Nothing Special   »   [go: up one dir, main page]

US20190106416A1 - Process for the preparation of propionic acid derivatives - Google Patents

Process for the preparation of propionic acid derivatives Download PDF

Info

Publication number
US20190106416A1
US20190106416A1 US16/216,214 US201816216214A US2019106416A1 US 20190106416 A1 US20190106416 A1 US 20190106416A1 US 201816216214 A US201816216214 A US 201816216214A US 2019106416 A1 US2019106416 A1 US 2019106416A1
Authority
US
United States
Prior art keywords
phenyl
tert
spirobiindane
phosphino
formula
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.)
Abandoned
Application number
US16/216,214
Inventor
Kurt Puentener
Michelangelo Scalone
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.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42110388&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20190106416(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US13/729,292 external-priority patent/US8802466B2/en
Application filed by Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Priority to US16/216,214 priority Critical patent/US20190106416A1/en
Publication of US20190106416A1 publication Critical patent/US20190106416A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is concerned with a novel process for the preparation of (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl ⁇ -propionic acid or a salt thereof.
  • the invention relates in particular to a process for the preparation of a compound of formula (I)
  • the compound of formula (I) is known in the art and is described for example in international application WO 02/092084. It is especially useful for the prophylaxis and/or treatment of diabetes mellitus type I and II.
  • the process according to the invention allows the synthesis of the compound of formula (I) with high enantiomeric excess. It can be performed in dichloromethane and the use of complex solvent mixtures can be avoided.
  • the process with the catalyst comprising iridium gives particularly high yield and high enantiomeric excess of the compound of formula (I).
  • optically pure compound of formula (I) is obtained without the use of multiple crystallization of diastereomeric salts.
  • the present invention relates to a process for the preparation of a compound of formula (I)
  • the present invention relates also to a compound of formula (I) or a salt thereof obtained using the above process.
  • catalyst refers to a complex of ruthenium or iridium respectively with a chiral ligand.
  • ruthenium is preferably characterized by the oxidation number II.
  • iridium is preferably characterized by the oxidation number I.
  • alkyl refers to a branched or straight chain monovalent alkyl radical of one to eight carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, iso-propyl, iso-butyl, n-butyl, tert-butyl and the like with methyl, tert-butyl and iso-propyl being preferred.
  • alkoxy refers to the group alkyl-O—.
  • a preferred alkoxy group is methoxy.
  • cycloalkyl refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cyclohexyl is a preferred cycloalkyl.
  • aryl relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono-, di- or tri-substituted by halogen, hydroxy, CN, CF 3 , NO 2 , NH 2 , N(H, alkyl), N(alkyl) 2 , carboxy, aminocarbonyl, alkyl, alkoxy, phenyl and/or phenyloxy.
  • Preferred substituents are halogen, alkyl, CF 3 and alkoxy, particularly alkyl, CF 3 and alkoxy.
  • heteroaryl refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl.
  • heteroaryl further refers to bicyclic aromatic groups comprising two 5- or 6-membered rings, in which one or both rings can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl.
  • a heteroaryl group may have a substitution pattern as described earlier in connection with the term “aryl”.
  • Preferred heteroaryl groups are 2-thienyl and 2-furyl. 2-Furyl is particularly preferred.
  • halide refers to a halogen atom bearing a negative charge such as fluoride, chloride, bromide and iodide.
  • pharmaceutically acceptable salts embraces salts of the compound of formula (I) with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or alkyl-substituted ammonium salts, such as e.g. trimethylammonium salts.
  • a preferred pharmaceutically acceptable salt of the compound of formula (I) is the sodium salt.
  • ⁇ 5 means eta5 as used normally in coordination chemistry. It indicates the number of electrons shared between a metal center and a ligand in a coordination compound or complex.
  • the present invention relates to a process for the preparation of a compound of formula (I)
  • a preferred process is process according to the invention wherein the catalyst comprises iridium and a compound of formula (III),
  • the catalyst comprises iridium and a compound of formula (III)
  • R 1 and R 2 are as defined above.
  • the catalyst comprises iridium and a compound of formula (X)
  • R 1 and R 2 are as defined above.
  • R 1 is hydrogen, iso-propyl, phenyl or benzyl. More preferably, R 1 is hydrogen, iso-propyl or benzyl.
  • R 2 is phenyl or phenyl substituted with one or two alkyl.
  • R 2 is phenyl, 3,5-di-methylphenyl or 3,5-di-tert-butyl-phenyl.
  • the compound of formula (IX) is (S,R,R)-1,1′-bis-[((1-N,N-dimethylamino) ethylferrocenyl)(phenylphosphino)]ferrocene.
  • a preferred compound of formula (VIII) is (S,S)-[1,3-dimethyl-1,3-propanediyl]bis[di-(3,5-dimethylphenyl)phosphine].
  • the catalyst is Ir(L 1 )(L 2 ) n Y wherein L 1 is a compound of formula (X) and wherein Ir, L 2 , Y and n are as defined above.
  • L 1 is a compound of formula (III).
  • Y is preferably chloride, tetrafluoroborate, hexafluorophosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, more preferably tetrafluoroborate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
  • the catalyst comprises ruthenium and a compound of formula (IV), (V), (VI) or (VII).
  • R 3 is tert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl or 3,5-di-methyl-phenyl.
  • R 4 is preferably alkyl, cyclohexyl, phenyl, naphthyl, furyl or phenyl substituted with one to three substituents independently selected from trifluoromethyl, alkyl and alkoxy.
  • R 4 is tert-butyl, cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl or 2-furyl is also preferred.
  • R 5 is preferably cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and alkoxy.
  • R 5 is phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl or 3,5-di-methyl-phenyl is also preferred.
  • R 6 is preferably cyclohexyl, norbornyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and trifluoromethyl.
  • R 6 is phenyl, cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl or norbornyl.
  • R 7 is preferably cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl, trifluoromethyl and alkoxy.
  • R 7 is cyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl or 2-methyl-phenyl.
  • R 8 is cyclohexyl or phenyl.
  • R 9 is cyclohexyl or phenyl is further preferred.
  • the compound of formula (II) can be hydrogenated under a pressure of hydrogen gas.
  • the process is preferably carried out at a temperature of 10 to 120° C., more preferably 40 to 100° C., particularly preferably 60 to 80° C.
  • a catalyst comprising iridium When a catalyst comprising iridium is used, the process is preferably carried out in a solvent selected from alcohols, fluorinated alcohols, tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkyl ethers, aromatic solvents such as benzene, toluene, CF 3 —C 6 H 5 , mono- and poly-fluorinated aromatic solvents and mixtures thereof, more preferred in methanol, tetrahydrofuran, dichloromethane and mixtures thereof, most preferably in methanol/tetrahydrofuran 3:2.
  • a solvent selected from alcohols, fluorinated alcohols, tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkyl ethers, aromatic solvents such as benzene, toluene, CF 3 —C 6 H 5 , mono- and poly-fluorinated aromatic solvent
  • the process is preferably carried out under a hydrogen pressure range of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
  • a hydrogen pressure range of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
  • a pressure of 10 bar preferred is a pressure of 10 bar.
  • a pressure of 30 bar preferred is a pressure of 30 bar.
  • the substrate-to-catalyst ratio (mol/mol) is preferably 10 to 50000, more preferably between 100 and 10000, particularly preferably between 1000 and 5000.
  • the process is preferably carried out at a temperature of 10 to 120° C., more preferably 20 to 80° C., particularly preferably 30 to 50° C.
  • a catalyst comprising ruthenium When a catalyst comprising ruthenium is used, the process is preferably carried out in a solvent selected from alcohols, tetrahydrofuran, dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloromethane and mixtures thereof, more preferably in a mixture dichloromethane/tetrahydrofuran 1:1 or in dichloromethane and particularly preferably in dichloromethane.
  • a solvent selected from alcohols, tetrahydrofuran, dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloromethane and mixtures thereof, more preferably in a mixture dichloromethane/tetrahydrofuran 1:1 or in dichloromethane and particularly preferably in dichlor
  • the process is preferably carried out under a hydrogen pressure of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
  • the substrate-to-catalyst ratio (mol/mol) is preferably 10 to 50000, more preferably 100 to 10000, particularly preferably 1000 to 5000.
  • the invention also relates to a compound of formula (I) as defined above or a salt thereof obtained by a process according to the invention.
  • the invention also relates to the use of a catalyst as defined above for the preparation of a compound of formula (I) as defined above.
  • the catalysts for use in the process of the present invention may be prepared by reacting a compound of formula [Ir(L)Cl] 2 , [Ir(L) 2 ]BARF or [Ir(L) 2 ]BF 4 where L denotes a neutral ligand, e.g. COD with the desired ligand of formula (III), (VIII), (IX) or (X), e.g. (S,S)-3,5-Xyl-Skewphos or (S,R,R)-TRIFER, in an appropriate solvent, such as e.g. dichloromethane or methanol.
  • the catalyst may be used after isolation or as prepared in situ.
  • the compounds [Ir(COD)Cl] 2 and [Ir + (COD) 2 ]BF 4 are either commercially available, e.g. from Strem Chemicals Inc., Newburgport, Mass. USA or can be prepared according to methods known per se, e.g. J. Herde et al., Inorg. Syn. 1974, 18-20 or M. Green et al., J. Chem. Soc. 1971, 2334-2337.
  • neutral ligand denotes a readily exchangeable ligand such as an olefin, e.g. ethylene, propylene, cyclooctene, 1,5-hexadiene, norbornadiene, 1,5-cyclooctadiene, a nitrile such as acetonitrile or benzonitrile, or also a solvent such as e.g. tetrahydrofuran, toluene etc. Where more than one such ligand is present, these can also be different from each other.
  • a preferred neutral ligand is cyclooctadiene.
  • All ferrocenyl-diphosphine ligands are commercially available from Solvias AG, CH-4002 Basel.
  • the ruthenium complexes are commercially available from Umicore AG, D-63457 Hanau-Wolfgang or can be prepared according to O. Briel et al. in “Catalysis of Organic Reactions”, 2009, 203, CRC Press, Boca Raton.
  • the oxazoline-monophosphine ligands (SIPHOX ligands) and their corresponding iridium complexes are commercially available from Nankai University, Tianjin 300071 China or can be prepared according to Q. L. Zhou et al. J. Am. Chem. Soc. 2008, 130, 8584.
  • Xyl-Skewphos and 3,5-tBu-MeOBIPHEP are commercially available from Solvias AG, CH-4002 Basel.
  • TRIFER is commercially available from Phoenix Chemicals, 34 Thursby Rod., Bromborough, Wirral CH62, 3PW, United Kingdom (UK) or can be prepared according to P. McCormack et al. Angew. Chem. Int. Ed. 2007, 46, 4141-44.
  • the (S a ,S) configuration of the SIPHOX ligand may also be noted (S,S).
  • HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150 ⁇ 4.6 mm; mobile phase A: mobile phase A: water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm.
  • HPLC method for ee determination (area-%): Chiralpak-ADH column, 25 cm ⁇ 4.6 mm, 85% heptane/10% ethanol with 0.4% trifluoroacetic acid, flow 0.7 ml/min, 30° C., 270 nm.
  • the crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of charcoal (Darko KB) at r.t. for 30 min. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp.
  • HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150 ⁇ 4.6 mm; mobile phase A: mobile phase A: water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm.
  • HPLC method for ee determination (area-%): Chiralpak-ADH column, 25 cm ⁇ 4.6 mm, 90% heptane/10% ethanol with 0.5% trifluoroacetic acid, flow 0.7 ml/min, 30° C., 270 nm.
  • Example 14 In an analogous manner to Example 14 the following hydrogenations were performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complex [Ru( ⁇ 5-2,4-DMP)((S)-(R)-2-Fur2PF-PtBu2)(NCMe)]BF4 as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl ⁇ -propionic acid (Acid I) as a white solid with a chemical purity of 99.3% (>99.9% conversion) and an enantiomeric purity of 73%.
  • ruthenium complex [Ru( ⁇ 5-2,4-DMP)((S)-(R)-2-Fur2PF-PtBu2)(NCMe)]BF4 as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phen

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

or a salt thereof.

Description

    PRIORITY TO RELATED APPLICATION(S)
  • This application is a continuation of U.S. Ser. No. 14/509,763 filed on Oct. 8, 2014, which is a continuation of U.S. Ser. No. 13/729,292 filed on Mar. 11, 2013, which is a divisional application of U.S. Ser. No. 12/725,480, filed Mar. 17, 2010, which claims the benefit of European Patent Application No. 09156074.8, filed Mar. 24, 2009, and of European Patent Application No. 09178220.1, filed Dec. 7, 2009, which are hereby incorporated by reference in their entirety.
    • FIELD OF THE INVENTION
  • The present invention is concerned with a novel process for the preparation of (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid or a salt thereof.
  • The invention relates in particular to a process for the preparation of a compound of formula (I)
  • Figure US20190106416A1-20190411-C00002
  • or a salt thereof, wherein a compound of formula (II)
  • Figure US20190106416A1-20190411-C00003
  • or a salt thereof is hydrogenated
    • (a) in the presence of a catalyst comprising iridium; or
    • (b) in the presence of a catalyst comprising ruthenium and a compound of: formula (IV),
  • Figure US20190106416A1-20190411-C00004
  • formula (V),
  • Figure US20190106416A1-20190411-C00005
  • formula (VI),
  • Figure US20190106416A1-20190411-C00006
  • or formula (VII),
  • Figure US20190106416A1-20190411-C00007
  • wherein
    • R3 is alkyl, cycloalkyl or aryl;
    • R4 is cycloalkyl, aryl or heteroaryl;
    • R5 is cycloalkyl or aryl;
    • R6 is cycloalkyl or aryl;
    • R7 is cycloalkyl or aryl;
    • R8 is cycloalkyl or aryl; and
    • R9 is cycloalkyl or aryl.
    BACKGROUND OF THE INVENTION
  • The compound of formula (I) is known in the art and is described for example in international application WO 02/092084. It is especially useful for the prophylaxis and/or treatment of diabetes mellitus type I and II.
  • The process according to the invention allows the synthesis of the compound of formula (I) with high enantiomeric excess. It can be performed in dichloromethane and the use of complex solvent mixtures can be avoided. The process with the catalyst comprising iridium gives particularly high yield and high enantiomeric excess of the compound of formula (I).
  • Furthermore, optically pure compound of formula (I) is obtained without the use of multiple crystallization of diastereomeric salts.
    • SUMMARY OF THE INVENTION
  • The present invention relates to a process for the preparation of a compound of formula (I)
  • Figure US20190106416A1-20190411-C00008
  • or a salt thereof, wherein a compound of formula (II)
  • Figure US20190106416A1-20190411-C00009
  • or a salt thereof is hydrogenated
    • (a) in the presence of a catalyst comprising iridium; or
    • (b) in the presence of a catalyst comprising ruthenium and a compound of: formula (IV),
  • Figure US20190106416A1-20190411-C00010
  • formula (V),
  • Figure US20190106416A1-20190411-C00011
  • formula (VI),
  • Figure US20190106416A1-20190411-C00012
  • or formula (VII),
  • Figure US20190106416A1-20190411-C00013
  • wherein
    • R3 is alkyl, cycloalkyl or aryl;
    • R4 is cycloalkyl, aryl or heteroaryl;
    • R5 is cycloalkyl or aryl;
    • R6 is cycloalkyl or aryl;
    • R7 is cycloalkyl or aryl;
    • R8 is cycloalkyl or aryl; and
    • R9 is cycloalkyl or aryl.
  • The present invention relates also to a compound of formula (I) or a salt thereof obtained using the above process.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The term “catalyst” refers to a complex of ruthenium or iridium respectively with a chiral ligand. In such ruthenium complexes, ruthenium is preferably characterized by the oxidation number II. In such iridium complexes, iridium is preferably characterized by the oxidation number I.
  • The term “alkyl” refers to a branched or straight chain monovalent alkyl radical of one to eight carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, iso-propyl, iso-butyl, n-butyl, tert-butyl and the like with methyl, tert-butyl and iso-propyl being preferred.
  • The term “alkoxy” refers to the group alkyl-O—. A preferred alkoxy group is methoxy.
  • The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cyclohexyl is a preferred cycloalkyl.
  • The term “aryl” relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono-, di- or tri-substituted by halogen, hydroxy, CN, CF3, NO2, NH2, N(H, alkyl), N(alkyl)2, carboxy, aminocarbonyl, alkyl, alkoxy, phenyl and/or phenyloxy. Preferred substituents are halogen, alkyl, CF3 and alkoxy, particularly alkyl, CF3 and alkoxy.
  • The term “heteroaryl” refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term “heteroaryl” further refers to bicyclic aromatic groups comprising two 5- or 6-membered rings, in which one or both rings can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term “aryl”. Preferred heteroaryl groups are 2-thienyl and 2-furyl. 2-Furyl is particularly preferred.
  • The term “halide” refers to a halogen atom bearing a negative charge such as fluoride, chloride, bromide and iodide.
  • The term “pharmaceutically acceptable salts” embraces salts of the compound of formula (I) with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or alkyl-substituted ammonium salts, such as e.g. trimethylammonium salts. A preferred pharmaceutically acceptable salt of the compound of formula (I) is the sodium salt.
  • The term “□5” means eta5 as used normally in coordination chemistry. It indicates the number of electrons shared between a metal center and a ligand in a coordination compound or complex.
  • The present invention relates to a process for the preparation of a compound of formula (I)
  • Figure US20190106416A1-20190411-C00014
  • or a salt thereof, wherein a compound of formula (II)
  • Figure US20190106416A1-20190411-C00015
  • or a salt thereof is hydrogenated
    • (c) in the presence of a catalyst comprising iridium; or
    • (d) in the presence of a catalyst comprising ruthenium and a compound of: formula (IV),
  • Figure US20190106416A1-20190411-C00016
  • formula (V),
  • Figure US20190106416A1-20190411-C00017
  • formula (VI),
  • Figure US20190106416A1-20190411-C00018
  • or formula (VII),
  • Figure US20190106416A1-20190411-C00019
  • wherein
    • R3 is alkyl, cycloalkyl or aryl;
    • R4 is cycloalkyl, aryl or heteroaryl;
    • R5 is cycloalkyl or aryl;
    • R6 is cycloalkyl or aryl;
    • R7 is cycloalkyl or aryl;
    • R8 is cycloalkyl or aryl; and
    • R9 is cycloalkyl or aryl.
  • A preferred process is process according to the invention wherein the catalyst comprises iridium and a compound of formula (III),
  • Figure US20190106416A1-20190411-C00020
  • formula (VIII),
  • Figure US20190106416A1-20190411-C00021
  • or formula (IX),
  • Figure US20190106416A1-20190411-C00022
  • wherein
    • R1 is hydrogen, alkyl, aryl or arylalkyl;
    • R2 is aryl; and
    • R10 is aryl.
  • Further preferred is a process according as defined above wherein the catalyst comprises iridium and a compound of formula (III)
  • Figure US20190106416A1-20190411-C00023
  • wherein R1 and R2 are as defined above.
  • Also particularly preferred is a process as defined above wherein the catalyst comprises iridium and a compound of formula (X)
  • Figure US20190106416A1-20190411-C00024
  • wherein R1 and R2 are as defined above.
    • R1 is preferably hydrogen, alkyl, phenyl or benzyl, more preferably hydrogen, alkyl or benzyl.
  • In particular, a process as defined above wherein R1 is hydrogen, iso-propyl, phenyl or benzyl is preferred. More preferably, R1 is hydrogen, iso-propyl or benzyl.
  • Also preferred is a process as defined above wherein R2 is phenyl or phenyl substituted with one or two alkyl.
  • Moreover, preferred is a process according to the invention wherein R2 is phenyl, 3,5-di-methylphenyl or 3,5-di-tert-butyl-phenyl.
  • A process according to the invention wherein R10 is 3,5-di-methyl-phenyl is further preferred.
  • The compound of formula (IX) is (S,R,R)-1,1′-bis-[((1-N,N-dimethylamino) ethylferrocenyl)(phenylphosphino)]ferrocene.
  • A preferred compound of formula (VIII) is (S,S)-[1,3-dimethyl-1,3-propanediyl]bis[di-(3,5-dimethylphenyl)phosphine].
  • Particularly preferred is a process according to the invention wherein the compound of formula (III) is
    • (Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1═-spirobiindane;
    • (Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;
    • (Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
    • (Sa,S)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
    • (Sa,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; or
    • (Sa)-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.
  • Further preferred is a process according to the invention wherein the compound of formula (III) is
    • (Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
    • (Sa,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; or
    • (Sa)-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.
  • Still further preferred is a process according to the invention wherein the compound of formula (X) is (Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;
    • (Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;
    • (Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
    • (Sa,R)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; or
    • (Sa,R)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane.
  • Moreover, preferred is a process as defined above wherein the catalyst is Ir(L1)(L2)nY wherein
    • Ir is iridium;
    • L1 is a compound of formula (III), (VIII) or (IX) as defined above;
    • L2 is cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene or norbornadiene;
    • Y is chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate or acetylacetonate; and
    • n is 1 or 2.
  • Also preferred is a process as defined above wherein the catalyst is Ir(L1)(L2)nY wherein L1 is a compound of formula (X) and wherein Ir, L2, Y and n are as defined above.
  • Particularly preferred is a process wherein L1 is a compound of formula (III).
  • Y is preferably chloride, tetrafluoroborate, hexafluorophosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, more preferably tetrafluoroborate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
  • In particular, preferred is a process according to the invention wherein the catalyst is
    • [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];
    • [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];
    • [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];
    • [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride];
    • [Ir((S,S)-7-[4,5-dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate]; or
    • [Ir((S)-7-[4,5-dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].
  • Further particularly preferred is a process according to the invention wherein the catalyst is
    • [Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];
    • [Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];
    • [Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate]; or
    • [Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride].
  • Also preferred is a process as defined above wherein the catalyst comprises ruthenium and a compound of formula (IV), (V), (VI) or (VII).
    • R3 is preferably alkyl, cyclohexyl, phenyl, alkylphenyl or dialkylphenyl.
  • In particular, preferred is a process as defined above wherein R3 is tert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl or 3,5-di-methyl-phenyl.
  • Moreover, R4 is preferably alkyl, cyclohexyl, phenyl, naphthyl, furyl or phenyl substituted with one to three substituents independently selected from trifluoromethyl, alkyl and alkoxy.
  • A process according to the invention wherein R4 is tert-butyl, cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl or 2-furyl is also preferred.
  • R5 is preferably cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and alkoxy.
  • Furthermore, a process according to the invention wherein R5 is phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl or 3,5-di-methyl-phenyl is also preferred.
  • R6 is preferably cyclohexyl, norbornyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and trifluoromethyl.
  • Moreover, preferred is a process as defined above wherein R6 is phenyl, cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl or norbornyl.
  • R7 is preferably cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl, trifluoromethyl and alkoxy.
  • Also preferred is a process according to the invention wherein R7 is cyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl or 2-methyl-phenyl.
  • Particularly preferred is a process according to the invention wherein R8 is cyclohexyl or phenyl.
  • A process according to the invention wherein R9 is cyclohexyl or phenyl is further preferred.
  • Furthermore, particularly preferred is a process according to the invention wherein the compound of formula (IV), (V), (VI), (VII) or (VIII) is
    • (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;
    • (S)-1-[(R)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;
    • (S)-1-[(R)-2-(Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butyl phosphine;
    • (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine;
    • (S)-1-[(R)-2-(Di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;
    • (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene;
    • (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene;
    • (R)-1-Diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene;
    • (S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethyl phenyl)phosphine;
    • (R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; or
    • (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine.
  • Moreover, further preferred is a process according to the invention wherein the compound of formula (IV), (V), (VI) or (VII) is
    • (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; or
    • (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine.
  • In particular, preferred is a process as defined above wherein the catalyst is Ru(L3)(L4)(L5)mYp wherein,
    • Ru is ruthenium;
    • L3 is a compound of formula (IV), (V), (VI) or (VII) as defined above;
    • L4 is □5-2,4-dimethylpentadienyl, cyclopentadienyl or □5-2,3,4-trimethylpenta-dienyl;
    • L5 is halide, acetonitrile, diethyl ether, water, acetone, tetrahydrofuran, dioxane, pyridine, imidazole or thiophene;
    • Y is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, hydrogen sulfate or perchlorate;
    • m is 0 or 1; and
    • p is 0 or 1.
    • L5 is preferably iodine.
    • m is preferably 1. p is preferably 1.
  • Particularly preferred is a process as defined above wherein the catalyst is
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl] ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl] ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(4-trifluoromethylphenyl) phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)] [tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl) phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)] [tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-2-furylphosphino)ferrocenyl] ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene) (acetonitrile)][tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl) phosphino]ferrocene)(acetonitrile)][tetrafluoroborate];
    • [RuI(□5-2,4-dimethylpentadienyl)((R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene)];
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(S)-2-(2′-diphenylphosphinophenyl) ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)] [tetrafluoroborate];
    • [Ru(□5-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl) ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)] [tetrafluoroborate]; or
    • [Ru(□5-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-diphenylphosphinophenyl) ferrocenyl]ethyldi-(2-norbornyl)phosphine)(acetonitrile)][tetrafluoroborate].
  • Further particularly preferred is a process according to the invention wherein the catalyst is
    • [Ru(␣5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl] ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate]; or
    • [Ru(□5-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl) phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)] [tetrafluoroborate].
  • According to the invention, the compound of formula (II) can be hydrogenated under a pressure of hydrogen gas.
  • When an iridium catalyst is used, the process is preferably carried out at a temperature of 10 to 120° C., more preferably 40 to 100° C., particularly preferably 60 to 80° C.
  • When a catalyst comprising iridium is used, the process is preferably carried out in a solvent selected from alcohols, fluorinated alcohols, tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkyl ethers, aromatic solvents such as benzene, toluene, CF3—C6H5, mono- and poly-fluorinated aromatic solvents and mixtures thereof, more preferred in methanol, tetrahydrofuran, dichloromethane and mixtures thereof, most preferably in methanol/tetrahydrofuran 3:2.
  • When a catalyst comprising iridium is used, the process is preferably carried out under a hydrogen pressure range of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar. When the ligand of formula (III) of (S,S) configuration is used, preferred is a pressure of 10 bar. When the ligand of formula (III) of (Sa,R) configuration is used, preferred is a pressure of 30 bar.
  • When a catalyst comprising iridium is used, the substrate-to-catalyst ratio (mol/mol) is preferably 10 to 50000, more preferably between 100 and 10000, particularly preferably between 1000 and 5000.
  • When a catalyst comprising ruthenium is used, the process is preferably carried out at a temperature of 10 to 120° C., more preferably 20 to 80° C., particularly preferably 30 to 50° C.
  • When a catalyst comprising ruthenium is used, the process is preferably carried out in a solvent selected from alcohols, tetrahydrofuran, dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloromethane and mixtures thereof, more preferably in a mixture dichloromethane/tetrahydrofuran 1:1 or in dichloromethane and particularly preferably in dichloromethane.
  • When a catalyst comprising ruthenium is used, the process is preferably carried out under a hydrogen pressure of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
  • When a catalyst comprising ruthenium is used, the substrate-to-catalyst ratio (mol/mol) is preferably 10 to 50000, more preferably 100 to 10000, particularly preferably 1000 to 5000.
  • The preferred (S) configuration of the compound of formula (I) has been obtained with the ligands disclosed in the tables in the experimental part. Should a chiral ligand or catalyst afford preferentially the compound of formula (I) with the (R) configuration, it is clear that the ligand or catalyst with the opposite configuration should be used in order to obtain the compound of formula (I) with the (S) configuration. Both enantiomers of the chiral ligands are equally well accessible.
  • The invention also relates to a compound of formula (I) as defined above or a salt thereof obtained by a process according to the invention.
  • Furthermore, the invention also relates to the use of a catalyst as defined above for the preparation of a compound of formula (I) as defined above.
  • The catalysts for use in the process of the present invention may be prepared by reacting a compound of formula [Ir(L)Cl]2, [Ir(L)2]BARF or [Ir(L)2]BF4 where L denotes a neutral ligand, e.g. COD with the desired ligand of formula (III), (VIII), (IX) or (X), e.g. (S,S)-3,5-Xyl-Skewphos or (S,R,R)-TRIFER, in an appropriate solvent, such as e.g. dichloromethane or methanol. The catalyst may be used after isolation or as prepared in situ. The compounds [Ir(COD)Cl]2 and [Ir+(COD)2]BF4 are either commercially available, e.g. from Strem Chemicals Inc., Newburgport, Mass. USA or can be prepared according to methods known per se, e.g. J. Herde et al., Inorg. Syn. 1974, 18-20 or M. Green et al., J. Chem. Soc. 1971, 2334-2337.
  • The term “neutral ligand” as used herein denotes a readily exchangeable ligand such as an olefin, e.g. ethylene, propylene, cyclooctene, 1,5-hexadiene, norbornadiene, 1,5-cyclooctadiene, a nitrile such as acetonitrile or benzonitrile, or also a solvent such as e.g. tetrahydrofuran, toluene etc. Where more than one such ligand is present, these can also be different from each other. A preferred neutral ligand is cyclooctadiene.
    • EXAMPLES Abbreviations
    • ␣5-2,4-DMP=␣5-2,4-dimethylpentadienyl,
    • THF=tetrahydrofuran,
    • NCMe=acetonitrile,
    • TFA=trifluoroacetic acid,
    • COD=1,5-cyclooctadiene,
    • BARF=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate,
    • r.t.=room temperature,
    • S/C=substrate-to-catalyst ratio (mol/mol),
    • HPLC=high pressure liquid chromatography,
    • ee=enantiomeric excess=[(S)−(R)]/[(S)+(R)].
    • DBT=DTB=3,5-di-tert.-butylphenyl
    • Triflate=trifluoromethanesulfonate
  • All ferrocenyl-diphosphine ligands are commercially available from Solvias AG, CH-4002 Basel. The ruthenium complexes are commercially available from Umicore AG, D-63457 Hanau-Wolfgang or can be prepared according to O. Briel et al. in “Catalysis of Organic Reactions”, 2009, 203, CRC Press, Boca Raton. The oxazoline-monophosphine ligands (SIPHOX ligands) and their corresponding iridium complexes are commercially available from Nankai University, Tianjin 300071 China or can be prepared according to Q. L. Zhou et al. J. Am. Chem. Soc. 2008, 130, 8584. Xyl-Skewphos and 3,5-tBu-MeOBIPHEP are commercially available from Solvias AG, CH-4002 Basel. TRIFER is commercially available from Phoenix Chemicals, 34 Thursby Rod., Bromborough, Wirral CH62, 3PW, United Kingdom (UK) or can be prepared according to P. McCormack et al. Angew. Chem. Int. Ed. 2007, 46, 4141-44.
  • The atom numbering of SIPHOX ligands is shown below:
  • Figure US20190106416A1-20190411-C00025
  • The asymmetric configuration of the (Sa,R) SIPHOX ligand is shown below:
  • Figure US20190106416A1-20190411-C00026
  • The (Sa,S) configuration of the SIPHOX ligand may also be noted (S,S).
    • Chiral Phosphorus Ligands
  • Acronyms Chemical Name
    Ph-Bn-SIPHOX 7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-
    diphenylphosphino-1,1′-spirobiindane
    Xyl-Bn-SIPHOX 7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-
    di-methylphenyl)phosphino-1,1′-spirobiindane
    DBT-Bn-SIPHOX 7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-
    di-tert-butylphenyl) phosphino-1,1′-
    spirobiindane
    DBT-Ph-SIPHOX 7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-
    di-tert-butylphenyl) phosphino-1,1′-
    spirobiindane
    DBT-iPr-SIPHOX 7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-
    di(3,5-di-tert-butylphenyl) phosphino-1,1′-
    spirobiindane
    DBT-H-SIPHOX 7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-
    butylphenyl)phosphino-1,1′-spirobiindane
    TRIFER 1,1′-Bis-[((1-N,N-
    dimethylamino)ethylferrocenyl)(phenylphosphi-
    no)]ferrocene
    Xyl-Skewphos [1,3-Dimethyl-1,3-propanediyl]bis[di-(3,5-
    dimethylphenyl)phosphine]
    PPF—PtBu2 1-[2-(Diphenylphosphino)ferrocenyl]
    ethyldi-tert.-butylphosphine
    Cy2PF—PtBu2 1-[2-(Dicyclohexylphosphino)ferro-cenyl]ethyl-
    di-tert.-butylphosphine
    (4-CF3Ph)2PF—PtBu2 1-[2-(Di-(4-trifluoromethylphenyl)
    phosphino)ferrocenyl]ethyldi-tert.-butyl
    phosphine
    (3,5-Me2-4- 1-[2-(Di-(3,5-dimethyl-4-methoxy
    MeOPh)2PF—PtBu2 phenyl)phosphino)ferrocenyl]ethyldi-tert.-
    butylphosphine
    2-Fur2PF—PtBu2 1-[2-(Di-2-furylphosphino)ferrocenyl]ethyldi-
    tert.-butylphosphine
    NMe2—PPh2- 2,2′-Bis(□-N,N-dimethylaminophenylmethyl)-
    Mandyphos 1,1′-bis(diphenylphosphino) ferrocene
    NMe2—P(3,5-Me-4- 2,2′-Bis(□-N,N-dimethylaminophenyl-
    MeOPh)2- methyl)-1,1′-bis[di(3,5-dimethyl-4-
    Mandyphos methoxyphenyl)-phosphino]ferrocene
    PPPhCHNMe2—F—PP 1-Diphenylphosphino-2-[□-(N,N-dimethyl-
    amino)- o-diphenylphosphinophenyl)
    methyl]ferrocene
    PPPhFCHCH3—P(3,5- 1-[2-(2′-Diphenylphosphinophenyl)
    CF3Ph)2 ferrocenyl]-ethyldi(bis-3,5-trifluoromethyl
    phenyl)phosphine
    Cy2PPhFCH 1-[2-(2′-Dicyclohexylphosphino
    CH3P(3,5- phenyl)ferrocenyl]ethyldi(bis-3,5-
    CF3Ph)2 trifluoromethylphenyl)phosphine
    PPPhFCHCH3—P(Nor- 1-[2-(2′-Diphenylphosphinophenyl)
    bornyl)2 ferrocenyl]ethyldi-(2-norbornyl)phosphine
    • Synthesis of Iridium Metal Complexes: Examples 1a-1h Example 1.a: Preparation of [Ir((S,S)-Xyl-Skewphos)(COD)]BF4
  • A 25-ml Schlenk tube was charged with 100 mg of (S,S)-Xyl-Skewphos (0.18 mmol), 60 mg of [Ir(COD)Cl]2 (0.09 mmol) and 5 ml of dichloromethane. To the formed dark red solution, 35 mg of silver tetrafluoroborate (0.18 mmol) was added in two portions and the resulting suspension was stirred for 2 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 6 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 8 ml of hexane and dried over high vacuum to afford 563 mg (85%) of [Ir((S,S)-Xyl-Skewphos)(COD)]BF4 as a red solid. FT-MS: 853.4 m/z [Ir((S,S)-Xyl-Skewphos)(COD)]+, 31P-NMR (CDCl3): 14.6 ppm (s).
    • Example 1.b: Preparation of [Ir((S,R,R)-Trifer)(COD)]BARF
  • A 100-ml Schlenk tube was charged with 400 mg of (S,R,R)-TRIFER (0.44 mmol), 584 mg of [Ir(COD)2]BARF (0.46 mmol) and 40 ml of methanol. The formed orange solution was stirred for 5 hours at r.t. Then, 12 ml of water was added and the formed crystals were filtered off. The filter cake was washed with 32 ml of a mixture of methanol/water (4:1) and dried over high vacuum to afford 804 mg (88%) of [Ir((S,R,R)-TRIFER)(COD)]BARF as orange crystals. FT-MS: 1213.2 m/z [Ir((S,R,R)-TRIFER)(COD)]+. 31P-NMR (CDCl3): 6.2 ppm (s).
    • Example 1.c: Preparation of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BARF
  • A 25-ml Schlenk tube was charged with 100 mg of (Sa,R)-DBT-Bn-SIPHOX (0.127 mmol), 168 mg of [Ir(COD)2]BARF (0.132 mmol) and 10 ml of methanol. To the formed yellow solution was stirred for 2 hours at r.t., then the reaction mixture rotary evaporated to dryness (50° C./5 mbar). The residue was dissolved in 5 ml of methanol. 0.5 ml of water was added and the formed yellow suspension was stirred for 30 min at r.t. The crystals were filtered off, washed with 3.5 ml of MeOH/water (6:1) and dried over high vacuum to afford 189 mg (76%) of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BARF as an orange solid. FT-MS: 1088.5 m/z [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.5 ppm (s).
    • Example 1.d: Preparation of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4
  • A 25-ml Schlenk tube was charged with 56 mg of (Sa,R)-DBT-Bn-SIPHOX (0.070 mmol), 24 mg of [Ir(COD)Cl]2 (0.035 mmol) and 5 ml of dichloromethane. To the formed orange solution, 14 mg of silver tetrafluoroborate (0.071 mmol) was added and the resulting orange suspension was stirred for 2 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 9 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 11 ml of hexane and dried over high vacuum to afford 69 mg (83%) of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 as an orange solid. FT-MS: 1088.5 m/z [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.6 ppm (s).
    • Example 1.e: Preparation of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]OTf
  • A 25-ml Schlenk tube was charged with 100 mg of (Ra,S)-DBT-Bn-SIPHOX (0.127 mmol), 44 mg of [Ir(COD)Cl]2 (0.505 mmol) and 4 ml of dichloromethane. To the formed orange solution, 34 mg of silver trifluoromethanesulfonate (0.130 mmol) was added and the resulting orange suspension was stirred for 2 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 6 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 11 ml of hexane and dried over high vacuum to afford 134 mg (85%) of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]OTf as an orange solid. FT-MS: 1088.5 m/z [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.6 ppm (s).
    • Example 1.f: Preparation of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF4
  • A 25-ml Schlenk tube was charged with 100 mg of (S,S)-DBT-Bn-SIPHOX (0.127 mmol), 43 mg of [Ir(COD)Cl]2 (0.063 mmol) and 5 ml of dichloromethane. To the formed orange solution, 26 mg of silver tetrafluoroborate (0.131 mmol) was added and the resulting orange suspension was stirred for 2 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 6 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 8 ml of hexane and dried over high vacuum to afford 148 mg (99%) of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF4 as an orange solid. FT-MS: 1088.5 m/z [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.0 ppm (s).
    • Example 1.g: Preparation of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF4
  • A 25-ml Schlenk tube was charged with 200 mg of (S,S)-DBT-Bn-SIPHOX (0.254 mmol), 87 mg of [Ir(COD)Cl]2 (0.128 mmol) and 5 ml of dichloromethane. To the formed orange solution, 43 mg of sodium tetrafluoroborate (0.384 mmol) was added and the resulting orange suspension was stirred for 5 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 8 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 11 ml of hexane and dried over high vacuum to afford 259 mg (87%) of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF4 as an orange solid. FT-MS: 1088.5 m/z [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.0 ppm (s).
    • Example 1.h: Preparation of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]BF4
  • A 25-ml Schlenk tube was charged with 40 mg of (Ra,S)-DBT-Bn-SIPHOX (0.058 mmol), 18 mg of [Ir(COD)Cl]2 (0.026 mmol) and 4 ml of dichloromethane. To the formed orange solution, 9 mg of sodium tetrafluoroborate (0.076 mmol) was added and the resulting orange suspension was stirred for 3 hours at r.t. The reaction mixture was filtered over dicalite speedex and the filter cake was washed with 6 ml of dichloromethane. The combined filtrates were rotary evaporated to dryness (50° C./5 mbar). The formed crude product was washed with 11 ml of hexane and dried over high vacuum to afford 51 mg (86%) of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]BF4 as an orange solid. FT-MS: 1088.5 m/z [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]+, 31P-NMR (CDCl3): 16.6 ppm (s).
    • Synthesis of 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid via asymmetric hydrogenation of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid: Examples 2-19 & Comparative Example A Example 2.1
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 35.9 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.018 mmol, S/C 250), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9% conversion) and an enantiomeric purity of 99.5%.
  • HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A: water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid; 12.4 min (E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid; 14.0 min (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid.
  • HPLC method for ee determination (area-%): Chiralpak-ADH column, 25 cm×4.6 mm, 85% heptane/10% ethanol with 0.4% trifluoroacetic acid, flow 0.7 ml/min, 30° C., 270 nm. Retention times: 22.4 min (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid; 26.3 min (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid.
    • Example 2.2
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.70 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9% conversion) and an enantiomeric purity of 99.8%. The crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of charcoal (Darko KB) at r.t. for 2 h. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) and allowed to cool to room temperature whereby crystallization started spontaneously. The formed crystals were filtered off, washed with 10 ml of isopropyl acetate and dried at 75° C./500 mbar for 4 h to yield 1.60 g (79%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white crystals with a chemical purity of 99.6% and an enantiomeric purity of 99.8% ee.
    • Examples 3.1-3.4
  • In an analogous manner to Example 2 the following hydrogenations were performed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) using iridium complexes of general formula [Ir(Phosphorous Ligand)(COD)]BARF as catalysts to afford crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as listed in Table 1.
  • TABLE 1
    Acid I Acid I
    Exp. Conv. Purity Ee [%]/
    No. Phosphorus Ligand [%] [%] Configuration
    3.1 (S,S)-Xyl-Bn-SIPHOX 99.8 97.6 88.9/S
    3.2 (S,S)-DBT-Ph-SIPHOX 99.9 99.4 98.0/S
    3.3 (S,S)-DBT-iPr-SIPHOX >99.9 99.3 99.3/S
    3.4 (S)-DBT-H-SIPHOX >99.9 98.3 99.3/S
    • Example 4
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 8.96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0046 mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.2% (99.8% conversion) and an enantiomeric purity of 99.3%.
    • Examples 5.1-5.2
  • In an analogous manner to Example 4 the following hydrogenations were performed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) using iridium complexes of general formula [Ir(Phosphorus Ligand)(COD)]BARF as catalysts to afford crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as listed in Table 2.
  • TABLE 2
    Acid I Acid I
    Exp. Conv. Purity Ee [%]/
    No. Phosphorus Ligand [%] [%] Configuration
    5.1 (S,S)-DBT-iPr-SIPHOX 99.9 99.5 98.7/S
    5.2 (S)-DBT-H-SIPHOX 99.9 98.1 99.3/S
    • Example 6.1
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 4.48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9% conversion) and an enantiomeric purity of 99.4%.
    • Example 6.2
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 4.48 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.0% (>99.9% conversion) and an enantiomeric purity of 99.8%.
    • Example 7
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 8.96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0046 mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 8 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford 2.24 g of the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9% conversion) and an enantiomeric purity of 99.2%. The crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of charcoal (Darko KB) at r.t. for 30 min. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) and allowed to cool to room temperature whereby crystallization started spontaneously. The formed crystals were filtered off, washed with 10 ml of isopropyl acetate and dried at 60° C./10 mbar for 2 h to yield 1.40 g (70%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white crystals with a chemical purity of 99.8% and an enantiomeric purity of >99.9% ee.
    • Example 8.1
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 4.48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 10 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.9% (>99.9% conversion) and an enantiomeric purity of 99.6%.
    • Example 8.2
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 5.40 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0046 mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 10 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.7% (91.1% conversion) and an enantiomeric purity of 99.8%.
    • Example 8.3
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.84 mg of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]OTf (0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.7% (99.7% conversion) and an enantiomeric purity of 99.8%.
    • Example 8.4
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 1.80 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0015 mmol, S/C 3′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 60 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.3% (99.4% conversion) and an enantiomeric purity of 99.7%.
    • Example 8.5
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 0.77 mg of [Ir(COD)Cl]2 (0.0012 mmol, S/C 2′000), 1.81 mg of (Ra,S)-DBT-Bn-SIPHOX (0.0023 mmol) and 10 ml of tetrahydrofuran. The formed yellow solution was stirred for 30 min at ambient temperature. Then 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 24 ml of methanol, 6 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol) were added. The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.5% (>99.9% conversion) and an enantiomeric purity of 99.5%.
    • Example 8.6
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 1.14 mg of [Ir(COD)2]BF4 (0.0023 mmol, S/C 2′000), 1.99 mg of (Ra,S)-DBT-Bn-SIPHOX (0.0025 mmol) and 10 ml of tetrahydrofuran. The formed yellow solution was stirred for 30 min at ambient temperature. Then 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 24 ml of methanol, 6 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol) were added. The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.7% (>99.9% conversion) and an enantiomeric purity of 99.6%.
    • Example 8.7
  • In a glove box (O2 content ≤2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 1.80 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0015 mmol, S/C 3′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 80° C. for 22 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 96.7% (99.9% conversion) and an enantiomeric purity of 99.5%.
    • Example 9
  • In an analogous manner to Example 4 the following hydrogenation was performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using [Ir((S,S)-Xyl-Skewphos)(COD)]BF4 (S/C 1′000) as catalysts to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.8% (99.4% conversion) and an enantiomeric purity of 85%.
    • Example 10
  • In an analogous manner to Example 2 the following hydrogenation was performed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) using [Ir((S,R,R)-Trifer)(COD)]BARF (S/C 250) as catalysts to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.0% (>99.9% conversion) and an enantiomeric purity of 86%.
    • Example 11
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol),1.99 mg of [Ru(□5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1′000), 12 ml of methanol, 8 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol). The autoclave was sealed and the hydrogenation was run at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9% conversion) and an enantiomeric purity of 89%.
  • HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A: water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid; 12.4 min (E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid; 14.0 min (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid.
  • HPLC method for ee determination (area-%): Chiralpak-ADH column, 25 cm×4.6 mm, 90% heptane/10% ethanol with 0.5% trifluoroacetic acid, flow 0.7 ml/min, 30° C., 270 nm. Retention times: 22.1 min (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid; 26.0 min (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid.
    • Examples 12.1-12.5
  • In an analogous manner to Example 11 the following hydrogenations were performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complexes of general formula [Ru(□5-2,4-DMP)(Phosphorous Ligand)(NCMe)]BF4 as catalysts to afford crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as listed in Table 3.
  • TABLE 3
    Acid I
    Acid I Ee [%]/
    Exp. Conv. Purity Config-
    No. Phosphorus Ligand [%] [%] uration
    12.1 (R)—(R)—PPPhFCHCH3—P(Nor- >99.9 97.1 69/S
    bornyl)2
    12.2 (R)—(R)-Cy2PPhFCH—CH3P(3,5- >99.9 99.4 79/S
    CF3Ph)2
    12.3 (R)—(S)—NMe2—PPh2- 99.6 99.1 69/S
    Mandyphos
    12.4 (R)—(S)—NMe2—P(3,5-Me-4- 99.3 98.8 70/S
    MeOPh)2-Mandyphos
    12.5 (R)—(R)—PPPhFCHCH3—P(3,5- >99.9 99.6 58/R
    CF3Ph)2
    • Example 13
  • In an analogous manner to Example 11 the following hydrogenations were performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complex [RuI(□5-2,4-DMP)((S)-(R)-PPPhCHNMe2F-PP)] as catalysts to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.7% (99.2% conversion) and an enantiomeric purity of 46%.
    • Example 14
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 2.26 mg of [Ru(□5-2,4-DMP)((S)-(R)-(3,5-Me2-4-MeOPh)2PF-PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1′000) and 6 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-y}-acrylic acid (2.30 mmol), 4 ml of dichloromethane, 10 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (>99.9% conversion) and an enantiomeric purity of 87%.
    • Example 15
  • In an analogous manner to Example 14 the following hydrogenations were performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complex [Ru(□5-2,4-DMP)((S)-(R)-2-Fur2PF-PtBu2)(NCMe)]BF4 as catalysts to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.3% (>99.9% conversion) and an enantiomeric purity of 73%.
    • Example 16
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 1.99 mg of [Ru(□5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1′000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9% conversion) and an enantiomeric purity of 90%.
    • Examples 17.1-17.2
  • In an analogous manner to Example 16 the following hydrogenations were performed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complexes of general formula [Ru(□5-2,4-DMP)(Phosphorus Ligand)(NCMe)]BF4 as catalysts to afford crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as listed in Table 4.
  • TABLE 4
    Acid I
    Acid I Ee [%]/
    Exp. Conv. Purity Config-
    No. Phosphorus Ligand [%] [%] uration
    17.1 (S)—(R)-Cy2PF—PtBu2 98.7 98.6 74/S
    17.2 (S)—(R)-(4-CF3Ph)2PF—PtBu2 99.9 99.6 84/S
    • Example 18
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(□5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3′000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 89%.
    • Example 19
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(□5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3′000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 10 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 90%.
    • Comparative Example A
  • In a glove box (O2 content ≤2 ppm), a 50-ml stainless steel autoclave was charged with 0.62 mg of [Ru(OAc)2((S)-TMBTP)] (0.0008 mmol, S/C 3′000) (prepared according to EP 1,670,792 B1; TMBTP=2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene) and 5 ml of methanol. The resulting orange solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of methanol, 6 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.7% (99.9% conversion) and an enantiomeric purity of 89%.

Claims (20)

1. A process for the preparation of a compound of formula (I)
Figure US20190106416A1-20190411-C00027
or a salt thereof, wherein a compound of formula (II)
Figure US20190106416A1-20190411-C00028
or a salt thereof is hydrogenated
(e) in the presence of a catalyst comprising iridium; or
(f) in the presence of a catalyst comprising ruthenium; and
a compound of: formula (III),
Figure US20190106416A1-20190411-C00029
formula (IV),
Figure US20190106416A1-20190411-C00030
formula (V),
Figure US20190106416A1-20190411-C00031
formula (VI),
Figure US20190106416A1-20190411-C00032
or formula (VII),
Figure US20190106416A1-20190411-C00033
wherein
R3 is alkyl, cycloalkyl or aryl;
R4 is cycloalkyl, aryl or heteroaryl;
R5 is cycloalkyl or aryl;
R6 is cycloalkyl or aryl;
R7 is cycloalkyl or aryl;
R8 is cycloalkyl or aryl; and
R9 is cycloalkyl or aryl.
2. A process according to claim 1, wherein the catalyst comprises iridium and a compound of formula (III),
Figure US20190106416A1-20190411-C00034
formula (VIII),
Figure US20190106416A1-20190411-C00035
or formula (IX),
Figure US20190106416A1-20190411-C00036
wherein
R1 is selected from the group consisting of: hydrogen, alkyl, aryl and arylalkyl;
R2 is aryl; and
R10 is aryl.
3. A process according to claim 2, wherein the catalyst comprises iridium and a compound of formula (III)
Figure US20190106416A1-20190411-C00037
4. A process according to claim 1, wherein the catalyst comprises iridium and a compound of formula (X)
Figure US20190106416A1-20190411-C00038
wherein:
R1 is selected from the group consisting of: hydrogen, alkyl, aryl and arylalkyl; and
R2 is aryl.
5. A process according to claim 2, wherein R1 is selected from the group consisting of: hydrogen, iso-propyl, phenyl and benzyl.
6. A process according to claim 2, wherein R2 is selected from the group consisting of: phenyl, 3,5-di-methylphenyl and 3,5-di-tert-butyl-phenyl.
7. A process according to claim 2, wherein R10 is 3,5-di-methyl-phenyl.
8. A process according to claim 2, wherein the compound of formula (III) is selected from the group consisting of:
(Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;
(Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;
(Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
(Sa,S)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
(Sa,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; and
(Sa)-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.
9. A process according to claim 2, wherein the compound of formula (III) is selected from the group consisting of:
(Sa,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
(Sa,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; and
(Sa)-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.
10. A process according to claim 4, wherein the compound of formula (X) is selected from the group consisting of:
(Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;
(Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;
(Sa,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane;
(Sa,R)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane; and
(Sa,R)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane.
11. A process according to claim 2, wherein the catalyst is Ir(L1)(L2)nY wherein:
Ir is iridium;
L1 is a compound of formula (III), (VIII) or (IX);
L2 is selected from the group consisting of: cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene and norbornadiene;
Y is selected from the group consisting of: chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate and acetylacetonate; and
n is 1 or 2.
12. A process according to claim 4 wherein the catalyst is Ir(L1)(L2)nY wherein:
Ir is iridium;
L1 is a compound of formula (X);
L2 is selected from the group consisting of: cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene and norbornadiene;
Y is selected from the group consisting of: chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate and acetylacetonate; and
n is 1 or 2.
13. A process according to claim 1, wherein the catalyst is selected from the group consisting of:
[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];
[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];
[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];
[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride];
[Ir((S,S)-7-[4,5-dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate]; and
[Ir((S)-7-[4,5-dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl) phenyl]borate].
14. A process according to claim 12, wherein the catalyst is selected from the group consisting of:
[Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];
[Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];
[Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate]; and
[Ir((Sa,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl) phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride].
15. A process according to claim 1, wherein the catalyst comprises ruthenium and a compound of formula (IV), (V), (VI) or (VII).
16. A process according to claim 1, wherein R3 is selected from the group consisting of: tert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl and 3,5-di-methyl-phenyl.
17. A process according to claim 1, wherein R4 is selected from the group consisting of: tert-butyl, cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl and 2-furyl.
18. A process according to claim 1, wherein R5 is selected from the group consisting of: phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl and 3,5-di-methyl-phenyl.
19. A process according to claim 1, wherein R6 is selected from the group consisting of: phenyl, cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl and norbornyl.
20. A process according to claim 1, wherein R7 is selected from the group consisting of: cyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl and 2-methyl-phenyl.
US16/216,214 2009-03-24 2018-12-11 Process for the preparation of propionic acid derivatives Abandoned US20190106416A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/216,214 US20190106416A1 (en) 2009-03-24 2018-12-11 Process for the preparation of propionic acid derivatives

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
EP09156074 2009-03-24
EP09156074.8 2009-03-24
EP09178220.1 2009-12-07
EP09178220 2009-12-07
US12/725,480 US8450496B2 (en) 2009-03-24 2010-03-17 Process for the preparation of propionic acid derivatives
US13/729,292 US8802466B2 (en) 2012-06-07 2012-12-28 Method for making light emitting diode
US14/509,763 US20150025249A1 (en) 2009-03-24 2014-10-08 Process for the preparation of propionic acid derivatives
US16/216,214 US20190106416A1 (en) 2009-03-24 2018-12-11 Process for the preparation of propionic acid derivatives

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US14/509,763 Continuation US20150025249A1 (en) 2009-03-24 2014-10-08 Process for the preparation of propionic acid derivatives

Publications (1)

Publication Number Publication Date
US20190106416A1 true US20190106416A1 (en) 2019-04-11

Family

ID=42110388

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/725,480 Expired - Fee Related US8450496B2 (en) 2009-03-24 2010-03-17 Process for the preparation of propionic acid derivatives
US13/792,292 Abandoned US20130184468A1 (en) 2009-03-24 2013-03-11 Process for the preparation of propionic acid derivatives
US14/509,763 Abandoned US20150025249A1 (en) 2009-03-24 2014-10-08 Process for the preparation of propionic acid derivatives
US16/216,214 Abandoned US20190106416A1 (en) 2009-03-24 2018-12-11 Process for the preparation of propionic acid derivatives

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US12/725,480 Expired - Fee Related US8450496B2 (en) 2009-03-24 2010-03-17 Process for the preparation of propionic acid derivatives
US13/792,292 Abandoned US20130184468A1 (en) 2009-03-24 2013-03-11 Process for the preparation of propionic acid derivatives
US14/509,763 Abandoned US20150025249A1 (en) 2009-03-24 2014-10-08 Process for the preparation of propionic acid derivatives

Country Status (23)

Country Link
US (4) US8450496B2 (en)
EP (1) EP2411385B1 (en)
JP (1) JP5479572B2 (en)
KR (1) KR101368501B1 (en)
CN (1) CN102361866B (en)
AR (1) AR075915A1 (en)
AU (1) AU2010227650B2 (en)
BR (1) BRPI1013871A2 (en)
CA (1) CA2754103C (en)
CL (1) CL2011002345A1 (en)
DK (1) DK2411385T3 (en)
ES (1) ES2548502T3 (en)
HK (1) HK1166065A1 (en)
IL (1) IL214849A (en)
MX (1) MX2011009898A (en)
PE (1) PE20120643A1 (en)
PL (1) PL2411385T3 (en)
RU (1) RU2544989C2 (en)
SG (1) SG174536A1 (en)
SI (1) SI2411385T1 (en)
TW (1) TWI415848B (en)
WO (1) WO2010108861A1 (en)
ZA (1) ZA201106628B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021156333A1 (en) 2020-02-05 2021-08-12 Sonova Ag Acoustic device with sma microspring switch
US11463803B2 (en) 2020-01-22 2022-10-04 Sonova Ag Acoustic device with deformable shape as valve

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8450496B2 (en) 2009-03-24 2013-05-28 Hoffman-La Roche Inc. Process for the preparation of propionic acid derivatives
MY181791A (en) * 2009-12-07 2021-01-07 Hoffmann La Roche Process for the preparation of propionic acid derivatives
WO2013181384A1 (en) 2012-05-31 2013-12-05 Ratiopharm Gmbh Solid state forms of aleglitazar sodium
BR112015005350A2 (en) * 2012-09-12 2017-07-04 Hoffmann La Roche solid forms of (2) -2-methoxy-3- {4- [2- (5-methyl-2-phenyloxazol-4-yl) -ethoxy] -benzo [b] thiophen-7-yl} -propionic acid and / or salts thereof
EP3118192A4 (en) * 2014-03-14 2017-12-13 Takeda Pharmaceutical Company Limited Process for producing heterocyclic compound
CN106582852B (en) * 2016-12-09 2019-04-05 黑龙江省科学院石油化学研究院 A kind of preparation method of double phosphine-rhodium (I) chiral catalysts of ferrocene

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564406B1 (en) 1992-04-02 1999-05-06 Novartis AG Ferrocenyldiphosphine as ligands for homogeneous catalysts
SG42938A1 (en) * 1993-02-26 1997-10-17 Ciba Geigy Ag Ferrocenc diphosphines as ligands for homogeneous catalysts
ME01310B (en) 2001-05-15 2011-10-10 Hoffmann La Roche Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes
ES2271886T3 (en) * 2003-05-09 2007-04-16 UMICORE AG & CO. KG FERROCENILDIFOSFINAS REPLACED AS LIGANDOS FOR HOMOGENEOS HYDROGENATION CATALYSTS.
US7262303B2 (en) 2003-09-29 2007-08-28 Hoffman-La Roche Inc. Process for the production of chiral propionic acid derivatives
GB0500700D0 (en) * 2005-01-14 2005-02-23 Stylacats Ltd Process for the manufacture of 2-alkyl-3-phenylpropionic acids and alcohols
CN100432083C (en) * 2006-07-11 2008-11-12 南开大学 Phosphorus-oxazoline ligand with spiro backbone and its uses in asymmetrical catalytic hydrogenation
EP1939182A1 (en) * 2006-12-22 2008-07-02 Speedel Experimenta AG Process for the preparation of (R or S)-2-Alkyl-3-heterocyclyl-1-propanols
JP2010519272A (en) * 2007-02-20 2010-06-03 ソルヴィーアス アクチェンゲゼルシャフト Bis (ferrocenylphosphino) ferrocene ligand used in asymmetric hydrogenation reaction
AR070176A1 (en) * 2008-01-17 2010-03-17 Novartis Ag SYNTHESIS PROCESSES OF NEP INHIBITORS, INTERMEDIATE COMPOUNDS AND USE OF THE SAME IN SYNTHESIS
CN101565434B (en) * 2008-04-25 2012-05-30 浙江九洲药业股份有限公司 Spiro phosphine-oxazoline and preparation method and application thereof
US8450496B2 (en) 2009-03-24 2013-05-28 Hoffman-La Roche Inc. Process for the preparation of propionic acid derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11463803B2 (en) 2020-01-22 2022-10-04 Sonova Ag Acoustic device with deformable shape as valve
WO2021156333A1 (en) 2020-02-05 2021-08-12 Sonova Ag Acoustic device with sma microspring switch

Also Published As

Publication number Publication date
MX2011009898A (en) 2011-09-30
SG174536A1 (en) 2011-10-28
US8450496B2 (en) 2013-05-28
IL214849A (en) 2015-10-29
TW201036963A (en) 2010-10-16
ZA201106628B (en) 2012-05-30
KR20110130500A (en) 2011-12-05
CA2754103A1 (en) 2010-09-30
EP2411385A1 (en) 2012-02-01
RU2011142614A (en) 2013-04-27
US20150025249A1 (en) 2015-01-22
HK1166065A1 (en) 2012-10-19
US20130184468A1 (en) 2013-07-18
AU2010227650A1 (en) 2011-09-22
CN102361866B (en) 2015-03-25
BRPI1013871A2 (en) 2015-08-25
CN102361866A (en) 2012-02-22
WO2010108861A1 (en) 2010-09-30
SI2411385T1 (en) 2015-10-30
KR101368501B1 (en) 2014-02-27
ES2548502T3 (en) 2015-10-19
AU2010227650B2 (en) 2015-06-04
CL2011002345A1 (en) 2012-03-30
JP5479572B2 (en) 2014-04-23
DK2411385T3 (en) 2015-08-17
AR075915A1 (en) 2011-05-04
JP2012521385A (en) 2012-09-13
PE20120643A1 (en) 2012-05-31
TWI415848B (en) 2013-11-21
US20100249428A1 (en) 2010-09-30
EP2411385B1 (en) 2015-08-05
CA2754103C (en) 2017-07-11
IL214849A0 (en) 2011-11-30
RU2544989C2 (en) 2015-03-20
PL2411385T3 (en) 2016-01-29

Similar Documents

Publication Publication Date Title
US20190106416A1 (en) Process for the preparation of propionic acid derivatives
AU2024202897A1 (en) Manufacture of compounds and compositions for inhibiting the activity of shp2
JP6657121B2 (en) Complex
WO2015191505A1 (en) Polydentate ligands and their complexes for molecular catalysis
EP1670792B1 (en) Process for the preparation of chiral propionic acid derivatives
CA3065683A1 (en) Method for producing optically active compound
EP2585452B1 (en) Process for the preparation of propionic acid derivatives
RU2575345C2 (en) Method for obtaining propionic acid derivatives
CA2732656A1 (en) Process for the preparation of propionic acid derivatives
JP5232374B2 (en) Method for producing optically active quinuclidinols having a substituent at the 2-position
Weber et al. Stille Cross‐Coupling of a Racemic Planar‐Chiral Ferrocene and Crystallographic Trace Analysis of Catalysis Intermediates and By‐products
CN113200939A (en) Bis (1, 3-thiazole) amine and preparation method thereof
EP1778627A1 (en) Method for producing enantiomeric form of 2, 3-diaminopropionic acid derivatives
Serre Synthesis of new N-heterocyclic carbene metal complexes
Sormunen Nickel-Catalyzed Reductive Couplings of Aldehydes and Alkynes: Controlling Stereochemistry and Regioselectivity using N-Heterocyclic Carbene Ligands.

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION