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WO2025224043A1 - Ligands d'aminophosphine chiraux, catalyseurs d'iridium comprenant ces ligands et utilisation de ces catalyseurs dans des hydrogénations asymétriques - Google Patents

Ligands d'aminophosphine chiraux, catalyseurs d'iridium comprenant ces ligands et utilisation de ces catalyseurs dans des hydrogénations asymétriques

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Publication number
WO2025224043A1
WO2025224043A1 PCT/EP2025/060836 EP2025060836W WO2025224043A1 WO 2025224043 A1 WO2025224043 A1 WO 2025224043A1 EP 2025060836 W EP2025060836 W EP 2025060836W WO 2025224043 A1 WO2025224043 A1 WO 2025224043A1
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alkyl
rbrc
hydrogen
phenyl
mmol
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Raphael BIGLER
Bin Chen
Anna-Lena GLASS
Yuanqiang Li
Kurt Puentener
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C07C29/149—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof with hydrogen or hydrogen-containing gases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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    • 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
    • C07F15/0033—Iridium compounds
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    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
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    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention in a further embodiment, also relates to the preparation of iridium catalysts of formula II or III comprising a treatment of a chiral aminophoshine ligand of formula I with a suitable iridium catalyst precursor.
  • the invention in still a further embodiment the invention relates to a process for the preparation of a chiral alcohol comprising the asymmetric hydrogenation of a compound, containing at least one prochiral keto group, with hydrogen in the presence of the novel iridium catalyst as defined above.
  • pre-formed catalyst either means that the iridium catalyst of formula II or III is added as pre-formed catalyst to the reaction, or, that the iridium catalyst of formula II or III is in-situ formed from an iridium catalyst precursor and a ligand of formula I.
  • Chiral alcohols are versatile building blocks for the preparation of various pharmaceutically active drug substances such as for instance for statin drugs (A. Lenhart, W.D. Chey “Adv. Nutr.2017, 8(4), 587-596).
  • the International Patent Publication WO2022152769A1 discloses a process for the asymmetric hydrogenation of ketones and the formation of a chiral triol with iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalysts). While the process is scalable and provides the triol in high enantiomeric and diastereomeric purity and high yield, the therein reported Ir-SpiroPAP catalysts turned out to be a massive cost driver for the process as its synthesis employs costly optically pure Spinol to install the chirality in the backbone of the SpiroPAP ligands, resp. the corresponding iridium catalysts thereof.
  • Ir-SpiroPAP catalysts iridium spiro-pyridylamidophosphine catalyst
  • the object of the present invention was to provide easily accessible, less costly alternative ligands and iridium catalysts, the latter of which equally are able to deliver chiral alcohols in high enantiomeric and, if applicable, diastereomeric purity and yield, but at much more moderate costs.
  • the object of the invention could be reached with the novel chiral aminophosphine ligands of the formula I, with the respective iridium catalysts and with a process for the preparation of a chiral alcohol via asymmetric hydrogenation with hydrogen, applying the iridium catalysts as defined above.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
  • chiral denotes the circumstance, when a structure of a molecule is not superimposable with its mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.
  • the term “chiral” signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers, optically pure diastereoisomers or mixtures of diastereoisomers.
  • the term “chiral” denotes optically pure enantiomers or optically pure diastereoisomers.
  • stereoisomer denotes a compound that possesses identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space.
  • diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers may have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • enantiomers denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • a dashed bond denotes that the substituent is below the plane of the paper
  • a wedged bond denotes that the substituent is above the plane of the paper
  • the spiral bond denotes both options i.e. either a dashed bond (a) or a wedged bond
  • C1-8-alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms.
  • C1-8-alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, tert-butyl or pentyl, hexyl, heptyl or octyl with its isomers.
  • the term denotes a C1-6-alkyl group.
  • C3-8-cycloalkyl denotes a saturated carbocycle of 3 to 8 carbon atoms.
  • C3-8-cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the term encompasses C4-7-cycloalkyl, more preferably cyclopentyl and cyclohexyl.
  • C1-6-alkoxy denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms attached to an oxygen atom.
  • C1-6-alkoxy examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or pentoxy or hexoxy with its isomers.
  • the term denotes a C1-4-alkoxy group, more preferably the methoxy group.
  • halogen denotes fluoro, chloro, bromo, or iodo, preferably fluoro, bromo or chloro. In its function as counter anion the preferred halogen is chloro.
  • C1-8-halogenalkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms which is substituted by one or more halogen atoms.
  • the term denotes C1-4-halogenalkyl, more preferably a methyl group which is substituted with one or more halogen atoms such as trifluoromethyl.
  • heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulphur, such as pyridinyl, pyrazolyl, pyrimidinyl, benzoimidazolyl, quinolinyl, thienyl, benzothienyl, furanyl and isoquinolinyl, preferably furanyl, thienyl, or benzothienyl.
  • coordinated ligand signifies a ligand which donates one of its electron lone pair to the complexing metal atom.
  • Scheme 1 As outlined above the invention relates in one embodiment to chiral aminophosphine ligands of the formula I wherein R 1 to R 8 , independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R 3 and R 4 , and R 5 and R 6 form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R 9 to R 12 , independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy;
  • R 1 to R 8 independent of each other are hydrogen or C1-8-alkoxy; or, R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; or R 3 and R 4 , and R 5 and R 6 form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-;
  • R 9 to R 12 independent of each other, are hydrogen or C1-8-alkyl;
  • R 14 or R 15 are independent of each other hydrogen or C1-4-alkyl;
  • R 20 is optionally substituted C1-8-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furanyl, thienyl, or benzothienyl, wherein
  • R 1 to R 8 independent of each other are hydrogen or methoxy; or, R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; or R 3 and R 4 , and R 5 and R 6 form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-;
  • R 9 to R 12 independent of each other, is hydrogen or methyl;
  • R 14 or R 15 are independent of each other hydrogen or methyl;
  • R 20 is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl, C1-8-alkoxy
  • R 1 to R 3 and R 6 to R 8 are hydrogen; R 4 and R 5 is methoxy; R 9 is methyl and R 10 to R 12 are hydrogen; R 14 and R 15 are hydrogen; R 20 is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl, or enantiomers thereof and chiral aminophosphine ligands of the formula I, wherein R 1 , R 2 , R 7 , R 8 are hydrogen; R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; R 9 is hydrogen or methyl and R 10 to R 12 are hydrogen; R 14 and R 15 are hydrogen or methyl; R 20 is phenyl, 3,5-dimethylphenyl, 3,5-
  • the chiral aminophosphine ligands of the formula I can be prepared in analogy to procedures reported in the literature (a: Q.-L. Zhou et al., Angew. Chem. Int. Ed.2013, 52, 7833; b: M. Kitamura et al., Angew. Chem. Int. Ed.2013, 52, 9313) either via a chiral resolution route or a stereoselective route as outlined in Scheme 2, resp. Scheme 3.
  • Chiral Resolution Route Ligands of type I were prepared in 8 steps starting from phenols of type A which were MOM protected first (step 1).
  • step 2 After deprotonation with BuLi and treatment with FeCl3 the racemic biphenyl products B were obtained (step 2).
  • step 3 and 4 the MOM protecting groups were removed and the free diols converted with Tf2O / pyridine into their bis triflates E.
  • step 5 Subsequent palladium catalyzed C-P cross coupling furnished the phosphine oxides F (step 5) which were reduced with aid of HSiCl3 to their phosphines G (step 6).
  • Ligands of type I were prepared in 5 steps starting from enantiopure biphenols of type D which were converted with Tf2O / pyridine into their bis triflates E. Subsequent palladium catalyzed C-P cross coupling furnished the phosphine oxides F (step 2) which were reduced with aid of HSiCl3 to their phosphines G (step 3). After coupling with 2-(azidomethyl)-pyridines and subsequent treatment with NaOH, the enantiopure (S)- or (R)-aminophosphine oxides K (step 4).
  • the invention relates in a further embodiment to iridium catalysts which are comprising chiral aminophosphine ligands of the formula I as defined above, particularly to iridium catalysts of formula II or III,
  • X is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group, which is optionally substituted with one or more halogen atoms; from halogen, C1-6-alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate, p- tolylsulfonate or trihalogenomethanesulfonate; R 1 to R 8 , independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alk
  • iridium catalysts of formula II or III wherein X is either a coordinated ligand or a counter anion from halogen, tetrahalogenoborate or tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate; R 1 to R 8 , independent of each other are hydrogen or C1-8-alkoxy; or, R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; or R 3 and R 4 , and R 5 and R 6 form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC
  • iridium catalysts of formula II or III wherein X is a coordinated ligand from halogen; R 1 to R 8 , independent of each other are hydrogen or methoxy; or, R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; or R 3 and R 4 , and R 5 and R 6 form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R 9 to R 12 , independent of each other, is hydrogen or methyl; R 14 or R 15 are independent of each other hydrogen or methyl; R 20 is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl;
  • iridium catalysts of formula II or III wherein X is a coordinated chloride; R 1 to R 3 and R 6 to R 8 are hydrogen; R 4 and R 5 is methoxy; R 9 is methyl and R 10 to R 12 are hydrogen; R 14 and R 15 are hydrogen; R 20 is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl; and L in formula II is 1,5-cyclooctadiene (COD); or enantiomers thereof; or iridium catalysts of formula II or III, wherein X is chloride; R 1 , R 2 , R 7 , R 8 are hydrogen; R 3 and R 4 , and R 5 and R 6 , taken together, form an aromatic 6-membered ring; R 9 is hydrogen or methyl and R 10 to R 12 are hydrogen; R 14 and R
  • the iridium catalyst of formula II can be prepared by treatment of a chiral aminophoshine ligand with a suitable iridium catalyst precursor of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, such as [Ir(COD)X]2, [Ir(COD)2]X, [Ir(NBD)X]2, [Ir(NBD)2]X or [Ir(COE)2X]2 in an organic solvent, such as a protic or aprotic solvent, for instance ethanol, dichloromethane or tetrahydrofuran, or a mixture thereof, at room temperature according to the general Scheme 4.
  • a protic or aprotic solvent for instance ethanol, dichloromethane or tetrahydrofuran, or a mixture thereof
  • the iridium catalyst of formula III can be prepared by treatment of a chiral aminophoshine ligand with a suitable iridium catalyst precursor of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, such as [Ir(COD)X]2 or [Ir(COD)2]X, in an organic solvent, such as a protic or aprotic solvent, for instance ethanol, dichloromethane or tetrahydrofuran, or a mixture thereof between 10°C and 100 °C, at a hydrogen pressure of 1 to 100 bar, according to the general Scheme 5.
  • a suitable iridium catalyst precursor of the type [Ir(L)X]2 or [Ir(L)2]X wherein L and X are as defined above, such as [Ir(COD)X]2 or [Ir(COD)2]X
  • an organic solvent such as a protic or aprotic solvent, for instance
  • Scheme 5 As outlined above in a further embodiment the invention relates to a process for the preparation of a chiral alcohol comprising the asymmetric hydrogenation of a compound, containing at least one prochiral keto group, with hydrogen in the presence of the novel iridium catalyst of formula II or III as defined above.
  • the process of the present invention can be illustrated with the Scheme 6.
  • the asymmetric hydrogenation can be performed according to method a) to c) in the presence of hydrogen and a base.
  • Asymmetric hydrogenation of the ketone of formula IV in the presence of a pre-formed iridium catalyst of formula II or III can be performed in the presence of suitable organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar, preferably of 30 bar to 70 bar and at a reaction temperature of 10°C to 90°C, preferably of 20°C to 40°C.
  • the organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like 1,1,1-trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or methyl tetrahydrofuran or from aromatic solvents like toluene or mixtures thereof. Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with methyl tetrahydrofuran.
  • the preferred solvent is methanol or ethanol, even more preferred ethanol.
  • Suitable bases are inorganic bases selected from alkali or earth alkali carbonates or hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines.
  • Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo(2.2.2)octane (DABCO) and 7-methyl-1,5,7- triazabicyclo[4.4.0]dec-5-ene (MTBD), most preferred is DBU.
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • DABCO 1,4-diazabicyclo(2.2.2)octane
  • MTBD 7-methyl-1,5,7- triazabicyclo[4.4.0]dec-5-ene
  • a substrate-to-catalyst ratio can expediently be chosen in a range of 100 to 10000, preferably in a range of 1000 to 5000.
  • the suitable separation method can depend on the structure of the chiral alcohol of formula V, but as a rule is common for the skilled practioner.
  • the chiral alcohol of formula V is obtained by evaporation of the solvent.
  • Subsequent purification e.g. by distillation, or chromatography or crystallization in a suitable solvent, typically in ketones like methyl iso-butyl ketone or esters like isopropyl acetate renders the chiral alcohol of formula V in good yields, high purity and, high enantiomeric and, if applicable, diastereomeric excess.
  • iridium catalyst of formula II or III are formed in situ in the course of the asymmetric hydrogenation reaction by bringing together a suitable iridium catalyst precursors of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, with a chiral aminophosphine ligand of the formula I.
  • the iridium catalyst of formula II is formed upon mixing the ligand of formula I with the iridium catalyst precursor.
  • iridium catalyst of formula II is transformed into the iridium catalyst of formula III.
  • Suitable iridium catalyst precursors are commercially available e.g. from Sigma Aldrich and can be selected e.g. from [Ir(COD)2]BF4, [IrCl(COD)]2, [Ir(acac)(COD)], [Ir(OMe)(COD)]2, [Ir(COD)2]BARF, [Ir(COD)2]PF6, [IrCl(COE)2]2 wherein COD has the meaning of 1,5-cyclooctadiene, COE the meaning of cylooctene, acac the meaning of acetylacetonate, BARF the meaning of tetrakis(3,5-bis(trifluoromethyl)phenyl)borate and OMe the meaning of methoxy.
  • Preferred iridium catalyst precursor is [IrCl(COD)]2.
  • the iridium catalyst precursor and the chrial aminophosphine ligand are typically mixed in the presence of the organic solvent and the base mentioned under embodiment a).
  • the substrate-to-iridium ratio as a rule is adjusted between 100 and 10000, preferably between 1000 and 5000.
  • the iridium-to-ligand ratio as a rule is adjusted between 0.5 and 1.5, preferably between 0.9 and 1.1.
  • the asymmetric hydrogenation conditions and the isolation of the chiral alcohol of formula V can otherwise be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise.
  • the asymmetric hydrogenation is performed with a mixture of an iridium catalyst of formula II or III or of an iridium catalyst formed from an iridium catalyst precursor and a chiral aminophosphine ligand of the formula I and an Ir-PEN catalyst of the formula VIa, VIb or VIc.
  • the substrate-to-iridium (2 nd , formula VI type catalyst) ratio as a rule is adjusted between 100 and 10000, preferably between 500 and 2500.
  • R 5 is
  • the Ir-PEN catalysts are of the formula VIa or VIc, or enantiomers thereof, wherein, R 5 is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl; tolylsulfonyl or 1,3,5-tri-isopropylphenyl sulfonyl; Y is a trifluoromethylsulfonyl group;
  • the Ir-PEN catalysts are of the formula IVc, or enantiomers thereof, wherein, R 5 is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl; tolylsulfonyl or 1,3,5-tri-isopropylphenyl sulfonyl.
  • the Ir-PEN catalysts are selected from compounds of the formula VIa-1 and VIc-1
  • the asymmetric hydrogenation conditions and the isolation of the chiral alcohol of formula V can be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise.
  • the process of the present invention comprises the process as illustrated in Scheme 7. Scheme 7: wherein, R 18 is hydrogen or halogen and R 19 is C 1-4 -alkyl. Further preferred is the process as illustrated in Scheme 8.
  • Scheme 8 wherein R 19 is C1-4-alkyl, preferably ethyl.
  • the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of a pre-formed iridium catalyst of formula II or III, under the asymmetric hydrogenation conditions outlined for embodiment a) above.
  • the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of an iridium catalyst in-situ formed from an iridium catalyst precursor and a chiral aminophosphine ligands of the formula I.
  • the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of an Ir-PEN catalyst of formula VIa, VIb or VIc, whereby the Ir-PEN catalyst of formula VIa, VIb or VIc only catalyzes the conversion of the ketone of formula IVa to the intermediate ketone IVb.
  • method c) offers to the possibility to c1) react the ketone of formula IVa to intermediate ketone IVb in the sole presence of the Ir- PEN catalyst of formula VIa, VIb or VIc and the subsequent asymmetric hydrogenation to the chiral alcohol of formula Va, according to method a) or method b); or c2) react the ketone of formula IVa to the chiral alcohol of formula Va in the presence of an Ir- PEN catalyst of formula VIa, VIb or VIc and the presence of a pre-formed iridium catalyst of formula II or III under the asymmetric hydrogenation conditions, according to method a); or c3) react the ketone of formula IVa to the chiral alcohol of formula Va in the presence of an Ir- PEN catalyst of formula VIa, VIb or VIc and the presence of an iridium catalyst in-situ formed from an iridium catalyst precursor and a chiral aminophosphine ligands of the formula I, according to method b).
  • Step 2 To a mixture of RBRC-060-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl 3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of RBRC-060-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated.
  • Step 4 To a solution of RBRC-060-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-060-50 (12.0 g, 23.5 mmol), the corresponding phosphine oxide (5.3g, 26 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-060-60 (8.5 g, 15.1 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C. The reaction mixture was stirred at 110 o C for 12 h.
  • Step 8 RBRC-060-80 (12.7 g, 19 mmol) was dissolved in EtOH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-060-90 as a white solid (10.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-070-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF(106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of RBRC-070-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated.
  • Step 4 To a solution of RBRC-070-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-070-50 (12.0 g, 23.5 mmol), the corresponding phosphine oxide (5.3g, 26 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-070-60 (8.5 g, 15.1 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C. The reaction mixture was stirred at 110 o C for 12 h.
  • Step 8 RBRC-070-80 (12.7 g, 19 mmol) was dissolved in EtOH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1800 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-070-90 as a white solid (10.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-061-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of RBRC-061-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-061-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated.
  • Step 4 To a solution of RBRC-061-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-061-50 (13.4 g, 26.3 mmol), the corresponding phosphine oxide (7.4g, 28.6 mmol), palladium acetate (300 mg, 1.33 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-061-60 (9.7 g, 15.7 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C.
  • the reaction mixture was stirred at 110 o C for 12 h. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure.
  • Step 8 RBRC-061-80 (18.7 g, 25.9 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-061-90 as a white solid (16.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-071-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of RBRC-071-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-071-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated.
  • Step 4 To a solution of RBRC-071-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-071-50 (13.4 g, 26.3 mmol), the corresponding phosphine oxide (7.4 g, 28.6 mmol), palladium acetate (300 mg, 1.33 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-071-60 (9.7 g, 15.7 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C.
  • the reaction mixture was stirred at 110 o C for 12 h. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure.
  • Step 8 RBRC-071-80 (18.7 g, 25.9 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-071-90 as a white solid (16.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-062-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of RBRC-062-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated.
  • Step 4 To a solution of RBRC-062-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-062-50 (13.0 g, 25.5 mmol), the corresponding phosphine oxide (12g, 28 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-062-60 (9.5 g, 12 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C. The reaction mixture was stirred at 110 o C for 12 h.
  • Step 8 RBRC-062-80 (18.7 g, 21 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-062-90 as a white solid (16.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-072-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78 o C. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0 o C and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0 o C. The reaction mixture was warmed to rt and stirred for 12 h.
  • Step 3 To a mixture of (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70 o C for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4, and concentrated.
  • Step 4 To a solution of RBRC-072-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-072-50 (13.0 g, 25.5 mmol), the corresponding phosphine oxide (12g, 28 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100 o C for 6 h. After cooling to 20 o C, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL).
  • Step 6 To a mixture of RBRC-072-60 (9.5 g, 12 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0 o C. The reaction mixture was stirred at 110 o C for 12 h.
  • Step 8 RBRC-072-80 (18.7 g, 21 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-072-90 as a white solid (16.0 g, 98% yield).
  • Step 2 To a mixture of RBRC-083-20 (10.0 g, 18.2 mmol), palladium acetate (250 mg, 1.10 mmol), dppb (780 mg, 1.80 mmol) and diphenylphosphine oxide (7.4 g, 36.40 mmol) was added DMSO (150 mL) and DIPEA (13 mL). The resulting mixture was heated with stirring at 100 o C for 12 h under N2. After cooling to 20 o C, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product.
  • Step 3 To a mixture of RBRC-083-30 (7.0 g, 11.62 mmol) and DIPEA (81.2 mL) in toluene (150 mL) was added HSiCl3 (18.9 mL) at 0 o C. The reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL).
  • Step 4 A dry 250 mL flask was charged with RBRC-083-40 (6.1 g, 10.3 mmol), toluene (50 mL) and 2-(azidomethyl) pyridine (2.1 g, 15.48 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed.
  • the crude mixture was dissolved in EtOH (50 mL) and 0.1 M NaOH aq (50 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (450 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (DCM / MeOH, 40:1) to provide the desired product RBRC-083-50 as yellow solid in 55% yield (3.3 g).
  • Step 2 To a mixture of RBRC-085-20 (7.6g, 13.8 mmol), palladium acetate (190 mg, 0.83 mmol), dppb (593 mg, 1.38 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (7 g, 16.60 mmol) was added DMSO (150 mL) and DIPEA (10 mL). The resulting mixture was heated with stirring at 100 o C for 12 h under N 2 . After cooling to 20 o C, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product.
  • Step 3 To a mixture of RBRC-085-30 (9.7 g, 12.0 mmol) and DIPEA (86.5 mL) in toluene (150 mL) was added HSiCl3 (20.1 mL) at 0 o C. The reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL).
  • Step 4 A dry 250 mL flask was charged with RBRC-085-40 (8.9 g, 11.19 mmol), toluene (100 mL) and 2-(azidomethyl) pyridine (2.5 g, 16.79 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL).
  • Step 2 To a mixture of RBRC-087-20 (20.0 g, 36.3 mmol), palladium acetate (490 mg, 2.18 mmol), dppb (1.55 g, 3.63 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (15.5 g, 36.33 mmol) was added DMSO (250 mL) and DIPEA (20 mL). The resulting mixture was heated with stirring at 100 o C for 12 h under N 2 . After cooling to 20 o C, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product.
  • reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 30 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (18.5 g, crude) which was use further reaction without any purification.
  • Step 4 A dry 250 mL flask was charged with RBRC-087-40 (18.5 g, 22.8 mmol), toluene (200 mL) and 2-(azidomethyl) pyridine (5.1 g, 34.2 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (200 mL) and 0.1 M NaOH aq. (200mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL).
  • Step 2 To a mixture of RBRC-087-20 (54.0 g, 98.1 mmol), palladium acetate (1.32 g, 5.88 mmol), dppb (5.50 g, 9.82 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (46.0 g, 107.92 mmol), DMSO (500 mL) and DIPEA (68 mL) were added. The resulting mixture was heated with stirring at 100 o C for 12 h under N2. After cooling to 20 o C, the reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product.
  • reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 40 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (900 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (36.5 g, crude) which was used in step 4 without any purification.
  • Step 4 A dry 1 L flask was charged with RBRC-087-40 (10.7 g, 13.2 mmol), toluene (100 mL) and 2- (azidomethyl) pyridine (2.7 g, 19.8 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL).
  • Step 5 The RBRC-114-10 (8.9 g, 11.3 mmol) and phenylsilane (20 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h.
  • Step 2 To a mixture of RBRC-087-20 (54.0 g, 98.1 mmol), palladium acetate (1.32 g, 5.88 mmol), dppb (5.50 g, 9.82 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (46.0 g, 107.92 mmol), DMSO (500 mL) and DIPEA (68 mL) were added. The resulting mixture was heated with stirring at 100 o C for 12 h under N 2 . After cooling to 20 o C, the reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (900 mL).
  • reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with aqueous NaOH (12 N, 40 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (900 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (36.5 g, crude) which was used in step 4 without any purification.
  • Step 4 A dry 1 L flask was charged with RBRC-087-40 (15.0 g, 18.5 mmol), toluene (200 mL) and BnN3 (3.7 g, 27.2 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, the reaction mixture was poured into H2O (200 mL).
  • Step 5 To a solution of RBRC-115-10 (9.9 g, 12.1 mmol) in MeOH (100 mL), Pd/C (1.0 g, 10 wt%) was added. The mixture was stirred at rt for 12 h under H2 (1 bar atmosphere), filtered and concentrated to get crude product. The crude product was purified by silica gel flash column chromatography (pentane / EtOAc, 2:1) to provide the desired product RBRC-115-20 as yellow solid in 87 % yield (7.5 g).
  • Step 7 To a solution of RBRC-115-30 (2.5 g, 3.5 mmol) in toluene (20 mL), 1-(pyridin-2-yl)ethan-1- one (2.1 g, 17.5 mmol), TsOH (67 mg, 0.4 mmol) and 4 ⁇ molecular sieve (1.0 g) were added. The mixture was stirred at 140 °C for 6 h. After cooling to 20 °C, the mixture was removed toluene under vacuum. To the resulting mixture toluene (10 mL) was added and the mixture was degassed with N2 (three times).
  • Step 1 To a solution of RBRC-089-01 (10.0 g, 31.8 mmol) in ether (100 mL) was added nBuLi (13.9 mL, 33.4 mmol) at -78 o C under N2. The mixture was stirred at -78 o C for 15 min. The resulting mixture was added TESCl (5.27 g, 34.9 mmol) and stirred at rt for 1 h. And then the mixture was added nBuLi (13.9 mL, 33.4 mmol) at -78 o C and stirred at -78 o C for 15 min.
  • Step 2 A vigorously stirred solution of RBRC-089-02 (9.8 g, 25.2 mmol) in 100 mL THF was placed in a -78 o C acetone bath. After 30 min, nBuLi (10.9 mL, 26.1 mmol) was added dropwise. The bath was maintained at -78 o C for 2 h, then (Et2N)PCl2 (1.89 g, 10.9 mmol) was added. The reaction was stirred at rt for 16 h and cooled to 0 o C. Concentrated HCl (6 mL) was added and stirred at rt for 5 h.
  • Step 3 To a solution of RBRC-089-10 (15.0 g, 52.39 mmol) in DCM (200 mL), was added pyridine (12.6 mL) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (36.9 g, 130.78 mmol). The reaction mixture was warmed up to 20 o C and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (600 mL). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-089-20 as yellow oil in 97% yield (28.1 g).
  • Step 4 To a mixture of RBRC-089-20 (1.0 g, 1.81 mmol), palladium acetate (25 mg, 0.11 mmol), dppb (77 mg, 0.18 mmol) and RBRC-089-03 (1.44 g, 2.2 mmol) was added DMSO (25 mL) and diisopropylethylamine (1 mL). The resulting mixture was heated with stirring at 100 o C for 12 h under N2. After cooling to 20 o C, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was concentrated to get crude product.
  • Step 5 To a mixture of RBRC-089-30 (1.5 g, 1.4 mmol) and diisopropylethylamine (9.7 mL) in toluene (15 mL) was added HSiCl3 (2.3 mL) at 0 o C. The reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (10 mL) and diluted with EtOAc (60 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (20 mL).
  • Step 6 A dry 100 mL flask was charged with RBRC-089-40 (1.3 g, 1.3 mmol), toluene (20 mL) and 2-(azidomethyl) pyridine (230 mg, 1.9 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (10 mL) and 0.1 M NaOH aq.
  • Step 4 To a solution of RBRC-088-04 (8.9 g, 29.56 mmol) in DCM (100 mL) was added 150 mL conc. HCl. The mixture was stirred at rt for 12 h. The resulting mixture was added water (100 mL) and extracted with DCM (300 mL). The combined organic layer was dried over Na2SO4 and concentrated. The product in DCM (100 mL) was added AlMe3 (52 mL, 118.24 mL) at -78 o C. The reaction was stirred at rt for 12 h. The reaction was quenched with 1M HCl (100 mL) and extracted with DCM (300 mL).
  • Step 5 A vigorously stirred solution of RBRC-088-05 (5.0 g, 16.8 mmol) in 50 mL THF was placed in a -78 o C acetone bath. After 30 min, nBuLi (7.3 mL, 17.6 mmol) was added dropwise. The bath was maintained at -78 o C for 2h, then (Et2N)PCl2 (1.3 g, 7.6 mmol) was added. The reaction was stirred at rt for 16 h and cooled to 0 o C. Concentrated HCl (6 mL) was added and stirred at rt for 5 h. The solution was poured into 1M HCl (100 mL), extracted with EtOAc (300 mL).
  • Step 6 To a solution of RBRC-088-10 (15.0 g, 52.4 mmol) in DCM (200 mL), was added pyridine (12.6 mL) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (36.9 g, 130.8 mmol). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (600 mL). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-088-20 as yellow oil in 97% yield (28.1 g).
  • Step 7 To a mixture of RBRC-088-20 (1.0 g, 1.8 mmol), palladium acetate (25 mg, 0.1 mmol), dppb (77 mg, 0.2 mmol) and RBRC-088-06 (1.1 g, 2.2 mmol) was added DMSO (25 mL) and diisopropylethylamine (1 mL). The resulting mixture was heated with stirring at 100 o C for 12 h under N2. After cooling to 20 o C, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (90 m). The organic layer was concentrated to get crude product.
  • Step 8 To a mixture of RBRC-088-30 (1.1 g, 1.3 mmol) and diisopropylethylamine (11 mL) in toluene (15 mL) was added HSiCl3 (30 mL) at 0 o C. The reaction mixture was stirred at 115 o C for 12 h under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (10 mL) and diluted with EtOAc (60 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (20 mL).
  • Step 9 A dry 100 mL flask was charged with RBRC-088-40 (1.0 g, 1.2 mmol, 1.0 eq), toluene (20 mL) and 2-(azidomethyl) pyridine (214 mg, 1.7 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (10 mL) and 0.1 M NaOH aq.
  • Step 2 To a mixture of RBRC-122-10 (50.0 g, 362 mmol, 1.00 eq) in DMF (500 mL) was added NaH (60%, 17.4 g, 434 mmol, 1.20 eq) at 0 o C. The reaction mixture was stirred at 25 o C for 2 hours.
  • Step 3 To a mixture of RBRC-122-20 (45.0 g, 247 mmol, 1.00 eq) in Et2O (500 mL) was added n BuLi (2.5 M, 109 mL, 272 mmol, 1.10 eq) at 0 o C. The reaction mixture was stirred at 25 o C for 2 hours under N2.
  • Step 5 To a solution of RBRC-122-40 (8.60 g, 31.4 mmol, 1.00 eq) in DCM (100 mL) was added Et3N (12.7 g, 125 mmol, 4.00 eq) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (26.5 g, 94.1 mmol, 3.00 eq). The reaction mixture was warmed up to 20 o C, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 6 To a mixture of RBRC-122-50 (12.0 g, 22.3 mmol, 1.00 eq), palladium acetate (300 mg, 1.34 mmol, 0.0600 eq), dppb (950 mg, 2.23 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.1 g, 24.5 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.0 g, 89.2 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100 o C for 12 hours under N2.
  • Step 7 To a mixture of RBRC-122-60 (8.60 g, 10.6 mmol, 1.00 eq) and diisopropylethylamine (57.1 g, 422 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (21.8 g, 169 mmol, 16.0 eq) at 0 o C. The reaction mixture was stirred at 115 o C for 12 hours under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL). The resulting suspension was extracted with EtOAc (200.0 mL x 3).
  • Step 8 A dry 250 mL flask was charged with RBRC-122-70 (7.90 g, 9.90 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (1.90 g, 14.9 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (50.0 mL) and 1.0 M NaOH aq.
  • Step 9 Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IK column (5.0 cm I.D. ⁇ 25 cm L, 10 ⁇ m).
  • Step 2 To a mixture of RBRC-123-20 (41.1 g, 270 mmol, 1.00 eq) in DMF (400 mL) was added NaH (60%, 7.80 g, 324 mmol, 1.20 eq) at 0 o C. The reacction mixture was stirred at 25 o C for 2 hours. And then, the reacction mixture was added MOMBr (42.5 g, 324 mmol, 1.20 eq) at 0 o C. The resulting mixture was quenched with water (500 mL) after stir at 25 o C for 12 h. And extracted with EtOAc (500 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 3 To a mixture of RBRC-123-30 (46.1 g, 235 mmol, 1.00 eq) in Et2O (400 mL) was added n BuLi(2.5 M, 103 mL, 258 mmol, 1.10 eq) at 0 o C. The reaction mixture was stirred at 25 o C for 2 hours under N2. And then, the mixture was added FeCl3 (41.9 g, 258 mmol, 1.10 eq) at 0 o C. The supernatant Et2O was removed after stirred at 25 o C for 4 hours.
  • Step 5 To a solution of RBRC-123-50 (8.40 g, 27.8 mmol, 1.00 eq) in DCM (100 mL), was added pyridine (6.70 g, 83.7 mmol, 3.00 eq) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (19.7 g, 69.8 mmol, 2.50 eq).
  • the reaction mixture was warmed up to 20 o C and allowed to stir until full consumption of starting materials.
  • the resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3).
  • the combined organic layer was dried over with Na2SO4 and filtered.
  • Step 6 To a mixture of RBRC-123-60 (13.4 g, 23.7 mmol, 1.00 eq), palladium acetate (314 mg, 1.42 mmol, 0.0600 eq), dppb (1.10 g, 2.37 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.1 g, 26.0 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.3 g, 94.6 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100 o C for 12 hours under N2.
  • Step 7 To a mixture of RBRC-123-70 (10.8 g, 13.1 mmol, 1.00 eq) and diisopropylethylamine (67.6 g, 523 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (28.2 g, 209 mmol, 16.0 eq) at 0 o C. The reaction mixture was stirred at 115 o C for 12 hours under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL).
  • Step 8 A dry 250 mL flask was charged with RBRC-123-80 (10.2 g, 12.6 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (2.50 g, 18.9 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed.
  • Step 9 Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IK column (5.0 cm I.D. ⁇ 25 cm L, 10 ⁇ m).
  • Preparative chiral LC method for separation of (S)-RBRC-123-100 and (R)-RBRC-123-100 Stationary phase: CHIRALPAK IK (5.0 cm I.D.
  • Step 2 To a mixture of RBRC-124-20 (70.1 g, 354 mmol, 1.00 eq) in Et2O (500 mL) was added n BuLi (2.5 M, 155.6 mL, 389 mmol, 1.10 eq) at 0 o C. The reaction mixture was stirred at 25 o C for 2 hours under N2. And then, the mixture was added FeCl3 (63.0 g, 389 mmol, 1.10 eq) at 0 o C. The supernatant Et2O was removed after stirred at 25 o C for 4 hours.
  • n BuLi 2.5 M, 155.6 mL, 389 mmol, 1.10 eq
  • Step 4 To a solution of RBRC-124-40 (10.2 g, 33.3 mmol, 1.00 eq) in DCM (100 mL), was added Et3N (13.9 mL, 100 mmol, 3.00 eq) at 0 o C. The mixture was allowed to stir at 0 o C for 5 min followed by dropwise addition of Tf2O (28.2 g, 83.3 mmol, 2.50 eq). The reaction mixture was warmed up to 20 o C and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered.
  • Step 5 To a mixture of RBRC-124-50 (13.4 g, 23.5 mmol, 1.00 eq), palladium acetate (316 mg, 1.41 mmol, 0.0600 eq), dppb (1.00 g, 2.35 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.0 g, 25.9 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.1 g, 94.0 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100 o C for 12 hours under N2.
  • Step 6 To a mixture of RBRC-124-60 (16.5 g, 20.5 mmol, 1.00 eq) and diisopropylethylamine (106 g, 820 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (44.3 g, 328 mmol, 16.0 eq) at 0 o C. The reaction mixture was stirred at 115 o C for 12 hours under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL). The resulting suspension was extracted with EtOAc (200 mL x 3).
  • Step 7 A dry 250 mL flask was charged with RBRC-124-70 (15.0 g, 19.0 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (3.70 g, 28.6 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed.
  • Step 8 Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IM column (5.0 cm I.D. ⁇ 25 cm L, 10 ⁇ m)
  • Step 2 To a mixture of RBRC-118-20 (54.0 g, 98.10 mmol, 1.0 eq), palladium acetate (1.32 g, 5.88 mmol, 0.06 eq), dppb (5.5 g, 9.81 mmol, 0.1 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (46.0 g, 107.92 mmol, 1.1 eq) was added DMSO (500.0 mL) and diisopropylethylamine (68.0 mL, 392.40 mmol, 4.0 eq). The resulting mixture was heated with stirring at 100 o C for 12 hours under N 2 .
  • Step 3 To a mixture of RBRC-118-30 (42.0 g, 50.79 mmol, 1.0 eq) and diisopropylethylamine (177.0 mL, 1.02 mol, 20.0 eq) in toluene (250 mL) was added HSiCl 3 (41.0 mL, 406.32 mmol, 8.0 eq) at 0 o C. The reaction mixture was stirred at 115 o C for 12 hours under N 2 . After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (400.0 mL) and diluted with EtOAc (300.0 mL). The resulting suspension was extracted with EtOAc (300.0 mL x 3).
  • Step 4 To a solution of RBRC-118-01 (5.0 g, 35.93 mmol, 1.0 eq) in Toluene (50.0 mL) was added DBU (6.6 g, 43.12 mmol, 1.2 eq). The mixture was degassed with N 2 three times and cooled to 0 o C. The reaction was added DPPA (9.9 g, 35.93 mmol, 1.0 eq) at 0 o C and stirred at rt for 12 h.
  • DBU 6.6 g, 43.12 mmol, 1.2 eq
  • Step 5 A dry 1L flask was charged with RBRC-118-40 (8.0 g, 9.86 mmol, 1.0 eq), toluene (80.0 mL) and RBRC-118-02 (2.4 g,14.79 mmol, 1.5 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C 2 H 5 OH (30.0 mL) and 0.1 M NaOH aq. (30.0 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H 2 O (50.0 mL).
  • Step 6 The RBRC-118-50 (6.5 g, 7.97 mmol, 1.0 eq) and phenylsilane (9.8 mL, 79.70 mmol, 10.0 eq) were placed in a dry 50 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil.
  • Step 2 To a mixture of RBRC-121-20 (54.0 g, 98.10 mmol, 1.0 eq), palladium acetate (1.32 g, 5.88 mmol, 0.06 eq), dppb (5.5 g, 9.81 mmol, 0.1 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (46.0 g, 107.92 mmol, 1.1 eq) was added DMSO (500.0 mL) and diisopropylethylamine (68.0 mL, 392.40 mmol, 4.0 eq).
  • Step 3 To a mixture of RBRC-121-30 (42.0 g, 50.79 mmol, 1.0 eq) and diisopropylethylamine (177.0 mL, 1.02 mol, 20.0 eq) in toluene (250 mL) was added HSiCl 3 (41.0 mL, 406.32 mmol, 8.0 eq) at 0 o C. The reaction mixture was stirred at 115 o C for 12 hours under N2. After cooling to 20 o C, the mixture was quenched with 12 N aqueous NaOH (400.0 mL) and diluted with EtOAc (300.0 mL). The resulting suspension was extracted with EtOAc (300.0 mL x 3).
  • Step 4 A dry 1L flask was charged with RBRC-121-40 (25.0 g, 30.83 mmol, 1.0 eq), toluene (300.0 mL) and BnN3 (6.2 g, 46.25 mmol, 1.5 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C 2 H 5 OH (100.0 mL) and 0.1 M NaOH aq.
  • Step 6 The RBRC-121-60 (14.7 g, 21.18 mmol, 1.0 eq) and phenylsilane (26.1 mL, 211.80 mmol, 10.0 eq) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave the crude product RBRC-121-70 as a yellow oil (14.5 g, crude) which was used further reaction without any purification.
  • Step 7 To a solution of RBRC-121-01 (40.0 g, 260.8 mmol, 1.0 eq) in DCM (200.0 mL) was degassed with N 2 and cooled to 0 o C. The resulting mixture was added (CF 3 CO) 2 O (108.3 mL, 782.4 mmol, 3.0 eq) and stirred at 0 o C for 1 h. And then the reaction stirred at rt for 3d. The reaction was quenched with 2 N aqueous NaOH (400.0 mL) and extracted by DCM (400.0 mL x 3). The combined organic layers were washed with brine (400.0 mL), and dried over anhydrous Na2SO4 to get crude product.
  • Step 8 To a solution of RBRC-121-02 (24.9 g, 97.98 mmol, 1.0 eq) in DCM (400.0 mL) was added Dess-Martin Oxidant (54.0 g, 127.38 mmol, 1.3 eq) and stirred at rt for 16 h. Then the reaction was quenched with saturated sodium bicarbonate (400.0 mL) and extracted by DCM (400.0 mL x 3). The combined organic layers were washed with brine (400.0 mL) and dried over anhydrous Na 2 SO 4 to get crude product.
  • DCM 400.0 mL
  • Step 9 To a solution of RBRC-121-70 (15.0 g, 22.13 mmol, 1.0 eq) in DCM (150.0 mL) was added RBRC-121-03 (4.2 g, 27.61 mmol, 1.2 eq) and stirred at rt for 1 h. The reaction was added NaBH(OAc) 3 (9.4 g, 44.26 mmol, 2.0 eq) and stirred at rt for 12 h. The mixture was poured into H2O (200.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (DCM) (200.0 mL x 3).
  • DCM ethyl acetate
  • Ketone 1 (5.0 g, 19.6 mmol), DBU (298.9 mg, 1.96 mmol, S/B 10), THF (50 mL) and EtOH (40 mL) were added.
  • the autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt.
  • Table 1.1 Exp Pre-Cat / Ligand Solvent Conv 3/4/5 6 trans-6 (Scale) [area-%] [area-%] [area-%] [%ee] (trans/cis) 1.2 Ir-2 / Lig-1265 EtOH (1 g) 98.9 89/2.6/1.3 - - 1.3 Ir-2 / Lig-1252 EtOH >99.
  • the formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min.
  • the crystals were filtered and washed with ice-cold iPrOAc (10 ml) in 2 portions to afford after drying (25 °C, 10 mbar) off-white, crystalline 6 (2.9 g, 68% yield) with 99.7 area-% purity and a trans/cis ratio of 622.
  • (S,S)-6 was obtained with >99.9% ee.
  • keto enol ester 1 was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S/B 10) and the pre-catalysts / ligands (S/C 1000), 2 nd -catalysts (S/C 1000), solvents and scales as listed in Table 2.1.
  • keto enol ester 1 was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S/B 10) and the pre-catalysts / ligands (S/C 1000 for Exp.2.6-7, resp. S/C 2500 for Exp.2.8), 2 nd -catalysst (S/C 1000), solvents and scales as listed in Table 2.2.
  • the formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min.
  • the crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 °C, 10 mbar) white, crystalline 6 (10.4 g, 81% yield) with 99.1 area-% purity and a trans/cis ratio of 309. (R,R)-6 was obtained with >99.9% ee.
  • Example 6.2 Asymmetric Hydrogenation of 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (1)
  • ketone 1 (15.0 g, 58.9 mmol)
  • THF 70 mL
  • EtOH 75 mL
  • the formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min.
  • the crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 °C, 10 mbar) white, crystalline 6 (10.4 g, 81% yield) with 99.1 area-% purity and a trans/cis ratio of 309. (R,R)-6 was obtained with >99.9% ee.

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Abstract

L'invention comprend des ligands d'aminophosphine chiraux de formule I, des catalyseurs d'iridium contenant les ligands d'aminophosphine chiraux de formule I, de formule II ou III ; et l'utilisation des catalyseurs d'iridium dans l'hydrogénation asymétrique d'un composé, contenant au moins une préparation de groupe céto prochiral et la formation d'alcools chiraux.
PCT/EP2025/060836 2024-04-23 2025-04-22 Ligands d'aminophosphine chiraux, catalyseurs d'iridium comprenant ces ligands et utilisation de ces catalyseurs dans des hydrogénations asymétriques Pending WO2025224043A1 (fr)

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WO2022152769A1 (fr) 2021-01-15 2022-07-21 F. Hoffmann-La Roche Ag Procédé de préparation d'un triol chiral
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