US10385004B2 - Process and intermediates for the preparation of NEP inhibitors - Google Patents

Process and intermediates for the preparation of NEP inhibitors Download PDF

Info

Publication number
US10385004B2
US10385004B2 US15/550,224 US201615550224A US10385004B2 US 10385004 B2 US10385004 B2 US 10385004B2 US 201615550224 A US201615550224 A US 201615550224A US 10385004 B2 US10385004 B2 US 10385004B2
Authority
US
United States
Prior art keywords
formula
compound
alkyl
acid
nmr
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.)
Active
Application number
US15/550,224
Other languages
English (en)
Other versions
US20180022690A1 (en
Inventor
Benjamin Martin
Francesca MANDRELLI
Francesco VENTURONI
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.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MANDRELLI, Francesca, MARTIN, BENJAMIN, VENTURONI, Francesco
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Publication of US20180022690A1 publication Critical patent/US20180022690A1/en
Application granted granted Critical
Publication of US10385004B2 publication Critical patent/US10385004B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/10—Preparation of nitro compounds by substitution of functional groups by nitro groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0241—Imines or enamines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0249—Ureas (R2N-C(=O)-NR2)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0251—Guanidides (R2N-C(=NR)-NR2)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0255—Phosphorus containing compounds
    • B01J31/0264—Phosphorus acid amides
    • B01J31/0265—Phosphazenes, oligomers thereof or the corresponding phosphazenium salts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0255—Phosphorus containing compounds
    • B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/01—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms
    • C07C205/03—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C205/04—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/44—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C205/51—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5355—Phosphoranes containing the structure P=N-
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a new chemical synthesis route and intermediates useful for the preparation of neprilysin (NEP) inhibitors and their prodrugs, in particular for the NEP inhibitor prodrug sacubitril.
  • NEP neprilysin
  • NEP inhibitor prodrug sacubitril N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester; IUPAC name 4- ⁇ [(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino ⁇ -4-oxobutanoic acid) is represented by the following formula (A)
  • Sacubitril together with valsartan a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex, known as LCZ696, comprising the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1:1:3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal), and which is schematically present in formula (B).
  • ARB angiotensin receptor blocker
  • Said complex is also referred to by the following chemical names: Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl ⁇ 2′′-(tetrazol-5-ylate)biphenyl-4′-ylmethyl ⁇ amino)butyrate] hemipentahydrate or Octadecasodium hexakis(4- ⁇ [(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino ⁇ -4-oxobutanoate) hexakis(N-pentanoyl-N- ⁇ [2′-(1H-tetrazol-1-id-5-yl)[1,1′-biphenyl]-4-yl]methyl
  • LCZ696 acts as angiotensin receptor neprilysin inhibitor (ARNI) and is therefore useful particularly in the treatment of hypertention or chronic heart failure. Its utility has been confirmed by clinical trials, e.g. in the landmark PARADIGM-HF trial.
  • ARNI angiotensin receptor neprilysin inhibitor
  • the invention relates to novel intermediates and process steps and processes for the manufacture of a compound (1), especially (1-a) represented below, and its further use in the manufacture of sacubitril.
  • the present invention provides the following new compounds:
  • R1 is hydrogen or C 1 -C 6 -alkyl.
  • the compound of the formula (1) is represented by formula (1-a) with the following stereochemistry
  • R 1 is hydrogen or C 1 -C 6 -alkyl, preferably ethyl.
  • the compound of the formula (2) is represented by formula (2-a) with the following stereochemistry
  • the present invention provides a new process for the manufacture of the compound of the formula (8), in particular of formula (8-a), or a salt thereof, as defined herein.
  • This process comprises several steps via novel intermediate compounds and is depicted in the following Schemes 1 to 5, respectively, wherein the process depicted in each SCHEME 1-4 represents a separate embodiment of the invention.
  • SCHEME 1 and SCHEME 1-a depict the process comprising hydrogenation of the novel intermediate compound of formula (1), preferably of formula (1-a), wherein R1 is hydrogen or C 1 -C 6 -alkyl, preferably ethyl, into a compound of formula (8), preferably of formula (8-a), wherein R′ and R′′ are independently of each other hydrogen or a nitrogen protecting group, preferably tert-butyloxycarbonyl, and R1 is hydrogen or C 1 -C 6 -alkyl, especially ethyl.
  • the compound of formula (1) can be obtained according to the following SCHEMES:
  • SCHEME 2 and SCHEME 2-a both depict a process comprising oxidising a compound of the formula (2), preferably of the formula (2-a), preferably under Pinnick oxidation conditions, to obtain a compound of formula (1), preferably of formula (1-a), wherein R1 is hydrogen or C 1 -C 6 -alkyl, preferably ethyl.
  • this can include (i) converting a free compound of the formula (1), preferably of formula (1-a), into its salt, (ii) converting a salt of the compound of the formula (1), preferably of formula (1a), into the free compound; or (iii) converting a salt of a compound of formula (1), preferably of formula (1a), into a different salt thereof; or (simultaneously or separately) esterifiying a compound of formula (1), preferably of formula (1-a), wherein R1 is hydrogen, or a salt or a reactive acid derivative thereof, with a C 1 -C 6 -aliphatic alcohol, especially ethanol, to yield the compound wherein R1 is C 1 -C 6 -alkyl, especially ethyl.
  • the compound of formula (2) can be obtained according to the following SCHEMES:
  • SCHEME 3-1 and SCHEME 3-1a depict a process for the manufacture of a compound of the formula (2), preferably of formula (2-a), said process comprising reacting a compound of formula (3) with methacroleine or a reactive derivative thereof in the presence of an organocatalyst for a Michael reaction.
  • the compound of formula (2) can be obtained according to the following SCHEMES:
  • SCHEME 3-2 and SCHEME 3-2a depict a process for the manufacture of a compound of formula (2), preferably of formula (2-a), said process comprising reacting a compound of formula (7) with propionaldehyde or a reactive derivative thereof in the presence of an organocatalyst for Michael reaction.
  • SCHEME 4 depicts a process for the manufacture of a compound of formula (7) comprising reacting a compound of formula (3) with formaldehyde or a reactive derivative thereof.
  • the compound of formula (3) is obtained according to the following SCHEME:
  • SCHEME 5 depicts a process for the manufacture of a compound of formula (3) said process comprising (a) reacting an aldehyde of formula (6) with nitromethane which leads to the compound of formula (5) or to a mixture of the compounds of formulae (4) and (5), (b) converting the obtained compound of formula (5) into a compound of formula (4) by reacting it with a dehydrating agent, such as an acid anhydride, and (c) hydrogenating the compound of formula (4) or the compound of formula (5) or the mixture of the compounds of formulae (4) and (5), preferably in the presence of a complex hydride, capable of selectively reducing the double bond, to obtain the compound of formula (3).
  • a dehydrating agent such as an acid anhydride
  • the Michael reaction (addition) depicted in SCHEMES 3-1 and 3-2 is performed in the presence of an organocatalyst for Michael reaction, preferably a prolinol and/or thiourea organocatalyst, in particular—then especially for chirally selective synthesis—a chiral prolinol or thiourea organocatalyst.
  • an organocatalyst for Michael reaction preferably a prolinol and/or thiourea organocatalyst, in particular—then especially for chirally selective synthesis—a chiral prolinol or thiourea organocatalyst.
  • the catalyst is of one of the formulae (I), (II), (III) or (IV)
  • Ra is C 6 -C 10 -aryl, a heterocyclic group or C 1 -C 6 -alkyl optionally substituted with C 6 -C 10 -aryl or a heterocyclic group;
  • Rb and Rc together with the two connecting carbon atoms and the attached nitrogen groups form a chiral scaffold, wherein (i) Rb and Rc together with the two connecting carbon atoms form a 5-10 membered ring system which is mono or bicyclic and can be saturated, partially unsaturated or unsaturated, or (ii) Rb and Rc are each independently selected from hydrogen, C 1 -C 7 -alkyl, C 6 -C 10 -aryl and a heterocyclic group, and Rd and Re are independently selected from hydrogen, C 6 -C 10 -aryl, a heterocyclic group, and C 1 -C 6 -alkyl optionally substituted with one, two or three substituents selected from halogen, hydroxyl, amino, C 6 -C 10
  • Rb is selected from hydrogen, C 1 -C 7 -alkyl, C 6 -C 10 -aryl and a heterocyclic group; and Rc together with the connecting carbon atom and the group —N(Rd)(Re) forms a fused bicyclic 7-9 membered ring system which is optionally substituted with C 1 -C 7 -alkyl or C 2 -C 7 -alkenyl; wherein each heterocyclic group is a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O) or S(O) 2 , and wherein each C 6 -C 10 -aryl or heterocyclic group is optionally substituted by one, two or three residues selected from the group consisting of C 1 -C 7 -alkyl, hydroxyl, oxo, C 1 -C 7 -alkoxy, C 2 -C 8 -alkanoyl-oxy
  • Rb is a quinolone, and wherein for all formulas Ra is a group
  • the present invention provides new organocatalysts suitable for the manufacture of a compound of formula (2) via Michael addition, as well as to processes for their synthesis as described in the Examples or in analogy thereto, which organocatalysts are selected from the group consisting of compounds with the following formulae:
  • the catalyst to be used in the process of the invention is selected from the group consisting of those with the following formulae:
  • the present invention provides the use of a novel compound of formula (1), (1-a), (2), (2-a) or (7) as depicted above in the manufacture of a compound of formula (10)
  • R1 is hydrogen or C 1 -C 6 -alkyl, preferably ethyl, preferably in the manufacture of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid, or salts thereof, or N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salts thereof.
  • the invention relates to any one or more of the novel compounds, processes and catalysts represented in the claims which are incorporated here by reference.
  • the invention also relates to any sequential combination of the process steps described above and below.
  • the synthesis route is suitable for industrial scale processing.
  • the synthesis route is economically and environmentally favourable.
  • the compound of formula (1-a) which is an intermediate desired for the synthesis of sacubitril is produced with in high yield and high stereoselectivity.
  • the compounds of the formula (1) and (2) are a mixture of compounds with configurations R,R; R,S; S,R and SS, or pure enantiomers/diastereomers, especially of the formula (1-a) or (2-a).
  • nitrogen protecting group comprises any group which is capable of reversibly protecting a nitrogen functionality, preferably an amine and/or amide functionality.
  • the nitrogen protecting group is an amine protecting group and/or an amide protecting group.
  • Suitable nitrogen protecting groups are conventionally used e.g. in peptide chemistry and are described e.g. in the relevant chapters of standard reference works such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in P. G. M. Wuts and T. W. Greene, “Greene's Protective Groups in Organic Synthesis’, fourth edition, Wiley, N.J., 2007, and “The Peptides”; volume 3 (editors: E.
  • Preferred nitrogen protecting groups generally comprise: unsubstituted or substituted C 1 -C 6 -alkyl, preferably C 1 -C 4 -alkyl, more preferably C 1 -C 2 -alkyl, most preferably C 1 -alkyl, unsubstituted or substituted C 2-4 -alkenyl, wherein C 1 -C 6 -alkyl and C 2-4 -alkenyl is optionally mono-, di- or tri-substituted by trialkylsilyl-C 1 -C 7 -alkoxy (e.g.
  • cycloalkyl cycloalkyl, aryl, preferably phenyl, or a heterocyclic group, preferably pyrrolidinyl, wherein the cycloalkyl group, the aryl ring or the heterocyclic group is unsubstituted or substituted by one or more, e.g. two or three residues, e.g.
  • C 1 -C 7 -alkyl selected from the group consisting of C 1 -C 7 -alkyl, hydroxy, C 1 -C 7 -alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; aryl-C 1 -C 2 -alkoxycarbonyl (preferably phenyl-C 1 -C 2 -alkoxycarbonyl e.g. benzyloxycarbonyl); C 1-10 -alkenyloxycarbonyl; C 1-6 -alkylcarbonyl (e.g. acetyl or pivaloyl); C 6-10 -arylcarbonyl; C 1-6 -alkoxycarbonyl (e.g.
  • tert-butoxycarbonyl C 6-10 -aryl-C 1-6 -alkoxycarbonyl; allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group, silyl, e.g. triarylsilyl or trialkylsilyl (e.g. triethylsilyl).
  • nitrogen protecting groups are acetyl, benzyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM), pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tert-butyl-dimethylsilyl (TBDMS), triethylsilyl (TES), triisopropylsilyl (TIPS), trimethylsilyethoxymethyl (SEM), tert-butoxycarbonyl (BOC), tert-butyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene, pyridinyl and pivaloyl.
  • nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), tert-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.
  • nitrogen protecting groups are, pivaloyl, pyrrolidinylmethyl, t-butoxycarbonyl, benzyl and silyl groups, particularly silyl groups according to the formula SiRaRbRc, wherein Ra, Rb and Rc are, independently of each other, alkyl or aryl.
  • Preferred examples for Ra, Rb and Rc are methyl, ethyl, isopropyl, t-butyl and phenyl.
  • nitrogen protecting groups are tert-butoxycarbonyl (BOC), benzoyl, styryl, 1-butenyl, benzyl, p-methoxybenzyl (PMB) and pyrrolidinylmethyl, in particular pivaloyl and tert-butoxycarbonyl (BOC).
  • nitrogen protecting group refers to a group which is selected from the group consisting of C 1 -C 6 -alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-C 1 -C 6 -alkylsilylC 1 -C 7 -alkoxy; C 6 -C 10 -aryl, or a heterocyclic group being a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O) or S(O) 2 , wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues, selected from the group consisting of C 1 -C 7 -alkyl, hydroxyl, C 1 -C 7 -alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3
  • nitrogen protecting group comprises any group which is capable of reversibly protecting a amino functionality.
  • the removal usually can be carried out by using known methods.
  • the nitrogen protecting group, as defined above is removed by using acidic or basic conditions.
  • acidic conditions are hydrochloric acid, trifluoroacetic acid, sulphuric acid.
  • basic conditions are lithium hydroxide, sodium ethoxide. Nucleophiles such as sodium borohydride can be used.
  • Silyl refers to a group according to the formula —SiR11R12R13, wherein R11, R12 and R13 are, independently of each other, alkyl or aryl.
  • R11, R12 and R13 are methyl, ethyl, isopropyl, tert-butyl, phenyl or phenyl-C 1-4 -alkyl.
  • Alkyl is defined as a radical or part of a radical as a straight or branch (one or, if desired and possible, more times) carbon chain, and is especially C 1 -C 7 -alkyl, preferably C 1 -C 4 -alkyl.
  • C 1 -C 7 - defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Cycloalkyl is, for example, C 3 -C 7 -cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
  • Alkoxy is, for example, C 1 -C 7 -alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
  • C 1 -C 4 -alkoxy is preferred.
  • Alkanoyl is, for example, C 2 -C 8 -alkanoyl and is, for example, acetyl [—C( ⁇ O)Me], propionyl, butyryl, isobutyryl or pivaloyl.
  • C 2 -C 5 -Alkanoyl is preferred, especially acetyl.
  • Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably, chloro, bromo, or iodo.
  • Halo-alkyl is, for example, halo-C 1 -C 7 -alkyl and is in particular halo-C 1 -C 4 -alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl.
  • Preferred halo-C 1 -C 7 -alkyl is trifluoromethyl.
  • Alkenyl may be linear or branched alkyl containing a double bond and comprising preferably 2 to 12 carbon atoms, 2 to 10 carbon atoms being especially preferred. Particularly preferred is a linear C 2 -C 7 -alkenyl, more preferably C 2 -C 4 -alkenyl.
  • alkyl groups are ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing a double bond. Especially preferred is allyl.
  • Alkylene is a bivalent radical derived from C 1-7 -alkyl and is especially C 2 -C 7 -alkylene or C 2 -C 7 -alkylene and, optionally, can be interrupted by one or more, e.g. up to three oxygen, NR14 or sulfur, wherein R14 is alkyl, each of which can be unsubstituted or substituted, by one or more substituents independently selected from for example, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy.
  • Alkenylene is a bivalent radical derived from C 2-7 -alkenyl and can be interrupted by one or more, e.g. up to three oxygen, NR14 or sulfur, wherein R14 is alkyl, and is unsubstituted or substituted by one or more, e.g. up to three substitutents, preferably independently selected from the substituents mentioned above for alkylene.
  • Aryl being a radical or part of a radical is, for example C 6-10 -aryl, and is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 10 carbon atoms, such as phenyl, naphthyl or fluorenyl preferably phenyl, and which can be unsubstituted or substituted, by one or more substituents, independently selected from, e.g. C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy.
  • arylalkyl refers to aryl-C 1 -C 7 -alkyl, wherein aryl is as defined herein and is for example benzyl.
  • carboxyl refers to —CO 2 H.
  • Aryloxy refers to an aryl-O— wherein aryl is as defined above.
  • Unsubstituted or substituted heterocyclyl is a mono- or polycyclic, preferably a mono-, bi- or tricyclic-, most preferably mono-, unsaturated, partially saturated, saturated or aromatic ring system with preferably 3 to 14 (more preferably 5 to 14) ring atoms and with one or more, preferably one to four, heteroatoms, independently selected from nitrogen, oxygen, sulfur, S( ⁇ O)— or S—( ⁇ O) 2 , and is unsubstituted or substituted by one or more, e.g.
  • up to three substitutents preferably independently selected from the group consisting of halo, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, such as trifluoromethoxy and C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy.
  • the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
  • Acetyl is —C( ⁇ O)C 1 -C 7 -alkyl, preferably —C( ⁇ O)Me.
  • Sulfonyl is (unsubstituted or substituted) C 1 -C 7 -alkylsulfonyl, such as methylsulfonyl, (unsubstituted or substituted) phenyl- or naphthyl-C 1 -C 7 -alkylsulfonyl, such as phenylmethanesulfonyl, or (unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein if more than one substituent is present, e.g.
  • the substituents are selected independently from cyano, halo, halo-C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyloxy- and C 1 -C 7 -alkyloxy.
  • C 1 -C 7 -alkylsulfonyl such as methylsulfonyl
  • (phenyl- or naphthyl)-C 1 -C 7 -alkylsulfonyl such as phenylmethanesulfonyl.
  • Sulfenyl is (unsubstituted or substituted) C 6-10 -aryl-C 1 -C 7 -alkylsulfenyl or (unsubstituted or substituted) C 6-10 -arylsulfenyl, wherein if more than one substituent is present, e.g. one to four substitutents, the substituents are selected independently from nitro, halo, halo-C 1 -C 7 -alkyl and C 1 -C 7 -alkyloxy.
  • Imide refers to a (unsubstituted or substituted) functional group consisting of two acyl groups bound to nitrogen, preferably a cyclic group derived from dicarboxylic acids. Especially preferred is succinimidyl derived from succinic acid or phthalimidyl derived from phthalic acid.
  • the imidyl group may be substituted by one or more substituents independently selected from for example, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy or halo.
  • Azide refers to a group —N ⁇ N + ⁇ N—.
  • chiral refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • the term “ ” on a C-sp 3 represents a covalent bond, wherein the stereochemistry of the bond is not defined.
  • the term “ ” on a C-sp 3 comprises an (S) configuration as well as an (R) configuration of the respective chiral centre.
  • mixtures e.g. mixtures of enantiomers such as racemates, are also encompassed by the present invention.
  • the term “ ” on a C-sp 2 represents a covalent bond, wherein the stereochemistry or the geometry of the bond is not defined. This means that the term “ ” on a C-sp 2 comprises a (Z) configuration as well as a (E) configuration of the respective double bond. Furthermore, mixtures, e.g., mixtures of double bond isomers are also encompassed by the present invention.
  • the compounds of the present invention can possess one or more asymmetric centers.
  • the preferred absolute configurations are as indicated herein specifically.
  • the term “ ” indicates a C-sp 3 -C-sp 3 bond or a C-sp 2 -C-sp 2 bond.
  • the compounds of the present invention can possess one or more asymmetric centers.
  • the preferred absolute configurations are as indicated herein specifically. However, any possible pure enantiomer, pure diastereoisomer, or mixtures thereof, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
  • Stereoisomeric, especially enantiomeric, purity is where mentioned referring to all diastereomers of the compound taken together (100%). It is determined by chiral chromatography (examples include HPLC, uPLC and GC) or NMR (with addition of chiral entities and or metals). Specific examples of methods include: chiral HPLC equipped with chiral column Chiralpak ID 4.6 mm ⁇ 250 mm, 5 ⁇ m (Daicel Corporation, Osaka, Japan) at 25° C.; mobil phase Hept:EtOAc:CH 3 CN, 90:8:2.
  • Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, except if salts are excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form.
  • salt forming groups such as basic or acidic groups
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1,2-disulfonic acid, benzene-sulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
  • carboxylic, phosphonic, sulfonic or sulfamic acids for example acetic acid, propionic acid
  • salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
  • any of the intermediates mentioned herein may also form internal salts.
  • any reference to “compounds”, “starting materials” and “intermediates” hereinbefore and hereinafter is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
  • Different crystal forms may be obtainable and then are also included.
  • pro-drug represents in particular compounds which are transformed in vivo to the parent compound, for example, by hydrolysis in blood, for example as described in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, volume 14 of the ACS Symposium Series; Edward B. Roche, editor, “Bioreversible Carriers in Drug Design”, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, editor, “Design of Prodrugs”, Elsevier, 1985; Judkins et al. Synthetic Communications 1996, 26, 4351-4367, and “The Organic Chemistry of Drug Design and Drug Action”, second edition, R. B. Silverman (particularly chapter 8, pages 497-557), Elsevier Academic Press, 2004.
  • Pro-drugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following:
  • Carboxylic acid Esters including e.g. alkyl esters Alcohol Esters, including e.g. sulfates and phosphates as well as carboxylic acid esters Amine Amides, carbamates, imines, enamines, Carbonyl (aldehyde, Imines, oximes, acetals/ketals, enol esters, ketone) oxazolidines and thiazoxolidines
  • Pro-drugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned:
  • NEP-inhibitor or a prodrug thereof such as a NEP inhibitor or pro-drug thereof comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, such as alkyl ester, backbone.
  • the NEP-inhibitor is N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt thereof or a prodrug thereof.
  • the compound of the formula (1) is represented by formula (1-a) with the following stereochemistry,
  • compound (1) is present as a mixture of steric forms, the shown steric form is present in at least 60%, preferably at least 65%, stereoisomeric, especially enantiomeric, purity.
  • the Michael addition according to any one of SCHEMES 3 is carried out with a organocatalyst selected from the group consisting of those represented by the following formulae:
  • catalysts are either commercially available or amenable according to methods known in the art (see especially the references cited in the preceding scheme, and/or they are novel, (these novel ones are marked with an asterisk * at their lower right side) and thus an invention embodiment and then can be synthesized according to the procedure given in the Examples.
  • the organocatalyst is selected from the group consisting of those represented by the following formulae:
  • the organocatalyst is a prolinol organocatalyst, preferably selected from the group consisting of those with the following formulae:
  • TMS trimethylsilyl, and which are used in the (R)- or in the (S) configuration, and with the following formulae:
  • catalysts can e.g. be obtained commercially from Sigma-Aldrich Corporation St. Louis, Mo., USA.
  • room temperature is mentioned in the present disclosure (except in the examples where it refers to 20 to 25° C.), this preferably refers to a temperature of 23 ⁇ 25° C., e.g. to 23° C.
  • Salt conversions can be made using metal (e.g. alkalimetal or earth alkali metal, such as sodium or potassium) salts of organic or inorganic acids, ion exchangers or the like according to methods known in the art.
  • metal e.g. alkalimetal or earth alkali metal, such as sodium or potassium
  • polar protic solvents e.g. methanol, ethanol, propanol, butanol
  • polar aprotic solvents e.g. tetrahydrofuran (THF), dimethylformamide (DMF), dichloromethane (DCM), acetonitrile (ACN)
  • apolar aprotic solvent e.g. toluene
  • polar solvents are used. More preferably, polar aprotic solvents are used to achieve high yields.
  • a particularly preferred solvent in this regard is THF.
  • the embodiment depicted in SCHEME 1 and 1-a refers to process, wherein a compound of the formula (1), especially of the formula (1-a), is subjected to a hydrogenation reaction to yield a compound of the formula (8), especially of the formula (8-a), which preferably takes place in the presence of a mild hydrogenation catalyst (not affecting the carboxyl or carboxyl ester function), for example by hydrogenation with hydrogen, e.g. at normal or slightly elevated pressure, in an appropriate solvent, such as an alcohol, e.g. methanol or ethanol, with e.g. at temperatures in the range from ⁇ 10 to 60° C., such as from 20 to 50° C.
  • a mild hydrogenation catalyst not affecting the carboxyl or carboxyl ester function
  • the hydrogenation comprises the use of a metal catalyst, preferably a metal catalyst comprising a metal selected from the group of nickel, palladium or platinum, more preferably Raney nickel, even more preferably Raney nickel type 3202.
  • a metal catalyst preferably a metal catalyst comprising a metal selected from the group of nickel, palladium or platinum, more preferably Raney nickel, even more preferably Raney nickel type 3202.
  • the process is preferably performed in a hydrogenation reactor.
  • the catalyst is applied to this process as 50% water slurry.
  • the process is performed with pressurized hydrogen, preferably the hydrogen is pressurized up to 10, e.g. up to 4 bar.
  • a nitrogen protecting group is to be inserted in parallel, the reactions are preferably conducted as described in the general part on nitrogen protecting groups above.
  • Boc 2 O is used for this process in excess over sum of compounds of formulas (1) or (1-a, preferably in an excess of 20-100%, more preferably in an excess of 50 ⁇ 10%.
  • the process preferably performed at elevated temperatures, preferably from 30-70° C., more preferably from 35-50° C., even more preferably from 40-45° C.
  • the process is performed with Raney nickel as 50% water slurry, using Boc 2 O in excess over sum of compound of formula (1) or (1-a), preferably in an excess of 20-100%, more preferably in an excess of 50+10%, using pressurized hydrogen, preferably using hydrogen pressurized up to 4 bar, at elevated temperatures, preferably from 30-70° C., more preferably from 35-50° C., even more preferably from 40-45° C.
  • the Oxidation reaction according to SCHEME 2 or 2-a of a compound (aldehyde) of the formula (2), especially (2-a), to yield the compound of formula (1) preferably takes place with an oxidant allowing for selective oxidation of the aldehyde function to a carboxyl (COOH or COO ⁇ ) function.
  • an oxidant allowing for selective oxidation of the aldehyde function to a carboxyl (COOH or COO ⁇ ) function.
  • Such oxidants and oxidation conditions are known to the person skilled in the art. Examples of possible oxidants include but are not limited to Oxone (e.g. in DMF, e.g. at room temperature), with H 5 IO 6 in the presence of a catalyst, such as pyridinium chloroformate, a solvent, e.g. acetonitrile, e.g.
  • a catalyst such as VO(acac) 2 and hydrogen peroxide, e.g. in a solvent such as acetonitrile or an alcohol, such as methanol or ethanol, e.g. at room temperature; with sodium perborate in acetic acid e.g. at elevated temperature, such as 20 to 70° C.; with potassium permanganate in a buffer, especially disodiumhydrogenphosphate buffer, e.g. in a solvent such as methanol; with hydrogen peroxide in the presence of a methyltrioxorhenium catalyst in an ionic liquid, such as [bmim]BF 4 or [bmim]PF 6 , e.g.
  • a methyltrioxorhenium catalyst in an ionic liquid, such as [bmim]BF 4 or [bmim]PF 6 , e.g.
  • a chlorite salt e.g. an alkalimetal chlorite, such as sodium chlorite (NaClO 2 ), preferably in the presence of a buffering substance, such as an alkali metal dihydrogen phosphate, e.g. sodium dihydrogen phosphate, in the presence of a scavenger for the byproduct hypochlorous acid (HOCl), such as an alkene-comprising chemical, e.g.
  • 2-methyl-2-butene or hydrogen peroxide of resorcinol or sulfamic acid and in a solvent or solvent mixture, e.g. an alcohol, such as butanol, or an ester, such as acetic acid ethyl ester, or a mixture thereof, for example at temperatures in the range from ⁇ 5 to 80° C., e.g. at room temperature.
  • a solvent or solvent mixture e.g. an alcohol, such as butanol, or an ester, such as acetic acid ethyl ester, or a mixture thereof.
  • the reaction may be conducted under simultaneous esterification to a compound of the formula (1), especially (1-a), wherein R 1 is C 1 -C 6 -alkyl, especially ethyl, or by subsequent esterification, in both cases reacting with a C 1 -C 6 -alkanol, especially ethanol, preferably in the presence of an activator of the carboxyl group in formula I that leads to an (at least intermediary) reactive derivative of a compound of the formula (1), especially (1-a), such as an acid anhydride, e.g.
  • acetic anhydride or a coupling agent selected from the group consisting of those customary in peptide synthesis, such as aminium compounds, carbodiimides, uranium compounds, and other coupling reagents, for example DCC, DIC, HOBt, HOAt, if appropriate in the presence of a tertiary nitrogen base, such as triethylamine, if required in an appropriate solvent; or by transesterification, e.g. from a corresponding C 1 -C 6 -alkyl, especially ethyl, ester e.g. of acetic acid; such conditions are known to the person skilled in the art.
  • a coupling agent selected from the group consisting of those customary in peptide synthesis, such as aminium compounds, carbodiimides, uranium compounds, and other coupling reagents, for example DCC, DIC, HOBt, HOAt, if appropriate in the presence of a tertiary nitrogen base, such
  • the reaction of the compound of the formula (3) with methacroleine or a reactive derivative thereof, such as an acetal, e.g. the dialkyl acetal, to a compound of the formula (2), especially (2-a), is conducted in the presence of an organocatalyst as described above, preferably one of those described above as being preferred, most especially a chiral prolinol or thiourea catalyst, especially one of those mentioned as preferred above, the catalyst preferably being present in a molar ratio, compared to the compound of the formula (3), of 1 to 50 mol %, e.g.
  • the organocatalyst is selected so as to achieve the preferred compound of formula (2-a), e.g. a thiourea catalyst of the formula (B) or (C) mentioned above, or a prolinol catalyst selected from those mentioned and represented as specific formulae above.
  • Organic acid or alcohols can be added especially benzoic acid or its derivatives, and/or catechol derivatives can be added to promote the catalysis of 1 to 50 mol %, e.g. at 5 to 15 mol % catalyst.
  • the compound of the formula (2) is obtained by reacting the compound of the formula (7) with propionaldehyde or a reactive derivative thereof, e.g.
  • an acetal such as a dialkyl a to a compound of the formula (2), especially (2-a) is conducted in the presence of an organocatalyst as described above, preferably one of those described above as being preferred, most especially a chiral prolinol or thiourea catalyst, especially one of those mentioned as preferred above, the catalyst preferably being present in a molar ratio, compared to the compound of the formula (3), of 1 to 50 mol %, e.g. at 5 to 15 mol %; especially in an organic solvent, such as toluene or dimethylformamide, at temperatures e.g. in the range from ⁇ 5 to 50° C., e.g. at 0 to 20° C.
  • the organocatalyst is selected so as to achieve the preferred compound of formula (2-a), e.g. a thiourea catalyst of the formula (B) or (C) mentioned above, or a prolinol catalyst selected from those mentioned and represented as specific formulae above.
  • the reaction takes place in the presence of organic acid or alcohols, especially benzoic acid or its derivatives or catechol derivatives, which can be added to promote the catalysis of 1 to 50 mol %, e.g. at 5 to 15 mol % catalyst.
  • the reaction as depicted in SCHEME 4 of a compound of formula (3) with formaldehyde or reactive derivative thereof, such as an acetal, e.g. a dialkylacetal, e.g. dimethoxymethane, dioxolane or 1,3,5-trioxane, to yield a compound of the formula (7) preferably takes place in analogy to or according to a Henry reaction, preferably first reacting the formaldehyde or reactive derivative thereof in the presence of a base, such as an alkalimetal hydroxide, e.g. sodium hydroxide, in an appropriate solvent, e.g. tetrahydrofurane, at a temperature e.g.
  • a base such as an alkalimetal hydroxide, e.g. sodium hydroxide
  • reaction product in the range from ⁇ 20 to 50° C., e.g. from ⁇ 10 to 10° C.
  • isolation of the reaction product e.g. by solvent extraction in the organic layer, and then subjecting the (e.g. crude) material to treatment with an acid anhydride, such as trifluoroacetic anhydride, in the presence of a tertiary nitrogen base, such as N,N-diisopropyl-N-ethylamine, in an organic solvent, such as toluene, at a preferred temperature e.g. in the range from ⁇ 10 to 50° C., e.g. from 0 to 30° C.
  • acid anhydride such as trifluoroacetic anhydride
  • a tertiary nitrogen base such as N,N-diisopropyl-N-ethylamine
  • organic solvent such as toluene
  • the hydrogenating (hydrogenation) of a compound of the formula (4), a compound of the formula (5) (preferred) or both (e.g. if obtained as a mixture in the process as described above or especially in a preferred version below) to yield the compound of the formula (3) is preferably conducted in the presence of a hydrogenating agent, especially a complex metal hydride, such as an alkalimetal borohydride, e.g. sodium borohydride, preferably in an appropriate solvent liquid at the reaction temperature, such as an organic acid, e.g.
  • a hydrogenating agent especially a complex metal hydride, such as an alkalimetal borohydride, e.g. sodium borohydride, preferably in an appropriate solvent liquid at the reaction temperature, such as an organic acid, e.g.
  • acetic acid an alcohol, such as methanol or ethanol, an organic sulfoxide, such as dimethyl sulfoxide (DMSO), or an ether, such as diethyl ether, or a mixture of two or more thereof, preferably at a temperature in the range from ⁇ 20 to 50° C., e.g. ⁇ 10 to 25° C.
  • DMSO dimethyl sulfoxide
  • ether such as diethyl ether
  • SCHEME 5 further embodies the process step wherein, the compound of the formula (5) is reacted with a dehydrating agent to the compound of the formula (4).
  • the dehydrating agent can be, for example, an acid anhydride of an inorganic (such as phosphorous pentoxide) or preferably organic acid (such as acetic anhydride).
  • the reaction is preferably conducted in the presence of a tertiary nitrogen base, such as trimethylamine, and in the presence of an appropriate solvent, such as dichloromethane, at temperatures e.g. in the range from ⁇ 20 to 50° C., such as from ⁇ 10 to 10° C.
  • SCHEME 5 also encompasses the process step wherein the aldehyde of the formula (6) or a reactive derivative thereof, e.g. an acetal, such as a dialkyl acetal, is preferably reacted with nitromethane in an appropriate solvent, such as an acholo, e.g. methanol or ethanol, in the presence of a base, such as an alkalimetal hydroxide, e.g. sodium hydroxide, especially in the form of an aqueous solution of the base, at a preferred temperature in the range from ⁇ 20 to 50° C., e.g. from ⁇ 10 to 10° C., and thus the compound of the formula (5) alone or in mixture with the compound of the formula (4) is obtained.
  • an appropriate solvent such as an acholo, e.g. methanol or ethanol
  • a base such as an alkalimetal hydroxide, e.g. sodium hydroxide, especially in the form of an aqueous solution of the base
  • the present invention also covers combinations of several reaction steps, e.g.
  • the intermediates and the products of the process of the present invention can be used in the synthesis of NEP inhibitors or salts or pro-drugs thereof, in particular they can be used in the synthesis of NEP inhibitors comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • NEP inhibitor describes a compound which inhibits the activity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11).
  • NEP inhibitors or salts or prodrugs thereof in particular to the NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or the corresponding NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid as described by Ksander et al. in J. Med. Chem. 1995, 38, 1689-1700, or as described in WO 2008/31567.
  • R1 is hydrogen or C 1 -C 6 -alkyl, preferably ethyl, by reaction with succinic acid or a derivative thereof, preferably succinic acid anhydride.
  • the ester can be saponified to the free acid providing the NEP inhibitor drug compound.
  • the compound of formula (10-a) is N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (known in the art as AHU377) or a salt thereof.
  • NEP inhibitor pro-drug N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester optionally is further reacted to obtain the NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid.
  • Example of catalyst includes (catalysts commercially available or reported in literature)
  • the enantio-enriched isomers E1-4 have been individually reacted with 5 equivalents of DIBAL 1M solution in THF at 0° C. After 1 h methanol was added at the same temperature and 15 w % brine solution was added. After the phase separation the organic phase was concentrated in vacuum. The residue was dissolved in DCM and Dess-Martin periodinane (1.1 equiv., DMP) was added. After 45 min hexane was added and the solid filtered off. The mix was filtered on a pad of silica affording the corresponding aldehydes 5.
  • the conditions for obtaining the X-ray data are as follows:
  • the compound is prepared from the compound of the formula (8-a) given above as described in Ksander (Med. Chem. 1995, 38, 1689-1700; compound 18 in the publication corresponds to formula (8-a) and is converted to AHU377 and salts thereof).
  • AHU377 can be manufactured as described in WO 2008/083967.
  • the members of series 1 can be prepared as follows:
  • Compound 114a was prepared from 122 by acetylation of the free amine and hydrolysis of the Boc residue. The compound 123 thus prepared, was treated with isothiocyanate 120. Catalyst 114a was obtained from following acid hydrolysis and chromatography purification (Scheme D).
  • This series was designed combining the chiral scaffold 110 with the tertiary amines corresponding to c-j.
  • the scaffold 110 and different residues on the basic nitrogen allowed us to explore a small range of pK a values (pK a ⁇ 10), the influence of steric bulk and potential additional interaction with the substrates during the formation of the intermediate complex (e.g. hydrogen bounds).
  • the last series were generated combining the chiral scaffold 110 and 111 with two different moieties: guanidine and iminophosphorane. Regarding the preparation of these compounds, the corresponding primary amines belonging to series 1 were used as starting materials.
  • the guanidine derivatives 110k and 111k were synthesized from the reaction of 110a and 111a respectively, with N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride (131) in the presence of triethylamine. Compound 131 was in turn generated by reacting tetramethylurea and oxalyl chloride under Vilsmeyer's conditions (Scheme I).
  • the iminophosphorane-bases 110l and 111l were synthesized by Staudinger reaction by employing the commercially available diazo-transfer reagent 132 and triphenylphosphine affording 110l and 111l respectively after filtration of the precipitated product from the reaction mixture (Scheme K).
  • step 2 It has been used directly for the step 2 and the product from step 1 was dissolved on 15 ml of THF.
  • the reaction mixture was concentrated under reduced pressure, then HCl 6 N (5 ml) and EtOH (10 ml) were added to the brownish solid.
  • the suspension was dissolved at reflux, 24 h, with magnetic stirring.
  • the reaction was monitored by HPLC.
  • the solution was cooled at rt. and small crystals were formed. The crystals were filtered to obtain a yellow solid.
  • step 1 The crude from step 1 was dissolved in EtOH (10 ml) and HCl 6 N (5 ml) was added in a microwave vial (20 ml). The solution was heated at 120° C. for 45 minutes. NaOH 2 N (40 ml) was added and the solution was extracted with EtOAc (25 ml*3), dried by MgSO4 and concentrated under reduced pressure to obtain a brownish oil which was employed directly for the Step 3.
  • reaction mixture was concentrated under reduced pressure, and purified by flash chromatography on biotage apparatus (Biotage EU Customer Service, Uppsala, Sweden) (DCM:MeOH from 100:0 to 98:2). 1.5 g of pure product were obtained as white powder (overall yield 56%)
  • reaction product was analyzed by HPLC ( ⁇ 97%), NMR and LC-MS
  • the reaction was monitored by HPLC and LC-MS.
  • the reaction mixture was filtered to remove triethylammonium salts; the organic phase was washed with NaOH 1 N (30 ml) and concentrated under reduced pressure to obtain a brownish oil.
  • the crude was purified by flash chromatography on Biotage apparatus.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US15/550,224 2015-02-13 2016-02-11 Process and intermediates for the preparation of NEP inhibitors Active US10385004B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP15155147.0 2015-02-13
EP15155147 2015-02-13
EP15155147 2015-02-13
PCT/IB2016/050725 WO2016128924A1 (en) 2015-02-13 2016-02-11 Process and intermediates for the preparation of nep inhibitors

Publications (2)

Publication Number Publication Date
US20180022690A1 US20180022690A1 (en) 2018-01-25
US10385004B2 true US10385004B2 (en) 2019-08-20

Family

ID=52472229

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/550,224 Active US10385004B2 (en) 2015-02-13 2016-02-11 Process and intermediates for the preparation of NEP inhibitors

Country Status (6)

Country Link
US (1) US10385004B2 (ja)
EP (1) EP3256444B1 (ja)
JP (1) JP6665193B2 (ja)
CN (1) CN107250100B (ja)
TW (1) TW201632493A (ja)
WO (1) WO2016128924A1 (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10851059B2 (en) * 2016-08-17 2020-12-01 Novartis Ag Processes and intermediates for NEP inhibitor synthesis

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10385007B2 (en) 2016-12-09 2019-08-20 Celtaxsys, Inc. Monamine and monoamine derivatives as inhibitors of leukotriene A4 hydrolase
CN109053800B (zh) * 2018-07-30 2020-08-14 湖北大学 季鏻盐支载手性氨基-硫脲及其制备方法和用途
CN113121342B (zh) * 2019-12-31 2022-05-31 浙江医药股份有限公司新昌制药厂 一种沙库必曲中间体的制备方法及应用
CN116987012A (zh) * 2022-04-29 2023-11-03 凯特立斯（深圳）科技有限公司 沙库必曲中间体、其制备方法及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009090251A2 (en) 2008-01-17 2009-07-23 Novartis Ag New processes
US20100305131A1 (en) * 2009-05-28 2010-12-02 Gary Mark Coppola Substituted Aminopropionic Derivatives as Neprilysin inhibitors
WO2014064466A2 (en) 2012-10-26 2014-05-01 Isis Innovation Limited Bifunctional organic catalysts
WO2015189862A1 (en) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Chiral amines, a process for preparation and use thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
EP1903027A1 (en) 2006-09-13 2008-03-26 Novartis AG Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
JP5715339B2 (ja) 2007-01-12 2015-05-07 ノバルティス アーゲー ５−ビフェニル−４−アミノ−２−メチルペンタン酸の製造方法
CN101774941A (zh) 2009-01-13 2010-07-14 浙江九洲药业股份有限公司 2-酰基氨基-3-联苯基丙酸的制备及拆分方法
EP2480523B1 (en) 2009-09-23 2017-03-01 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Process for manufacture of n-acylbphenyl alanine
PT2526088E (pt) 2010-01-22 2015-11-03 Novartis Ag Intermediários dos inibidores da endopeptidase neutra e método de preparação dos mesmos
CN103080072B (zh) 2010-08-23 2016-03-16 诺华有限公司 制备可用于生产nep抑制剂的中间体的新方法
WO2012025501A1 (en) 2010-08-23 2012-03-01 Novartis Ag Process for the preparation of intermediates for the manufacture of nep inhibitors
AR092278A1 (es) 2012-08-31 2015-04-08 Novartis Ag Proceso de obtencion de derivados n-acilicos de bifenil-alanina e intermediarios relacionados

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009090251A2 (en) 2008-01-17 2009-07-23 Novartis Ag New processes
CN101952249A (zh) 2008-01-17 2011-01-19 诺瓦提斯公司 制备5-联苯-4-基-2-甲基戊酸衍生物的方法和中间体
US20100305131A1 (en) * 2009-05-28 2010-12-02 Gary Mark Coppola Substituted Aminopropionic Derivatives as Neprilysin inhibitors
WO2014064466A2 (en) 2012-10-26 2014-05-01 Isis Innovation Limited Bifunctional organic catalysts
WO2015189862A1 (en) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Chiral amines, a process for preparation and use thereof

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
Albertshofer "Assembly of Spirooxindole Derivatives Containing Four Consecutive Stereocenters via Organocatalytic Michael-Henry Cascade Reactions" Organic Letters, 14, 2012, p. 1834-1837) (Year: 2012). *
Chandrasekar ("Useful Extensions of the Henry Reaction: Expeditious Routes to Nitroalkanes and Nitroalkenes in Aqueous Media" Synthetic Communications, 44, 2014, p. 3008-3018) (Year: 2014). *
Chang ("Palladium-Catalyzed Synthesis of Substituted Nitroolefins" Tetrahedron Letters, 54, 2013, p. 3194-3198) (Year: 2013). *
Ding ("Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone to acrylaldehyde: a concise two-step synthesis of chiral building block 1-azaspiro[4.5]decan-6-one"   Tetrahedron Letters, 54, 2013, p. 1956-1959) (Year: 2013). *
Ding ("Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone to acrylaldehyde: a concise two-step synthesis of chiral building block 1-azaspiro[4.5]decan-6-one" Tetrahedron Letters, 54, 2013, p. 1956-1959) (Year: 2013). *
Ding Xiao-Hua et al: "Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone to acrylaldehyde: a concise two-step synthesis of chiral building block 1-azaspiro[4.5]decan-6-one", Tetrahedron Letters, Pergamon, GB, vol. 54, No. 15, Feb. 4, 2013 pp. 1956-1959.
Gogoi ("A total synthesis of (-)-bestatin using Shibaski's asymmetric Henry reaction" Tetrahedron Letters, 46, 2005, p. 7581-7582) Year: 2005). *
Gotoh ("Diphenylprolinol Silyl Ether as Catalyst of an Asymmetric, Catalytic, and Direct Michael Reaction of Nitroalkanes with a, b-Unsaturated Aldehydes" Organic Letters, vol. 9, 2007, p. 5307-5309) (Year: 2007). *
Jinlong Zhang et al: "Organocatalyzed asymmetric vinylogous Michael addition of [alpha], [beta]-unsaturated [gamma]-butyrolactam", Chemical Communications, vol. 49, No. 81, Jan. 1, 2013, p. 9329.
Ono ("New Synthetic Methods. Conjugate Addition of Alkyl Groups to Electron Deficient Olefins with Nitroalkanes as Alkyl Anion Equivalents" J. Org. Chem, 1985, 50, p. 3692-3698) (Year: 1985). *
Silva ("An expeditious synthesis of 3-nitropropionic acid and its ethyl and methyl esters" Synthetic Communications, 31, 2001, p. 595-600) (Year: 2001). *
Zheng ("A novel method to access chiral non-natural 2,4-disubstituted pyrrolidines from aldehydes and nitroolefins only with an alpha-substituent" Chem Commun, 2013, 49, p. 4561-4563, including Supporting Information (SI), p. 1-54) (Year: 2013). *
Zhijie Mao et al: "Chiral Tertiary Amine Thiourea-Catalyzed Asymmetric Inverse-Electron-Demand Diels-Aider Reaction of Chromone Heterodienes Using 3-Vinylindoles as Dienophiles", The Journal of Organic Chemistry, vol. 78, No. 20, Oct. 18, 2013, pp. 10233-10239.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10851059B2 (en) * 2016-08-17 2020-12-01 Novartis Ag Processes and intermediates for NEP inhibitor synthesis

Also Published As

Publication number Publication date
EP3256444B1 (en) 2019-03-27
US20180022690A1 (en) 2018-01-25
CN107250100A (zh) 2017-10-13
JP2018506541A (ja) 2018-03-08
TW201632493A (zh) 2016-09-16
JP6665193B2 (ja) 2020-03-13
CN107250100B (zh) 2019-12-06
WO2016128924A1 (en) 2016-08-18
EP3256444A1 (en) 2017-12-20

Similar Documents

Publication Publication Date Title
US10385004B2 (en) Process and intermediates for the preparation of NEP inhibitors
US20220098200A1 (en) Synthesis of a bruton's tyrosine kinase inhibitor
US9624163B2 (en) Process for preparing intermediates useful in the manufacture of NEP inhibitors
US9522915B2 (en) Method for preparing an important intermediate of linagliptin
KR101476937B1 (ko) Ｎｅｐ 억제제의 제조를 위한 중간체의 제조 방법
US9278972B2 (en) Synthesis of triazolopyrimidine compounds
US11434192B2 (en) Process and intermediates
CN109415308B (zh) 用于早期沙卡布曲中间体的新方法
US9040738B2 (en) Intermediate compounds of tamiflu, methods of preparation and uses thereof
US11040977B2 (en) Synthesis of trans-8-chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10B-tetraaza-benzo[e]azulene and crytalline forms thereof
US9701684B2 (en) Chiral fluorinating reagents
US20090088571A1 (en) Synthesis of 6,7-Dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonic acid amides
US11370807B2 (en) Process for preparing sulfonamide compounds
US20180079715A1 (en) Method for producing alkylamine derivative and its production intermediate of alkylamine derivative
US10851059B2 (en) Processes and intermediates for NEP inhibitor synthesis
EP3892615A1 (en) Process for the preparation of silodosin
US12006315B2 (en) Intermediate useful for the synthesis of TGF-beta inhibitors and a method of preparing TGF-beta inhibitors using the same
US20230303568A1 (en) Intermediate useful for the synthesis of tgf-beta inhibitors and a method of preparing tgf-beta inhibitors using the same
WO2012165268A1 (ja) エステル化合物の製造方法
JPWO2005026108A1 (ja) Ｎ，ｎ’−ジアルコキシ−ｎ，ｎ’−ジアルキルオキサミドの製法
WO2017060287A1 (en) Process for the preparation of encenicline from 7-chloro-benzo[b]thiophene-2-carboxylic acid chloride and (r)-quinuclidin-3-amine in the presence of imidazole
WO2016146599A1 (de) Herstellverfahren für phenylalanin-derivate

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS PHARMA AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MARTIN, BENJAMIN;MANDRELLI, FRANCESCA;VENTURONI, FRANCESCO;SIGNING DATES FROM 20150325 TO 20150401;REEL/FRAME:043283/0105

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS PHARMA AG;REEL/FRAME:043541/0229

Effective date: 20150706

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4