for the major asymmetric catalytic transformation at commercial scales. Development of efficient chiral phosphorus ligands is essential for the success of asymmetric hydrogenation.
  • Known chiral phosphorus ligands in this field include Knowles' DIP AMP [Knowles, W. S. Acc. Chem. Res. 1983, 16, 106], Kagan's DIOP [Kagan et al, J. Am. Chem. Soc. 1972, 94, 6429], Noyori' s BINAP [Noyori, R. Chem. Soc. Rev. 1989, 18, 187], Burk's Duphos and BPE [Burk, M. J. et al,
  • FIG. 1 shows an x-ray crystal structure of Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 (the H atoms are omitted), where each of the letters on the atoms (C, O, P, Rh, B, and F) refer to carbon, oxygen, phosphorus, rhodium, boron and fluorine, respectively.
  • nbd norbornadiene
  • TfO " trifluoromethanesulfonate or triflate
  • the present invention relates to novel phosphine ligands, novel metal complexes containing the novel phosphine ligands of the invention, and methods of using the novel metal complexes to carry out asymmetric hydrogenations as described below.
  • the present invention relates to a compound of formula (la), (lb), or a mixture thereof ("the phosphine ligand of the invention”):
  • X is O, S, or -NR 5 ;
  • R 1 is -(Ci-C 6 )alkyl, -CF 3 , -(C3-C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 - C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -Cio)aryl and -(5 to 11- membered)heteroaryl of said R 1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ;
  • R 2 is H, -0(Ci-C 6 )alkyl, -(C 1 -C 6 )alkyl, -(C 3 -Ci 0 )carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, -NR 5 R 6 , or -SR 5 ; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C 6 - C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C 1 -C 6 )alkyl, -(C 1 -C 6 )al
  • R 3 is -PR 7 R 8 , -CH 2 PR 7 R 8 , -CH 2 OPR 7 R 8 , or a group of formula (A) or (B):
  • R 4 is H, -(CrC 6 )alkyl, -(C 3 -C 6 )cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, (5- to 6-membered)heteroaryl, or -SiR 5 3 ; wherein said -(Ci-C 6 )alkyl of said R 4 is optionally substituted with 1 to 3 substituents independently selected from -0(C - C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl; and wherein said -(C 3 -C 6 )cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, and (5- to 6- membered)heteroaryl of said R 4 is optionally substituted with 1 to 3 substituents independently selected from
  • R 5 and R 6 are each independently H, -(CrC 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, or -(5 to l l-membered)heteroaryl; wherein each -(Ci-C 6 )alkyl, -CF 3 , -(C3-C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R 5 and R 6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(C 1 -C 6 )alkyl, -(C
  • R 7' and R 8° are each independently -(Ci-C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl,
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein X is O.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is S
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is NR 5 .
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R 1 is -(Q- C 6 )alkyl selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , or
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 1 is -(C 3 -C 1 o)carbocyclyl selected from cyclopentyl, cyclohexyl, and 1-adamantyl.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 1 is -(C 6 -C 1 o)aryl selected from phenyl, ortho-tolyl, para-tolyl, 3,5-dimethylphenyl, 3,5-di-i- butylphenyl, 3,5-di-CF 3 -phenyl, ortho-CF 3 -phenyl, ortho-anisyl, and naphthyl.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R is H, -CH 3 or -OCH 3 .
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above wherein R is phenyl.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R 4 is -H.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 4 is -(C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from -OCH 3 , -(C 3 -C 6 )cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein R 4 is -CH 2 (chiral oxazoline) or -CH 2 (o/ /iosubstituted pyridine).
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 4 is a -(5- to 6-membered)heteroaryl selected from ori/iosubstituted pyridine, oxazoline, and chiral oxazoline.
  • the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R 3 is -PR 7 R 8 or a group of formula (A) ("the bis-phosphine ligand of the invention")
  • the invention relates to a bis-phosphine ligand of the invention, wherein R 1 is -C(CH 3 ) 3 ; R 2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is -PR 7 R 8 .
  • the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each independently H, -(Ci-C 6 )alkyl, or -(C 3 -C 6 )cycloalkyl.
  • the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each -C(CH 3 ) 3 .
  • the invention relates to a bis-phosphine ligand of the invention, wherein, X is S.
  • the invention relates to a bis-phosphine ligand of the invention, wherein, X is O.
  • the invention relates to a bis-phosphine ligand of the invention, wherein, X is NR 5 .
  • the invention relates to a bis-phosphine ligand of the invention, wherein X is O, R 1 is -C(CH 3 ) 3 ; R 2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is -PR 7 R 8 .
  • the invention relates to a bis-phosphine ligand of the invention, wherein R 3 is a group of formula (A) or (B).
  • the invention relates to a bis-phosphine ligand of the invention, according to the embodiment described immediately above, wherein R 1 is -C(CH 3 ) 3 ; and R 2 is -H, -CH 3 , -OCH 3 , or phenyl.
  • the invention relates to a bis-phosphine ligand of the invention, wherein X is O; R 1 is -C(CH 3 ) 3 ; and R2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is a group of formula of formula (A) or (B)..
  • the invention relates to a bis-phosphine ligand of the invention having the formula (Ila) or (lib)
  • R 1 is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 )(CH 3 ) 2 , cyclohexyl, 1-adamantyl, phenyl, ortho- tolyl, 3,5-xylyl, ortho-anisyl, or ferrocenyl ; and
  • R 2 is H, -OCH 3 , -CH 3 , -CF 3 , phenyl, or -N(CH 3 ) 2 .
  • the invention relates to a bis-phosphine ligand of the invention having the formula (Ilia) or (Illb):
  • R 1 is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 )(CH 3 ) 2 , cyclohexyl, or 1-adamantyl;
  • R is H, -OCH 3 , -CH 3 , -CF 3 , phenyl, or -N(CH 3 ) 2 ; and R 7 and R 8 are each -C(CH 3 ) 3 .
  • the invention relates to a phosphine ligand of the invention selected from:
  • the invention relates to complexes formed between a transition metal and the phosphine ligands of the invention. Accordingly, in one embodiment, the invention relates to a metal complex of formula (IVa), (IVb), (Va) or (Vb) ("the metal complexes of the invention"):
  • M is a transition metal selected from Co, Ni, Pd, Pt, Cu, Ag, Au, Ru, Fe, Rh and Ir;
  • a " is a counter anion;
  • n is the oxidation state of the transition metal M;
  • L 1 and L2 are each olefins, or L 1 and L2 together represent a diolefin;
  • X is O, S, or -NR 5 ;
  • R 1 is -(Ci-C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 - C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl and -(5 to 11- membered)heteroaryl of said R 1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ;
  • R is H, -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, -(C 3 -Ci 0 )carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, -NR 5 R 6 , or -SR 5 ; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C 6 - C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl
  • each -(C 1 -C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R 5 and R 6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ; and
  • R 7' and R 8° are each independently -(C 1 -C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, yl and -(5 to 1 l-membered)heteroaryl of said R 7 and R 8
  • -(C 6 -C 1 o)ar are each optionally independently substituted with 1 to 3 substituents independently selected from -0(C - C 6 )alkyl, -(C 1 -C 6 )alkyl, and -CF 3 .
  • the invention relates to a metal complex of the invention wherein M is Rh and n is i.
  • the invention relates to a metal complex of the invention according to any of the two embodiments described immediately above, wherein A " is BF 4 " , SbF 6 " , TfO ,B(C 6 H 5 ) 4 “ , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 -, or PF 6 " .
  • the invention relates to a metal complex of the invention according to any of the three embodiments described immediately above, wherein M is Rh, A " is BF 4 " , and n is i.
  • the invention relates to a metal complex of the invention according to any of the four embodiments described immediately above, wherein R 1 is -C(CH 3 ) 3 , and R 2 is -H, -CH 3 , -OCH 3 , or phenyl.
  • the invention relates to a metal complex of the invention wherein
  • L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
  • the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVa).
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 ⁇ ; and n is 1.
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
  • the invention relates to a metal complex of the invention, wherein the metal complex is of formula (Va).
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 " ; and n is 1.
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
  • the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVb).
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 " ; and n is 1.
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
  • the invention relates to a metal of the invention, wherein the metal complex is of formula (Vb).
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 ⁇ ; and n is 1.
  • the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
  • the invention relates to a metal complex of the invention selected from:
  • the invention relates to a process for the asymmetric hydrogenation of a compound having a carbon-carbon or carbon-heteroatom double bond ("the asymmetric hydrogenation process of the invention"), the process comprising allowing said compound having a carbon-carbon or carbon-heteroatom double bond to react with hydrogen in the presence of a catalytic amount of the metal complex of the invention described in any of the embodiments above.
  • carbon- heteroatom double bonds include those formed between carbon and nitrogen, oxygen, or sulfur.
  • carbon-heteroatom double bond is formed between carbon and nitrogen or carbon and oxygen.
  • the invention relates to the asymmetric hydrogenation process of the invention in the embodiment described immediately above, wherein L 1 and L 2 together represent norbornadiene.
  • the invention relates to the asymmetric hydrogenation process of the invention in the broadest embodiment described above, wherein L 1 and L 2 together represent octadiene.
  • the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein M is Rh, A " is BF 4 ⁇ , and n is i.
  • the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein R 1 is -C(CH 3 ) 3 ; R 2 is - H, -CH 3 , -OCH 3 , or phenyl; and R 7 and R 8 are each -C(CH 3 ) 3 .
  • compounds of the invention refers to the phosphine ligands of the invention (including bis-phosphine ligands of the invention) and the metal complexes of the invention.
  • isotopically-labelled form of a compound of the present invention is identical to said compound of the invention but for the fact that one or more atoms of said compound of the invention have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature.
  • isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon,
  • a compound of the present invention which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the present invention.
  • the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
  • Some of the compounds of the invention can exist in more than one tautomeric form.
  • the invention includes methods using all such tautomers.
  • C 1-6 alkoxy or "0(Ci- 6)alkyl” is a (C 1-6 )alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy.
  • All alkyl, alkenyl, and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows: The term “alkyl” refers to both branched and unbranched alkyl groups.
  • alk or “alkyl” prefix refers to analogs according to the above definition of “alkyl”.
  • terms such as “alkoxy”, “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
  • one or more carbon atoms can be optionally replaced by heteroatoms such as O, S or N. It shall be understood that if N is not substituted then it is NH. It shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain.
  • Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
  • nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
  • nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
  • a -S-C 1-6 alkyl radical unless otherwise specified, shall be understood to include -S(0)-C 1-6 alkyl and
  • (C3_ 1 o)carbocycle refers to a nonaromatic 3 to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, or spirocyclic carbocyclic radical.
  • the C3.10 carbocycle may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the creation of a stable structure.
  • Non-limiting examples of 3 to 10-membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone.
  • Non-limiting examples of 6 to 10-membered fused bicyclic carbocyclic radicals include bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalenyl).
  • Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicals include bicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl.
  • Non-limiting examples of 6 to 10-membered spirocyclic carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.
  • the term "(C 6-1 o)aryl" refers to aromatic hydrocarbon rings containing from six to ten carbon ring atoms.
  • C 6-10 aryl includes monocyclic rings and bicyclic rings where at least one of the rings is aromatic.
  • Non-limiting examples of C 6 -io aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.
  • (5 to l l-membered)heterocycle refers to a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical.
  • the 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur.
  • the heterocycle may be either saturated or partially unsaturated.
  • Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l,l-dioxo-l 6 -thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl.
  • Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl.
  • Non-limiting examples of nonaromatic 6 to 11-membered bridged bicyclic radicals include 2- azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl.
  • Non-limiting examples of nonaromatic 6 to 11-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3,4]octanyl.
  • (5 to l l-membered)heteroaryl refers to an aromatic 5 to 6-membered monocyclic heteroaryl or an aromatic 7 to 11-membered heteroaryl bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such as N, O and S.
  • Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl.
  • Non-limiting examples of 7 to 11-membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl and benzothiazolyl.
  • heteroatom as used herein shall be understood to mean atoms other than carbon such as O, N, and S.
  • halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
  • alkyl a non-limiting example would be -CH 2 CHF 2 , -CF 3 etc.
  • olefin refers to an unsaturated hydrocarbon containing carbon atoms linked by a double bond (i.e., an alkene) such as, for example, ethylene, propene, 1-butene, 2-butene, styrene, norbornadiene, or cyclooctadiene.
  • alkene such as, for example, ethylene, propene, 1-butene, 2-butene, styrene, norbornadiene, or cyclooctadiene.
  • diolefin refers an unsaturated hydrocarbon containing two pairs of carbon atoms linked by double bonds, e.g., norbornadiene, or cyclooctadiene.
  • the invention also provides processes for making compounds of formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb.
  • R 1 , R 2 , R 3 , R 4 R 7 , R 8 , L 1 , L 2 , A, M and n in the formulas below shall have the meaning of R 2 , R 3 , R 4 R 7 , R 8 , L 1 , L 2 , A, M and n in formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb of the invention described herein above.
  • reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.
  • TLC thin layer chromatography
  • intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.
  • dichlorophosphine of formula VII in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula VIII.
  • Demethylation of the methoxy groups of compound IX by a reagent such as boron tribromide (BBr 3 ) followed by cyclization provides the corresponding cyclized intermediate of formula X.
  • Resolution of the intermediate X using a resolving agent such as (+) menthyl chloroformate provides the corresponding ( R ) isomer of formula XIa.
  • the hydroxyl group of compound XIa may be modified to other groups, such as methoxy, aryl etc., under standard reaction conditions known in the literature, to provide a compound of formula Xlla.
  • Reaction of the compound of formula Xlla, in a suitable solvent, in the presence of suitable base and copper chloride provides the corresponding bisphosphine oxide of formula XHIa.
  • Reduction of the bisphosphine oxide XHIa provides a compound of formula la or Ila.
  • resolution of the intermediate X using a resolving agent such as (-) menthyl chloroformate provides the corresponding ( S ) isomer Xlb which may be converted to compounds of formula lb or lib using the above Scheme.
  • Compounds of formula Ilia and Illb may be prepared as illustrated in Scheme 2.
  • reaction of a compound of formula Xllb, obtained via Scheme 1, with a phosphorus chloride of formula XIV, in the presence of a suitable base and hydrogen peroxide provides a bisphosphine oxide of formula XVb.
  • Reduction of the bisphosphine oxide XVb as in Scheme 1, provides a compound of formula Illb.
  • a compound of formula Xlla may be converted to a compound of formula Ilia using the method depicted in Scheme 2.
  • reaction of a compound of formula Ila with a transition metal salt [ ⁇ ( ⁇ 2 )] ⁇ + nA ⁇ provides a compound of formula IVa.
  • reaction of a compound of formula Illb with a transition metal salt [ ⁇ ( ⁇ 2 )] ⁇ + nA " provides a compound of formula Vb.
  • dichlorophosphine of formula VII in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula XVII.
  • X O, S or NR 5 , PG 1 1 and PG 2" are suitable protecting groups such as methyl, benzyl, methoxymethyl etc. Iodination of the phosphine oxide XVII, in a suitable solvent, in the presence of a suitable base, provides the iodinated intermediate of formula XVIII.
  • Example 1 Preparation of ieri-butyl(2,6-dimethoxyphenyl)(methyl)phosphine oxide (1).
  • dichloromethylphosphine (6.61 g, 57 mmol, 1.0 equiv.) in THF (50 mL) was added dropwise 1.0 M iBuMgCl (57 mL, 57 mmol, 1.0 equiv.) over 1 h while controlling the reaction temperature ⁇ - 10°C.
  • the mixture was stirred at -10 to 0°C for 1 h and then warmed to 25°C over 1 h and stirred at 25°C for at least 1 h.
  • the dichloromethane layer was washed with brine (300 mL), dried over magnesium sulfate, and purified by column chromatography (eluents: EtOAc to EtOAc/MeOH 4/1; monitored at 290 nm) to provide 1 as a thick oil (9.5 g, 37 mmol, 65 %).
  • Example 2 Preparation of ieri-butyl(2,6-dimethoxyphenyl)(iodomethyl)phosphine (2). To a solution of 1 (7.4 g, 28.9 mmol, 1 equiv.) and TMEDA (6.50 mL, 43 mmol, 1.5 equiv.) in THF (40 mL) at -78°C was added 2.5 M BuLi in hexanes (13.9 mL, 35 mmol, 1.2 equiv.) over 10 min. The resulting mixture was stirred at -78°C for 1 h.
  • Example 3 Preparation of racemic 3-ieri-butyl-2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
  • BBr 3 2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
  • BBr 3 2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
  • BBr 3 21.2 g, 64.8 mmol, 4 equiv.
  • MeOH 200 mL
  • MeOH 200 mL X3
  • the CH 2 C1 2 layer was separated, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluents: hexanes to EtOAc) to provide the triflate product (65 mg, 0.18 mmol, 82%) as white solid.
  • Example 6 Preparation of (2 l S , ,2' l S , ,3R,3'R)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (7a). To a solution of 6a (155 mg, 0.737 mmol, 1 equiv) in THF (4 mL) at -78°C was added LDA (0.49 mL, 1.8 M in
  • dichloromethane solution was washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:THF 3: 1 to 2: 1) to provide 7a (93 mg, 0.22 mmol, 60%) as white solid.
  • Example 7 Preparation of (2 l S , ,2' l S , ,3 l S , ,3' l S , )-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (8a).
  • 8a To a solution of 7a (70 mg, 0.17 mmol, 1 equiv), triethylamine (169 mg, 1.7 mmol, 10 equiv) in toluene (10 mL) at 25°C was added trichlorosilane (114 mg, 0.84 mmol, 5 equiv).
  • the mixture was heated to 80°C and stirred under nitrogen for 12 h. To the mixture at 0°C was added degassed 30% NaOH (10 mL) over 5 min. The resulting mixture was stirred at 60°C for about 1 h until the two layers became clear.
  • the toluene layer was separated under N 2 and the aqueous layer was further extracted with toluene twice (5 mL X 2). The combined toluene was dried over Na 2 S0 4 , concentrated under N 2 , and purified by passing through a neutral alumina plug (eluent: hexanes/ether 1/1) to provide 8a (60 mg, 0.155 mmol, 93 %) as white solid.
  • Example 10 Preparation of ((2 l S , ,2' l S , ,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7b).
  • 6b 150 mg, 0.624 mmol
  • THF 5 mL
  • LDA 0.416 mL, 0.749 mmol, 1.2 equiv
  • Example 11 (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -dimethoxy-2,2 , ,3,3 , -tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole (8b).
  • 7b 100 mg, 0.209 mmol
  • triethylamine 422 mg, 4.18 mmol, 20 equiv
  • the combined toluene solution was dried over sodium sulfate, concentrated under N 2 , and purified by passing through a neutral alumina plug (eluent: hexanes/ether 5/1) to provide 8b (70 mg, 0.157 mmol, 75%) as a white solid.
  • Example 13 Preparation of (R)-3-tert-butyl-4-phenyl-2,3- dihydrobenzo[d][l,3]oxaphosphole.
  • phenylboronic acid (1.02 g, 8.37 mmol, 1.5 equiv)
  • Pd 2 dba 3 153 mg, 0.17 mmol, 3 mol%)
  • PCy 3 (0.31 g, 1.12 mmol, 20 mol
  • potassium fluoride (1.30 g, 23.3 mmol, 4.0 equiv) was charged degassed dioxane (30 mL).
  • Example 14 Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7c).
  • Compound 7c was prepared as a white solid (43%) under similar conditions to those described for compound 7b in Example 10 except that compound 6c was used instead of compound 6b.
  • Example 15 Preparation of (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -diphenyl-2,2 , ,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Ph-BIBOP) (8c).
  • Example 16 Preparation of Rh[(25,2'5,35,3'5)-Ph-BIBOP(nbd)]BF 4 (9c).
  • Examples 17-20 describe the preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF 4 (9d) as depicted in below:
  • Example 17 Preparation of (R)-3-tert-butyl-4-methyl-2,3- dihydrobenzo[JJ[l,3]oxaphosphole (6d).
  • (R)-3 chiral triflate 0.5 g, 1.4 mmol
  • trimethylboroxine 0.21 g, 1.7 mmol, 1.2 equiv
  • Pd 2 dba 3 38 mg, 0.042 mmol, 3 mol%)
  • PCy 3 0.078 g, 0.28 mmol, 20 mol
  • potassium fluoride (0.33 g, 5.6 mmol, 4.0 equiv) was charged degassed dioxane (10 mL).
  • Example 18 Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7d).
  • Compound 7d was prepared as a white solid (74%) under similar conditions to those described for compound 7b in Example 10 except that compound 6d was used instead of compound 6b.
  • Example 19 Preparation of (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -dimethyl-2,2 , ,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Me-BIBOP, 8d).
  • Example 20 Preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF 4 (9d).
  • Metal complex 9d was prepared as a yellow-red solid (85%) under similar conditions to those described in Example 12 for compound 9b except that compound 8d was used instead of compound 8b.
  • Example 22 Preparation of (2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4-methoxy- 2,3-dihydrobenzo[d][l,3]oxaphosphole (10b).
  • 10a (0.12 g, 0.30 mmol) in toluene (10 mL) at 25°C under nitrogen was added triethylamine (0.61 g, 5.99 mmol, 20 equiv) and trichlorosilane (0.41 g, 2.99 mmol).
  • the mixture was heated to 120°C for 12 h.
  • Example 23 Preparation of Rh[(2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4- methoxy-2,3-dihydrobenzo[JJ[l,3]oxaphosphole (nbd)]BF 4 (10c).
  • Rh(NBD) 2 BF 4 46 mg, 0.122 mmol
  • 10b 50 mg, 0.136 mmol, 1.1 equiv
  • the mixture was stirred at 25°C for 0.5 h, and then concentrated to about 1 mL.
  • Example 24 Preparation of (2 l S',3 l S , )-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole bisoxide (11a).
  • Example 25 Preparation of (2 l S',3R)-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (lib).
  • Example 26 Preparation of Rh[(2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (nbd)]BF 4 (11c).
  • Rh(NBD) 2 BF 4 (0.27 g, 0.718 mmol) in THF (2 mL)
  • lib 0.27 g, 0.798 mmol, 1.1 equiv
  • ((S)-3) was then reacted with the same reagents and in the same as described in Examples 6 and 7 to provide the bis-phosphine ligand (2R,2'R,3R,3'R)-3,3'- di-tert-butyl-2,2',3,3'-tetrahydro-2,2'-bibenzo[ ⁇ i][l,3]oxaphosphole bisoxide.
  • the bis- phoshine ligand was then reacted with Rh(bbd) 2 BF 4 in a manner similar to that described in Example 8 to provide the title compound.
  • Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 (the H atoms are omitted) is shown in FIG. 1.
  • Example 28 describes the use of the exemplary rhodium complex
  • Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 from Example 27 for hydrogenation of cc- arylenamides, cc-dehydroamino acid derivatives, -(acetylamino)acrylates, and dimethyl itaconate
  • Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 is efficient for the enantioselective hydrogenation of cc-arylenamides, cc-dehydro amino acid derivatives, ⁇ - (acetylamino)acrylates, and dimethyl itaconate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/US2010/054912 2009-11-05 2010-11-01 Novel chiral phosphorus ligands Ceased WO2011056737A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/504,146 US8552212B2 (en) 2009-11-05 2010-11-01 Chiral phosphorus ligands
EP10774398.1A EP2496589B1 (en) 2009-11-05 2010-11-01 Novel chiral phosphorus ligands
JP2012537924A JP5750449B2 (ja) 2009-11-05 2010-11-01 新規キラルリンリガンド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25841709P 2009-11-05 2009-11-05
US61/258,417 2009-11-05

Publications (1)

Publication Number Publication Date
WO2011056737A1 true WO2011056737A1 (en) 2011-05-12

Family

ID=43587465

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/054912 Ceased WO2011056737A1 (en) 2009-11-05 2010-11-01 Novel chiral phosphorus ligands

Country Status (4)

Country Link
US (1) US8552212B2 (enExample)
EP (1) EP2496589B1 (enExample)
JP (1) JP5750449B2 (enExample)
WO (1) WO2011056737A1 (enExample)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103087105A (zh) * 2013-01-18 2013-05-08 中国科学院上海有机化学研究所 手性膦配体以及包含该配体的金属催化剂和它们的应用
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
WO2015002769A1 (en) * 2013-07-01 2015-01-08 Boehringer Ingelheim International Gmbh Novel ruthenium catalysts and their use for asymmetric reduction of ketones
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
WO2015006458A1 (en) * 2013-07-10 2015-01-15 Boehringer Ingelheim International Gmbh Novel chiral nitrogen-phosphorus ligands and their use for asymmetric hydrogenation of alkenes
CN104558038A (zh) * 2013-10-23 2015-04-29 中国科学院上海有机化学研究所 一种取代的2,3-二氢苯并[d][1,3]氧杂磷杂茂配体的制备方法
CN104650145A (zh) * 2015-02-06 2015-05-27 中国科学院上海有机化学研究所 手性膦配体以及包含该配体的金属催化剂和它们的应用
WO2015077286A1 (en) 2013-11-20 2015-05-28 Boehringer Ingelheim International Gmbh Hexahydroindenopyridine derivatives
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
CN105732249A (zh) * 2016-01-27 2016-07-06 中国科学院上海有机化学研究所 芳基醇类化合物及艾司西酞普兰合成方法
CN107445999A (zh) * 2017-08-15 2017-12-08 中国科学院上海有机化学研究所 金属络合物、制备方法和应用及其中间体
WO2018106621A1 (en) * 2016-12-06 2018-06-14 Boehringer Ingelheim International Gmbh Novel chiral dihydrobenzoazaphosphole ligands and synthesis thereof
WO2018106746A3 (en) * 2016-12-06 2018-07-19 Boehringer Ingelheim International Gmbh Novel chiral dihydrobenzooxaphosphole ligands and synthesis thereof
CN109096338A (zh) * 2018-09-10 2018-12-28 中国科学院上海有机化学研究所 苯并氮杂磷杂茂膦氧配体及含其络合物、制备方法和应用
WO2020073962A1 (zh) * 2018-10-10 2020-04-16 中国科学院上海有机化学研究所 一种金属配合物、中间体、其制备方法及应用
CN111647020A (zh) * 2020-04-09 2020-09-11 宁波赜军医药科技有限公司 一种膦氧双齿配体的合成方法
CN111848680A (zh) * 2019-04-30 2020-10-30 中国科学院上海有机化学研究所 双齿膦-膦氧配体及其中间体、制备方法和应用
CN112574234A (zh) * 2019-09-27 2021-03-30 江苏恒瑞医药股份有限公司 一种海鞘素衍生物的制备方法
WO2025103462A1 (en) * 2023-11-17 2025-05-22 Shenzhen Catalys Technology Co., Ltd Substituted 2, 3-dihydrobenzo [d] [1, 3] oxaphosphole ligand, preparation method and use thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5803042B2 (ja) * 2010-04-05 2015-11-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング クロスカップリング反応におけるモノリン配位子及びそれらの使用
EP2920189B1 (en) 2012-11-15 2017-08-02 Boehringer Ingelheim International GmbH Process for making novel chiral phosphorus ligands
CN107827929B (zh) * 2017-11-17 2020-03-10 中国科学院上海有机化学研究所 一种联芳基双膦配体、其制备方法及应用
CN113636950B (zh) 2020-05-11 2023-01-17 浙江医药股份有限公司新昌制药厂 一种手性4-芳基-β-氨基酸衍生物的制备方法
CN118619995A (zh) * 2024-04-16 2024-09-10 凯特立斯（深圳）科技有限公司 一种富电子双膦配体、制备及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229846A1 (en) 2001-11-09 2004-11-18 The Penn State Research Foundation P-chiral phospholanes and phosphocyclic compounds and their use in asymmetric catalytic reactions
WO2005087370A1 (en) 2004-03-12 2005-09-22 Warner-Lambert Company Llc C1-symmetric bisphosphine ligands and their use in the asymmetric synthesis of pregabalin

Family Cites Families (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681349A (en) 1970-03-05 1972-08-01 Morton Norwich Products Inc 1-(substituted benzyl) tetrahydro-2-(1h) pyrimidones
US5610294A (en) 1991-10-11 1997-03-11 The Du Pont Merck Pharmaceutical Company Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors
AU668818B2 (en) 1993-04-07 1996-05-16 Taiho Pharmaceutical Co., Ltd. Thiazolidine derivative and pharmaceutical composition containing the same
JP3948744B2 (ja) 1994-11-04 2007-07-25 大日本住友製薬株式会社 新規なラクタム誘導体
FR2729954B1 (fr) 1995-01-30 1997-08-01 Sanofi Sa Composes heterocycliques substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
US5776959A (en) 1995-06-05 1998-07-07 Washington University Anticonvulsant and anxiolytic lactam and thiolactam derivatives
DE69730980T2 (de) 1996-07-31 2006-02-23 Nikken Chemicals Co., Ltd. 6-phenyltetrahydro-1,3-oxazin-2-on derivate und medizinische zusammensetzungen, die sie enthalten
US7410995B1 (en) 1998-08-14 2008-08-12 Gpi Nil Holdings Inc. N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
CA2381111A1 (en) 1999-08-26 2001-03-01 Leah M. Giupponi Npy antagonists: spiroisoquinolinone derivatives
ES2258485T3 (es) 1999-12-17 2006-09-01 Schering Corporation Antagonistas selectivos de neuroquinina.
DE10034623A1 (de) 2000-07-17 2002-01-31 Bayer Ag Heterocyclisch substituierte Pyridine als Cytokin-Inhibitoren
AU2002360818A1 (en) 2001-12-28 2003-07-24 Bayer Pharmaceuticals Corporation 1h-pyrazolyl derivative compounds, for use in diseases associated with the 5-ht2c receptor
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
WO2004094375A2 (en) 2003-04-16 2004-11-04 Memory Pharmaceuticals Corporation 4 - (3,4 - disubstituted phenyl) - pyrrolidin-2-one compounds as phosphodiesterase 4 inhibitors
MXPA06012929A (es) 2004-05-07 2007-01-26 Janssen Pharmaceutica Nv Derivados de adamantil pirrolidin-2-ona como inhibidores de 11-beta hidroxiesteroide deshidrogenasa.
BRPI0510394A (pt) 2004-05-24 2007-11-13 Amgen Inc inibidores de 11-beta-hidroxiesteróide desidrogenase tipo 1
WO2006002349A1 (en) 2004-06-24 2006-01-05 Incyte Corporation Amido compounds and their use as pharmaceuticals
DOP2005000123A (es) 2004-07-02 2011-07-15 Merck Sharp & Dohme Inhibidores de cetp
MX2007001399A (es) 2004-08-02 2007-04-18 Osi Pharm Inc Compuestos que inhiben pirrolopirimidina multi-cinasa aril-amino sustituidas.
ES2338441T3 (es) 2004-08-30 2010-05-07 Janssen Pharmaceutica Nv Derivados de n-2-adamantil-2-fenoxi-acetamida como inhibidores de 11-betahidroxiesteroide-deshidrogenasa.
EP1786774B1 (en) 2004-08-30 2009-10-14 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
EP1791821B1 (en) 2004-09-10 2013-06-05 Janssen Pharmaceutica NV Novel imidazolidin-2-one derivatives as selective androgen receptor modulators (sarms)
WO2006040329A1 (en) 2004-10-12 2006-04-20 Novo Nordisk A/S 1 ibeta- hydroxysteroid dehydrogenase type 1 active spiro compounds
DK1807072T3 (da) 2004-10-29 2009-03-16 Lilly Co Eli Cycloalkyllactamderivater som inhibitorer af 11-beta-hydroxysteroid-dehydrogenase 1
BRPI0607820A2 (pt) 2005-02-24 2010-03-23 Nihon Nohyaku Co Ltd derivado de haloalquilsulfonanilida ou um sal do mesmo, herbicida, e, mÉtodo para usar um herbicida
EP1864971A4 (en) 2005-03-31 2010-02-10 Takeda Pharmaceutical PROPHYLACTIC / THERAPEUTIC AGENT AGAINST DIABETES
WO2007061661A2 (en) 2005-11-22 2007-05-31 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
US8865707B2 (en) 2005-12-30 2014-10-21 Merck Sharp & Dohme Corp. Cholesteryl ester transfer protein inhibitors
TW200808807A (en) 2006-03-02 2008-02-16 Incyte Corp Modulators of 11-β hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
WO2007103719A2 (en) 2006-03-03 2007-09-13 Incyte Corporation MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME
JP2007254409A (ja) 2006-03-24 2007-10-04 Taisho Pharmaceut Co Ltd イミダゾリジノン誘導体
US8088776B2 (en) 2006-04-21 2012-01-03 Eli Lilly And Company Biphenyl amide lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
AU2007240450B2 (en) 2006-04-21 2011-12-22 Eli Lilly And Company Cyclohexylimidazole lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
JP5161869B2 (ja) 2006-04-21 2013-03-13 イーライ リリー アンド カンパニー １１−β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤としての、シクロヘキシルピラゾール−ラクタム誘導体
DK2029529T3 (da) 2006-04-24 2010-09-20 Lilly Co Eli Substitueret pyrrolidinone som inhibitor af 11-beta-hydroxysteroiddehydrogenase 1
ES2344616T3 (es) 2006-04-25 2010-09-01 ELI LILLY & COMPANY Inhibidores de 11-beta-hidroxiesteroide deshidrogenasa 1.
JP5420408B2 (ja) 2006-08-25 2014-02-19 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１型のインヒビター
RU2439062C2 (ru) 2006-10-19 2012-01-10 Ф.Хоффманн-Ля Рош Аг Производные имидазолона и имидазолидинона как 11в-hsd1 ингибиторы при диабете
TW200829171A (en) 2006-11-17 2008-07-16 Nihon Nohyaku Co Ltd Haloalkyl sulfonanilide derivatives or salts thereof, herbicide using it as effective constituent and use-method thereof
WO2008106128A2 (en) 2007-02-26 2008-09-04 Vitae Pharmaceuticals, Inc. CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1
EP2183229B1 (en) 2007-07-26 2012-04-18 Vitae Pharmaceuticals, Inc. Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
WO2009020140A1 (ja) 2007-08-06 2009-02-12 Dainippon Sumitomo Pharma Co., Ltd. アダマンチルウレア誘導体
AR069207A1 (es) 2007-11-07 2010-01-06 Vitae Pharmaceuticals Inc Ureas ciclicas como inhibidores de la 11 beta - hidroxi-esteroide deshidrogenasa 1
TW200927115A (en) 2007-11-16 2009-07-01 Boehringer Ingelheim Int Aryl-and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
CA2708303A1 (en) 2007-12-11 2009-06-18 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
WO2009094169A1 (en) 2008-01-24 2009-07-30 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2252598A2 (en) 2008-02-11 2010-11-24 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2715290A1 (en) 2008-02-15 2009-08-20 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8383629B2 (en) 2008-02-27 2013-02-26 Vitae Pharmaceuticals, Inc. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1
EP2274287B1 (en) 2008-03-18 2016-03-09 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
TW200944526A (en) 2008-04-22 2009-11-01 Vitae Pharmaceuticals Inc Carbamate and urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2009134384A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
ES2421537T3 (es) 2008-05-01 2013-09-03 Vitae Pharmaceuticals Inc Inhibidores cíclicos de la 11beta-hidroxiesteroide deshidrogenasa 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
WO2009134392A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2323994A1 (en) 2008-07-25 2011-05-25 Boehringer Ingelheim International GmbH Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
ES2432150T3 (es) 2008-07-25 2013-12-02 Boehringer Ingelheim International Gmbh Inhibidores cíclicos de la 11 beta-hidroxiesteroide deshidrogenasa 1
JP5777030B2 (ja) 2008-07-25 2015-09-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング １１β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤
CA2744946A1 (en) 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1
US8598163B2 (en) 2009-02-04 2013-12-03 Vitae Pharmaceuticals, Inc. Derivatives of [1,3]Oxazin-2-one useful for the treatment of metabolic diseases such as lipid disorders
EP2405913A1 (en) 2009-03-09 2012-01-18 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
GEP20156309B (en) 2009-04-30 2015-07-10 Vitae Pharmaceuticals Inc Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
AR076936A1 (es) 2009-06-02 2011-07-20 Vitae Pharmaceuticals Inc Inhibidores de carbamato y urea de la 11 beta hidroxiesteroide deshidrogenasa 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
WO2011002910A1 (en) 2009-07-01 2011-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
BR112012005550A2 (pt) 2009-09-11 2015-09-08 Cylene Pharmaceuticals Inc lactamas heterociclo-substituídas farmaceuticamente úteis
JP5750449B2 (ja) 2009-11-05 2015-07-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規キラルリンリガンド
EP2582698B1 (en) 2010-06-16 2016-09-14 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
WO2011161128A1 (en) 2010-06-25 2011-12-29 Boehringer Ingelheim International Gmbh Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders
EA201300522A1 (ru) 2010-11-02 2013-11-29 Бёрингер Ингельхайм Интернациональ Гмбх Фармацевтические комбинации для лечения метаболических нарушений

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229846A1 (en) 2001-11-09 2004-11-18 The Penn State Research Foundation P-chiral phospholanes and phosphocyclic compounds and their use in asymmetric catalytic reactions
WO2005087370A1 (en) 2004-03-12 2005-09-22 Warner-Lambert Company Llc C1-symmetric bisphosphine ligands and their use in the asymmetric synthesis of pregabalin

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Catalytic Asymmetric Synthesis", 1993
ALURI ET AL, CHEM. EUR. J., vol. 14, 2008, pages 4328 - 4335, XP002624440 *
ALURI, BHASKAR REDDY ET AL: "Bulky N-Substituted 1,3-Benzazaphospholes: Access via Pd-Catalyzed C-N and C-P Cross Coupling, Lithiation, and Conversion to Novel P:C-PtBu2 Hybrid Ligands", INORGANIC CHEMISTRY (WASHINGTON, DC, UNITED STATES) , 47(15), 6900-6912 CODEN: INOCAJ; ISSN: 0020-1669, 2008, XP002624439 *
BURK, M. J. ET AL., ANGEW. CHEM., INT. ED. ENGL., vol. 29, 1990, pages 1462
BURK, M. J. ET AL., ORGANOMETALLICS, vol. 9, 1990, pages 2653
C. SENANAYAKE: "Timely Chemical Process Research is a CriticalPart for Efficient Drug Development", 23 September 2010 (2010-09-23), pages 1 - 91, XP002624445, Retrieved from the Internet <URL:http://www.siegfried.ch/fileadmin/User2/Bilder/Fotogalerien/Symposium_2010/Award_Talk_Senanayake.pdf> [retrieved on 20100223] *
FANDRICK ET AL, J. AM. CHEM. SOC., vol. 132, 18 May 2010 (2010-05-18), pages 7600 - 7601, XP002624444 *
HOGE, G. ET AL., J. AM. CHEM. SOC., vol. 126, 2004, pages 5966
IMAMOTO, T. ET AL., J. AM. CHEM. SOC., vol. 119, 1997, pages 1799
JACOBSEN, E. N; PFALTZ, A; YAMAMOTO, H: "Comprehensive Asymmetric Catalysis", 1999, SPRINGER
KAGAN ET AL., J. AM. CHEM. SOC., vol. 94, 1972, pages 6429
KNOWLES, W. S., ACC. CHEM. RES., vol. 16, 1983, pages 106
LIGHTBURN ET AL, J. AM. CHEM. SOC., vol. 130, 2008, pages 9210 - 9211, XP002624449 *
NOYORI, R, CHEM. SOC. REV., vol. 18, 1989, pages 187
NOYORI, R.: "Asymmetric Catalysis In Organic Synthesis", 1994, JOHN WILEY & SONS, INC
TANG ET AL, ORG. LETT., vol. 12, no. 5, 11 February 2010 (2010-02-11), pages 1104 - 1107, XP002624443 *
TANG, WENJUN ET AL: "Novel, Tunable, and Efficient Chiral Bisdihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation", ORGANIC LETTERS , 12(1), 176-179 CODEN: ORLEF7; ISSN: 1523-7060, 1 December 2009 (2009-12-01), XP002624442 *
WORTHY ET AL, ORG. LETT., vol. 11, 2 June 2009 (2009-06-02), pages 2764 - 2767, XP002624441 *
ZHANG, X. ET AL., ANGEW. CHEM. INT. ED., vol. 41, 2002, pages 1613
ZHANG, X. ET AL.: "Angew. Chem. Int. Ed. Engl.", vol. 38, 1999, pages: 516

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
CN103087105A (zh) * 2013-01-18 2013-05-08 中国科学院上海有机化学研究所 手性膦配体以及包含该配体的金属催化剂和它们的应用
WO2015002769A1 (en) * 2013-07-01 2015-01-08 Boehringer Ingelheim International Gmbh Novel ruthenium catalysts and their use for asymmetric reduction of ketones
US9029540B2 (en) 2013-07-01 2015-05-12 Boehringer Ingelheim International Gmbh Ruthenium catalysts and their use for asymmetric reduction of ketones
WO2015006458A1 (en) * 2013-07-10 2015-01-15 Boehringer Ingelheim International Gmbh Novel chiral nitrogen-phosphorus ligands and their use for asymmetric hydrogenation of alkenes
US8946418B1 (en) 2013-07-10 2015-02-03 Boehringer Ingelheim International Gmbh Chiral nitrogen-phosphorus ligands and their use for asymmetric hydrogenation of alkenes
CN104558038A (zh) * 2013-10-23 2015-04-29 中国科学院上海有机化学研究所 一种取代的2,3-二氢苯并[d][1,3]氧杂磷杂茂配体的制备方法
WO2015077286A1 (en) 2013-11-20 2015-05-28 Boehringer Ingelheim International Gmbh Hexahydroindenopyridine derivatives
CN104650145A (zh) * 2015-02-06 2015-05-27 中国科学院上海有机化学研究所 手性膦配体以及包含该配体的金属催化剂和它们的应用
CN105732249B (zh) * 2016-01-27 2019-03-15 中国科学院上海有机化学研究所 芳基醇类化合物及艾司西酞普兰合成方法
CN105732249A (zh) * 2016-01-27 2016-07-06 中国科学院上海有机化学研究所 芳基醇类化合物及艾司西酞普兰合成方法
US10544177B2 (en) 2016-12-06 2020-01-28 Boehringer Ingelheim International Gmbh Chiral dihydrobenzooxaphosphole ligands and synthesis thereof
US10196413B2 (en) 2016-12-06 2019-02-05 Boehringer Ingelheim International Gmbh Chiral dihydrobenzoazaphosphole ligands and synthesis thereof
US10221203B2 (en) 2016-12-06 2019-03-05 Boehringer Ingelheim International Gmbh Chiral dihydrobenzooxaphosphole ligands and synthesis thereof
WO2018106621A1 (en) * 2016-12-06 2018-06-14 Boehringer Ingelheim International Gmbh Novel chiral dihydrobenzoazaphosphole ligands and synthesis thereof
WO2018106746A3 (en) * 2016-12-06 2018-07-19 Boehringer Ingelheim International Gmbh Novel chiral dihydrobenzooxaphosphole ligands and synthesis thereof
CN107445999B (zh) * 2017-08-15 2020-11-13 中国科学院上海有机化学研究所 金属络合物、制备方法和应用及其中间体
CN107445999A (zh) * 2017-08-15 2017-12-08 中国科学院上海有机化学研究所 金属络合物、制备方法和应用及其中间体
CN109096338A (zh) * 2018-09-10 2018-12-28 中国科学院上海有机化学研究所 苯并氮杂磷杂茂膦氧配体及含其络合物、制备方法和应用
CN109096338B (zh) * 2018-09-10 2020-05-12 中国科学院上海有机化学研究所 苯并氮杂磷杂茂膦氧配体及含其络合物、制备方法和应用
WO2020073962A1 (zh) * 2018-10-10 2020-04-16 中国科学院上海有机化学研究所 一种金属配合物、中间体、其制备方法及应用
US12110302B2 (en) 2018-10-10 2024-10-08 Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences Metal complex, intermediate, and preparation method and application thereof
CN111848680A (zh) * 2019-04-30 2020-10-30 中国科学院上海有机化学研究所 双齿膦-膦氧配体及其中间体、制备方法和应用
CN111848680B (zh) * 2019-04-30 2021-12-14 中国科学院上海有机化学研究所 双齿膦-膦氧配体及其中间体、制备方法和应用
CN112574234A (zh) * 2019-09-27 2021-03-30 江苏恒瑞医药股份有限公司 一种海鞘素衍生物的制备方法
CN111647020A (zh) * 2020-04-09 2020-09-11 宁波赜军医药科技有限公司 一种膦氧双齿配体的合成方法
WO2025103462A1 (en) * 2023-11-17 2025-05-22 Shenzhen Catalys Technology Co., Ltd Substituted 2, 3-dihydrobenzo [d] [1, 3] oxaphosphole ligand, preparation method and use thereof

Also Published As

Publication number Publication date
US8552212B2 (en) 2013-10-08
EP2496589A1 (en) 2012-09-12
EP2496589B1 (en) 2014-03-05
JP2013510154A (ja) 2013-03-21
US20120277455A1 (en) 2012-11-01
JP5750449B2 (ja) 2015-07-22

Similar Documents

Publication Publication Date Title
EP2496589B1 (en) Novel chiral phosphorus ligands
EP3019509B1 (en) Novel chiral nitrogen-phosphorus ligands and their use for asymmetric hydrogenation of alkenes
JP4488739B2 (ja) Ｐ−キラルホスホランおよびホスホ環式化合物並びにその不斉触媒反応における使用
CZ393798A3 (cs) Asymetrická syntéza katalyzovaná komplexy přechodných kovů s cyklickými chirálními fosfinovými ligandy
EP2556077B1 (en) Monophosphorus ligands and their use in cross-coupling reactions
CN102516300A (zh) 一类膦配体及其对映体或消旋体及其制备方法
US5274125A (en) Chirale phosphines
WO2005117907A2 (en) P-chiral phospholanes and phosphocyclic compounds and their use in asymmetric catalytic reactions
US6573389B1 (en) Bidentate organophosphorous ligands and their use
US20050107608A1 (en) Ligands for use in catalytic processes
AU2011301115A1 (en) Biaryl diphosphine ligands, intermediates of the same and their use in asymmetric catalysis
EP3551639B1 (en) Novel chiral dihydrobenzoazaphosphole ligands and synthesis thereof
US10544177B2 (en) Chiral dihydrobenzooxaphosphole ligands and synthesis thereof
CA2597883A1 (en) Catalyst for asymmetric synthesis, ligand for use therein, and process for producing optically active compound through asymmetric synthesis reaction using them
CN101314608A (zh) 二齿有机磷配体及其用途
WO2005010013A1 (ja) 新規光学活性リンキラルジホスフェタン化合物、該化合物の中間体、及び該化合物を配位子とする遷移金属錯体
US20080242534A1 (en) Novel bisphosphine ligand
WO2025224043A1 (en) Chiral aminophosphine ligands, iridium catalysts comprising these ligands and use of these catalysts in asymmetric hydrogenations
JP2015524398A (ja) キラル芳香族スピロケタール骨格のジホスフィン配位子およびその製造方法と応用
WO2006082054A1 (en) 1,4-bis-diphosphines, 1,4-bis-diphosphites and 1,4-bis- diphosphonites from optically active (z)-olefines as chiral ligands
Hirai The synthesis and applications of a biaryl-based asymmetric phosphine ligand
Qiu Highly efficient asymmetric synthesis of novel diphosphine ligands with additional chiral centers on the backbone and their applications in asymmetric hydrogenation reactions

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10774398

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010774398

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2012537924

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13504146

Country of ref document: US