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 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)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (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)

Abstract

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.

Description

RELATED APPLICATIONS
This application is a national stage application, filed under 35 U.S.C. § 371, of International Application No. PCT/IB2016/050725, filed Feb. 11, 2016, which claims priority to and the benefit of, European Patent Application No. 15155147.0, filed Feb. 13, 2015, the entire contents of which are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
The 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)
Figure US10385004-20190820-C00001
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).
Figure US10385004-20190820-C00002
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}-L-valinate)-water (1/15) (IUPAC nomenclature).
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.
Chemical synthesis routes to prepare NEP inhibitors and their prodrugs, in particular sacubitril, and its precursors have been described previously, e.g. in Ksander et al. J. Med. Chem. 1995, 38, pp. 1689-1700; in U.S. Pat. No. 5,217,996 and in the international patent applications WO 2008/031567, WO 2008/083967, WO 2009/090251, WO 2010/081410, WO 2011/035569, WO 2011/088797, WO 2012/025501, WO 2012/025502 and WO 2014/032627.
However, there is still a need to design a chemical process for the synthesis of sacubitril which is suitable for industrial scale production under economically and environmentally favorable conditions and provides the drug substance in high chemical purity and with high stereo-chemical selectivity.
SUMMARY OF THE INVENTION
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.
In a first aspect, the present invention provides the following new compounds:
A compound of formula (1), or a salt thereof
Figure US10385004-20190820-C00003
wherein R1 is hydrogen or C1-C6-alkyl.
In one embodiment thereof, the compound of the formula (1) is represented by formula (1-a) with the following stereochemistry
Figure US10385004-20190820-C00004
wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl.
A compound of formula (2) or a salt thereof,
Figure US10385004-20190820-C00005
In one embodiment thereof, the compound of the formula (2) is represented by formula (2-a) with the following stereochemistry
Figure US10385004-20190820-C00006
A compound of the formula (7)
Figure US10385004-20190820-C00007
In a second aspect, 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.
Figure US10385004-20190820-C00008
Figure US10385004-20190820-C00009
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 C1-C6-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 C1-C6-alkyl, especially ethyl.
If desired—and not explicitly disclosed in the SCHEME 1—this can be followed by converting a compound of the formula (8), especially (8-a), wherein each of R′ and R″ are hydrogen, into a salt, e.g. with an acid. Alternatively, the reduction can take place with parallel introduction of a nitrogen protecting group or the nitrogen protecting group can be added subsequently.
In one embodiment, the compound of formula (1) can be obtained according to the following SCHEMES:
Figure US10385004-20190820-C00010
Figure US10385004-20190820-C00011
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 C1-C6-alkyl, preferably ethyl.
If desired—and not explicitly disclosed in the SCHEME 2—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 C1-C6-aliphatic alcohol, especially ethanol, to yield the compound wherein R1 is C1-C6-alkyl, especially ethyl.
In one embodiment, the compound of formula (2) can be obtained according to the following SCHEMES:
Figure US10385004-20190820-C00012
Figure US10385004-20190820-C00013
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.
In an alternative embodiment, the compound of formula (2) can be obtained according to the following SCHEMES:
Figure US10385004-20190820-C00014
Figure US10385004-20190820-C00015
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.
In a further embodiment, the compound of formula (7) is obtained according to the following SCHEMES:
Figure US10385004-20190820-C00016
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.
In one embodiment thereof, the compound of formula (3) is obtained according to the following SCHEME:
Figure US10385004-20190820-C00017
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).
In one embodiment, 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.
In one embodiment thereof the catalyst is of one of the formulae (I), (II), (III) or (IV)
Figure US10385004-20190820-C00018
wherein
Ra is C6-C10-aryl, a heterocyclic group or C1-C6-alkyl optionally substituted with C6-C10-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, C1-C7-alkyl, C6-C10-aryl and a heterocyclic group, and
Rd and Re are independently selected from hydrogen, C6-C10-aryl, a heterocyclic group, and C1-C6-alkyl optionally substituted with one, two or three substituents selected from halogen, hydroxyl, amino, C6-C10-aryl or a heterocyclic group; or
Rd and Re together with the connecting Nitrogen atom form a group selected from:
Figure US10385004-20190820-C00019
or Rb is selected from hydrogen, C1-C7-alkyl, C6-C10-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 C1-C7-alkyl or C2-C7-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 C6-C10-aryl or heterocyclic group is optionally substituted by one, two or three residues selected from the group consisting of C1-C7-alkyl, hydroxyl, oxo, C1-C7-alkoxy, C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3.
In another embodiment thereof the catalyst is of one of the following formulae
Figure US10385004-20190820-C00020
wherein the group —NRdRe forms a group selected from:
Figure US10385004-20190820-C00021
or the catalyst is of the formula (V)
Figure US10385004-20190820-C00022
wherein Rb is a quinolone,
and wherein for all formulas
Ra is a group
Figure US10385004-20190820-C00023
In a third aspect, 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:
Figure US10385004-20190820-C00024
Figure US10385004-20190820-C00025
Figure US10385004-20190820-C00026
In one embodiment thereof, the catalyst to be used in the process of the invention is selected from the group consisting of those with the following formulae:
Figure US10385004-20190820-C00027
In a fourth aspect, 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)
Figure US10385004-20190820-C00028
preferably of formula (10-a)
Figure US10385004-20190820-C00029
wherein R1 is hydrogen or C1-C6-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.
In further embodiments, 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.
In its above mentioned aspects which are also given in more detail below the present invention provides the following advantages: 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.
DETAILED DESCRIPTION OF THE INVENTION General Terms
The general definitions used above and below, unless defined differently, have the following meanings, where replacement of one or more or all expressions or symbols by the more specific definitions can be made independently for each invention embodiment and lead to more preferred embodiments:
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).
The term “nitrogen protecting group” comprises any group which is capable of reversibly protecting a nitrogen functionality, preferably an amine and/or amide functionality. Preferably 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. Gross and J. Meienhofer), Academic Press, London and New York 1981, and “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, fourth edition, volume 15/I, Georg Thieme Verlag, Stuttgart 1974.
Preferred nitrogen protecting groups generally comprise: unsubstituted or substituted C1-C6-alkyl, preferably C1-C4-alkyl, more preferably C1-C2-alkyl, most preferably C1-alkyl, unsubstituted or substituted C2-4-alkenyl, wherein C1-C6-alkyl and C2-4-alkenyl is optionally mono-, di- or tri-substituted by trialkylsilyl-C1-C7-alkoxy (e.g. trimethylsilylethoxy), 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. selected from the group consisting of C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3; aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl e.g. benzyloxycarbonyl); C1-10-alkenyloxycarbonyl; C1-6-alkylcarbonyl (e.g. acetyl or pivaloyl); C6-10-arylcarbonyl; C1-6-alkoxycarbonyl (e.g. tert-butoxycarbonyl); C6-10-aryl-C1-6-alkoxycarbonyl; allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group, silyl, e.g. triarylsilyl or trialkylsilyl (e.g. triethylsilyl).
Examples of preferred 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. Most preferred nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), tert-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.
Examples of more preferred 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.
Examples of most preferred nitrogen protecting groups are tert-butoxycarbonyl (BOC), benzoyl, styryl, 1-butenyl, benzyl, p-methoxybenzyl (PMB) and pyrrolidinylmethyl, in particular pivaloyl and tert-butoxycarbonyl (BOC).
In one embodiment the term nitrogen protecting group refers to a group which is selected from the group consisting of C1-C6-alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-C1-C6-alkylsilylC1-C7-alkoxy; C6-C10-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 C1-C7-alkyl, hydroxyl, C1-C7-alkoxy, C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3; and C6-C10-aryl-C1-C2-alkoxycarbonyl; C1-C10-alkenyloxycarbonyl; C1-C6-alkylcarbonyl; C6-C10-arylcarbonyl; C1-C6-alkoxycarbonyl; C6-C10-aryl-C1-C6-alkoxycarbonyl; allyl; cinnamyl; sulfonyl; sulfenyl; succinimidyl, and silyl, wherein each silyl group is a SiR11R12R13 group, wherein R11, R12 and R13 are, independently of each other, C1-C6-alkyl or C6-C10-aryl.
Generally, in the present application the term “nitrogen protecting group” comprises any group which is capable of reversibly protecting a amino functionality.
If an embodiment requires the removal of the nitrogen protecting group, as defined above, the removal usually can be carried out by using known methods. Preferably, the nitrogen protecting group, as defined above, is removed by using acidic or basic conditions. Examples for acidic conditions are hydrochloric acid, trifluoroacetic acid, sulphuric acid. Examples of basic conditions are lithium hydroxide, sodium ethoxide. Nucleophiles such as sodium borohydride can be used.
Silyl, as used herein, refers to a group according to the formula —SiR11R12R13, wherein R11, R12 and R13 are, independently of each other, alkyl or aryl. Preferred examples for R11, R12 and R13 are methyl, ethyl, isopropyl, tert-butyl, phenyl or phenyl-C1-4-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 C1-C7-alkyl, preferably C1-C4-alkyl.
The term “C1-C7-” 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, C3-C7-cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
Alkoxy is, for example, C1-C7-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. C1-C4-alkoxy is preferred.
Alkanoyl is, for example, C2-C8-alkanoyl and is, for example, acetyl [—C(═O)Me], propionyl, butyryl, isobutyryl or pivaloyl. C2-C5-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-C1-C7-alkyl and is in particular halo-C1-C4-alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl. Preferred halo-C1-C7-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 C2-C7-alkenyl, more preferably C2-C4-alkenyl. Some examples of 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 C1-7-alkyl and is especially C2-C7-alkylene or C2-C7-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, C1-C7-alkyl, C1-C7-alkoxy-C1-C7-alkyl or C1-C7-alkoxy.
Alkenylene is a bivalent radical derived from C2-7-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 C6-10-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. C1-C7-alkyl, C1-C7-alkoxy-C1-C7-alkyl or C1-C7-alkoxy.
The term arylalkyl refers to aryl-C1-C7-alkyl, wherein aryl is as defined herein and is for example benzyl.
The term carboxyl refers to —CO2H.
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, C1-C7-alkyl, halo-C1-C7-alkyl, C1-C7-alkoxy, halo-C1-C7-alkoxy, such as trifluoromethoxy and C1-C7-alkoxy-C1-C7-alkoxy. When the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
Acetyl is —C(═O)C1-C7-alkyl, preferably —C(═O)Me.
Sulfonyl is (unsubstituted or substituted) C1-C7-alkylsulfonyl, such as methylsulfonyl, (unsubstituted or substituted) phenyl- or naphthyl-C1-C7-alkylsulfonyl, such as phenylmethanesulfonyl, or (unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein if more than one substituent is present, e.g. one to three substitutents, the substituents are selected independently from cyano, halo, halo-C1-C7-alkyl, halo-C1-C7-alkyloxy- and C1-C7-alkyloxy. Especially preferred is C1-C7-alkylsulfonyl, such as methylsulfonyl, and (phenyl- or naphthyl)-C1-C7-alkylsulfonyl, such as phenylmethanesulfonyl.
Sulfenyl is (unsubstituted or substituted) C6-10-aryl-C1-C7-alkylsulfenyl or (unsubstituted or substituted) C6-10-arylsulfenyl, wherein if more than one substituent is present, e.g. one to four substitutents, the substituents are selected independently from nitro, halo, halo-C1-C7-alkyl and C1-C7-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, C1-C7-alkyl, C1-C7-alkoxy-C1-C7-alkyl, C1-C7-alkoxy or halo.
Azide refers to a group —N═N+═N—.
The term “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.
In the formulae of the present application the term “
Figure US10385004-20190820-P00001
” on a C-sp3 represents a covalent bond, wherein the stereochemistry of the bond is not defined. This means that the term “
Figure US10385004-20190820-P00001
” on a C-sp3 comprises an (S) configuration as well as an (R) configuration of the respective chiral centre. Furthermore, mixtures, e.g. mixtures of enantiomers such as racemates, are also encompassed by the present invention. Especially preferred are single stereoisomers of the compounds of the formula (1) or (2), especially the specific ones of formula (1-a) and (1-b).
In the formulae of the present application the term “
Figure US10385004-20190820-P00001
” on a C-sp2 represents a covalent bond, wherein the stereochemistry or the geometry of the bond is not defined. This means that the term “
Figure US10385004-20190820-P00001
” on a C-sp2 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.
In the formulae of the present application the term “
Figure US10385004-20190820-P00002
” on a C-sp3 indicates the absolute stereochemistry, either (R) or (S).
In the formulae of the present application the term “
Figure US10385004-20190820-P00003
” on a C-sp3 indicates the absolute stereochemistry, either (R) or (S).
In the formulae of the present application, the term “
Figure US10385004-20190820-P00004
” indicates a C-sp3-C-sp3 bond or a C-sp2-C-sp2 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 ø×250 mm, 5 μm (Daicel Corporation, Osaka, Japan) at 25° C.; mobil phase Hept:EtOAc:CH3CN, 90:8:2.
The term “substantially optically pure” compound, as defined herein, refers to a compound obtained by a process according to the invention wherein the compound has an optical purity of at least 70% (ee=enantiomeric excess), more preferably of at least 90% (e.e.) and most preferably at least 95% (ee) or more, such as 100% (ee).
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.
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.
In the presence of negatively charged radicals, such as carboxy or sulfo, 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.
When a basic group and an acid group are present in the same molecule, any of the intermediates mentioned herein may also form internal salts.
For isolation or purification purposes of any of the intermediates mentioned herein it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
In view of the close relationship between the compounds and intermediates in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the compounds or salts thereof, 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.
Where the plural form is used for compounds, starting materials, intermediates, salts, pharmaceutical preparations, diseases, disorders and the like, this intends to mean one (preferred) or more single compound(s), salt(s), pharmaceutical preparation(s), disease(s), disorder(s) or the like, where the singular or the indefinite article (“a”, “an”) is used, this does not intend to exclude the plural, but only preferably means “one”.
The term “pro-drug”, as used herein, 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:
Functional Group Reversible derivative
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:
Oxidative Activation
    • N- and O-dealkylation
    • Oxidative deamination
    • N-oxidation
    • Epoxidation
Reductive Activation
    • Azo reduction
    • Sulfoxide reduction
    • Disulfide reduction
    • Bioreductive alkylation
    • Nitro reduction
Each of the above described reactions and/or reaction steps can be used individually or in combination in a method to prepare a NEP-inhibitor or a prodrug thereof, such as a NEP inhibitor or pro-drug thereof comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, such as alkyl ester, backbone. In particular 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.
Embodiments
The following sections describe the individual process steps as laid out in SCHEMES 1 to 5 above.
Compounds:
In one embodiment the compound of the formula (1) is represented by formula (1-a) with the following stereochemistry,
Figure US10385004-20190820-C00030
wherein, if 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.
In another embodiment the compound of the formula (2) is represented by formula (2-a) with the following stereochemistry,
Figure US10385004-20190820-C00031
wherein, if compound (2) 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.
Michael Addition—Catalysts
In one embodiment, 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:
Figure US10385004-20190820-C00032
Disclosed in
Left:
  • (1) Li, De Run; Organic Letters 2010, V12(8), P1756-1759 CAPLUS
  • (2) Zhang, Xue-jing; Tetrahedron: Asymmetry 2009, V20(12), P1451-1458 CAPLUS
  • (3) Yu, Feng; Organic & Biomolecular Chemistry 2010, V8(20), P4767-4774 CAPLUS
  • (4) Fu, Ji-Ya; Tetrahedron Letters 2010, V51(37), P4870-4873 CAPLUS
    Right:
  • (5) Galzerano, Patrizia; Chemistry—A European Journal 2009, V15(32), P7846-7849, S7846/1-S7846/45 CAPLUS
Figure US10385004-20190820-C00033
  • Disclosed by Sigma-Aldrich Corporation, St. Louis, Mo., United States of America
Figure US10385004-20190820-C00034
Disclosed in
Left:
  • (1) Sakamoto, Shota; Inokuma, Tsubasa; Takemoto, Yoshiji From Organic Letters (2011), 13(24), 6374-6377
  • (2) Bai, Jian-Fei; Wang, Liang-Liang; Peng, Lin; Guo, Yun-Long; Jia, Li-Na; Tian, Fang; He, Guang-Yun; Xu, Xiao-Ying; Wang, Li-Xin, From Journal of Organic Chemistry (2012), 77(6), 2947-2953
  • (3) Tripathi, Chandra Bhushan; Mukherjee, Santanu, from Organic Letters (2014), 16(12), 3368-3371
    Middle:
  • (4) Hu, Zhi-Peng; Lou, Chun-Liang; Wang, Jin-Jia; Chen, Chun-Xia; Yan, Ming, from Journal of Organic Chemistry (2011), 76(10), 3797-3804
  • (5) Sakamoto, Shota; Inokuma, Tsubasa; Takemoto, Yoshiji, from Organic Letters (2011), 13(24), 6374-6377.
Figure US10385004-20190820-C00035
Figure US10385004-20190820-C00036
Left & middle compound disclosed in
  • (1) Nunez, Marta G.; Farley, Alistair J. M.; Dixon, Darren J., from Journal of the American Chemical Society (2013), 135(44), 16348
Figure US10385004-20190820-C00037
Left compound disclosed in
  • (1) Sigma-Aldrich Corporation, St. Louis, Mo., United States of America
Figure US10385004-20190820-C00038
Right Compound disclosed in
  • (1) Gao, Yaojun; Ren, Qiao; Wu, Hao; Li, Maoguo; Wang, Jian, from Chemical Communications (Cambridge, United Kingdom) (2010), 46(48), 9232-9234
  • (2) Ren, Qiao; Gao, Yaojun; Wang, Jian, from Chemistry—A European Journal (2010), 16(46), 13594-13598,
Figure US10385004-20190820-C00039
Disclosed in
  • (1) Berkessel, Albrecht; Seelig, Bianca; Schwengberg, Silke; Hescheler, Juergen; Sachinidis, Agapios, from ChemBioChem (2010), 11(2), 208
  • (2) Okino, Tomotaka; Hoashi, Yasutaka; Takemoto, Yoshiji, from Journal of the American Chemical Society (2003), 125(42), 12672
Figure US10385004-20190820-C00040
Figure US10385004-20190820-C00041
Catalysts commercially available (@), where not otherwise specified, have been both from DAICEL CHIRAL TECHNOLOGIES (CHINA) CO., LTD., Shanghai, People's Republic of China.
These 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.
In one embodiment thereof, the organocatalyst is selected from the group consisting of those represented by the following formulae:
Figure US10385004-20190820-C00042
These have the names 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(pyrrolidin-1-yl)cyclohexyl)thiourea and 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(piperidin-1-yl)cyclohexyl)thiourea, respectively.
In another embodiment thereof, the organocatalyst is a prolinol organocatalyst, preferably selected from the group consisting of those with the following formulae:
Figure US10385004-20190820-C00043
wherein TMS=trimethylsilyl, and which are used in the (R)- or in the (S) configuration, and with the following formulae:
Figure US10385004-20190820-C00044
wherein Ph=phenyl and Tf=trifluoromethanesulfonyl.
These catalysts can e.g. be obtained commercially from Sigma-Aldrich Corporation St. Louis, Mo., USA.
The proline derivative below is known from the literature
Figure US10385004-20190820-C00045
  • see Cobb, Alexander J. A.; Organic & Biomolecular Chemistry 2005, V3(1), P84-96; and Longbottom, Deborah A.; Franckevicius, Vilius; Ley, Steven V. Chimia (2007), 61(5), 247-256.
    Processes
Wherever 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 (here and anywhere else where mentioned in the present disclosure) 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.
As solvent for the processes according to the invention, as alternative to those mentioned specifically polar protic solvents (e.g. methanol, ethanol, propanol, butanol), polar aprotic solvents (e.g. tetrahydrofuran (THF), dimethylformamide (DMF), dichloromethane (DCM), acetonitrile (ACN)), or apolar aprotic solvent (e.g. toluene) may be used. Alternatively, mixtures of those solvents/solvent groups or ionic liquids may be used. Preferably, 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.
More specifically, there is provided the process according to the reaction depicted in SCHEME 1 or 1-a, wherein 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.
The process is preferably performed in a hydrogenation reactor. Preferably 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.
If 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. For example, to insert a ter-butoxycarbonyl protecting group, Boc2O 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.
In a specific embodiment, the process is performed with Raney nickel as 50% water slurry, using Boc2O 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. 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 H5IO6 in the presence of a catalyst, such as pyridinium chloroformate, a solvent, e.g. acetonitrile, e.g. at room temperature; with sodium perborate in the presence of 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]BF4 or [bmim]PF6, e.g. at elevated temperature, such as 30 to 80° C.; or especially under Pinnick oxidation conditions (also known as Lindgren oxidation), using a chlorite salt, e.g. an alkalimetal chlorite, such as sodium chlorite (NaClO2), 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. Further possible methods for the oxidation are known to the person skilled in the art and can, for example, be derived from Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents Steven D. Burke (Editor), Rick L. Danheiser (Editor) ISBN: 978-0-471-97926-5.
The reaction may be conducted under simultaneous esterification to a compound of the formula (1), especially (1-a), wherein R1 is C1-C6-alkyl, especially ethyl, or by subsequent esterification, in both cases reacting with a C1-C6-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 C1-C6-alkyl, especially ethyl, ester e.g. of acetic acid; such conditions are known to the person skilled in the art.
In the process according to SCHEME 3-1 or 3-1a, 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. at 5 to 15 mol %; especially in an organic solvent, such as toluene, at temperatures e.g. in the range from −5 to 50° C., e.g. at 0 to 20° C. Preferably 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.
According to the reaction as depicted in SCHEME 3-2 or 3-2a, as an alternative to the reaction according to SCHEME 3-1 which is starting from the compound of the formula (3), the compound of the formula (2), especially (2-a), 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. Preferably 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. Preferably 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. in the range from −20 to 50° C., e.g. from −10 to 10° C., if desired 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.
In the process as depicted in SCHEME 5 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. 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.
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.
Further Embodiments
The present invention also covers combinations of several reaction steps, e.g.
    • a process for the manufacture of a compound of formula (8), preferably of formula (8-a) from a compound of formula (1), preferably of formula (1-a) according to SCHEME 1, wherein the starting compound of formula (1), preferably of formula (1-a), is obtained from a compound of formula (2), preferably of formula (2-a) by a process according to SCHEME 2;
    • a process for the manufacture of a compound of formula (1), preferably of formula (1-a) from a compound of formula (2) preferably of formula (2-a) according to SCHEME 2, wherein the starting compound of formula (2), preferably of formula (2-a), is obtained by a process according to SCHEME 3-1 or 3-2;
    • a process for the manufacture of a compound of formula (8), preferably of formula (8-a) from a compound of formula (1), preferably of formula (1-a) according to SCHEME 1, wherein the compound of formula (1), preferably of formula (1-a), is obtained from a compound of formula (2), preferably of formula (2-a) by a process according to SCHEME 2, and wherein the starting compound of formula (2), preferably of formula (2-a), is obtained by a process according to SCHEME 3-1 or 3-2;
    • a process for the manufacture of a compound of formula (2), preferably of formula (2-a) from a compound of formula (7) according to SCHEME 3-2, wherein the starting compound of formula (7) is obtained by a process according to SCHEME 4;
    • a process for the manufacture of a compound of formula (1), preferably of formula (1-a) from a compound of formula (2) according to SCHEME 2, wherein the starting compound of formula (2), preferably of formula (2-a), is obtained from a compound of formula (7) by a process according to SCHEME 3-2, wherein the starting compound of formula (7) is obtained by a process according to SCHEME 4;
    • a process for the manufacture of a compound of formula (8), preferably of formula (8-a) from a compound of formula (1), preferably of formula (1-a) according to SCHEME 1, wherein the compound of formula (1), preferably of formula (1-a), is obtained from a compound of formula (2), preferably of formula (2-a) by a process according to SCHEME 2, and wherein the starting compound of formula (2), preferably of formula (2-a), is obtained by a process according to SCHEME 3-2, wherein the starting compound of formula (7) is obtained by a process according to SCHEME 4;
    • a process for the manufacture of a compound of formula (7) from a compound of formula (3) according to SCHEME 4, wherein the starting compound of formula (7) is obtained by a process according to SCHEME 5;
    • a process for the manufacture of a compound of formula (2) preferably of formula (2-a) from a compound of formula (3) according to SCHEME 3-1, wherein the starting compound of formula (3) is obtained by a process according to SCHEME 5;
    • a process for the manufacture of a compound of formula (2), preferably of formula (2-a), from a compound of formula (7) according to SCHEME 3-2, wherein the starting compound of formula (7) is obtained is obtained from a compound of formula (3) by a process according to SCHEME 4, and wherein the starting compound of formula (3) is obtained by a process according to SCHEME 5.
      Follow on Reaction of a Compound of Formula (8) to Produce a NEP Inhibitor
In another embodiment of the invention 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 γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone. NEP inhibitors or pro-drugs thereof comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone include, for example, the NEP inhibitor pro-drug N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester and the corresponding NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid.
The term “NEP inhibitor” describes a compound which inhibits the activity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11).
Compounds of formula (8) or salts thereof, preferably of formula (8-a), or salts thereof, as described herein above can be further reacted to a NEP inhibitor 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.
In a preferred embodiment of the invention a compound according to formula (8), preferably of formula (8-a), or salt thereof, is further reacted to obtain the NEP inhibitor pro-drug of formula (10)
Figure US10385004-20190820-C00046
preferably of formula (10-a)
Figure US10385004-20190820-C00047
wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl, by reaction with succinic acid or a derivative thereof, preferably succinic acid anhydride.
Deprotection of the nitrogen functionality, i.e. removal of the Boc group, —if necessary—re-introduction of the ethyl ester group, and subsequent coupling with succinic anhydride delivers the desired NEP inhibitor prodrug compound. Optionally, the ester can be saponified to the free acid providing the NEP inhibitor drug compound.
In one embodiment, 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.
Figure US10385004-20190820-C00048
The 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.
For example, this conversion can be performed using the Boc protected amino acid e.g. according to scheme Z below where the Boc corresponds to R′ and R″ is H in formula (8-a) and R1 is H and the aminoethyl ester (upper right formula in scheme Z below with R′=H, R″=H, R1=Et). If R1 is ethyl, the reaction works identically. If R1 is a different alkyl group, then transesterification or saponification is needed before.
Figure US10385004-20190820-C00049
EXAMPLES
The following examples serve to illustrate the invention without limiting the scope thereof, while they on the other hand represent preferred embodiments of the reaction steps, intermediates and/or the process of the present invention.
Abbreviations
δ chemical shift
μl microliter
Ac acetyl
ACNL acetonitrile
AcOH acetic acid
Ac2O acetic acid anhydride
Bn benzyl
Boc tert-butoxycarbonyl
BOC2O di-tert-butyl carbonate
Brine saturated (at room temperature) sodium chloride solution in water
BuOH n-butanol
Cbz benzyl carbamate
Cbz-Cl benzyl chloroformate
DBU 1,8-Diazabicycloundec-7-ene
DCM dichloromethane/methylenechloride
de diastereomeric excess
DIPEA diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMSO dimethylsulfoxide
ee enantiomeric excess
ES electrospray
ESI electrospray ionisation
Et ethyl
Et2O diethyl ether
Et3N triethanolamine
EtOH ethanol
EtOAc ethyl acetate
GC gas chromatography
h hour(s)
Hep heptane(s)
Hex hexane(s)
HNMR proton nuclear magnetic resonance
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
i-Pr isopropyl
IPA or iPrOAc isopropyl acetate
iPr2O isopropyl alcohol
IR infra red
KHMDS potassium bis(trimethylsilyl)amide
L liter
LC-MS liquid chromatography-mass spectrometry
LDA lithium diisopropylamide
LHMDS lithium bis(trimethylsilyl)amide
M molarity
m/e mass-to-charge ratio
Me methyl
MeOH methanol
mg milligram
min minute(s)
mL milliliter
mmol(s) millimole(s)
mol(s) mole(s)
MS mass spectrometry
NaHMDS sodium bis(trimethylsilyl)amide
nm nanometer
NMR nuclear magnetic resonance
Pd/C palladium on carbon
Ph phenyl
PHCH3 toluene
Piv pivaloyl
Piv-Cl pivaloyl chloride
ppm parts per million
psi pounds per square inch
RP reverse phase
RT room temperature
rt retention time
SEM 2-(trimethylsilyl)ethoxymethyl
SEM-Cl (2-chloromethoxyethyl)-trimethylsilane
SM starting material
TEMPO (2,2,6,6-tetramethyl-piperidin-1-yl)oxidanyl
TES triethylsilyl
Tf triflyl, trifluoromethanesulfonyl
TFA trifluoroacetic acid
TFAA trifluoroacetic acid anhydride
THF tetrahydrofuran
TLC thin layer chromatography
TMEDA N,N,N′,N′-tetramethylethylenediamine
TMS trimethylsilyl
tR retention time
Ts tosyl
TsO tosylate
uPLC Ultra Performance Liquid Chromatography
In quoting NMR data, the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartext; quint., quintet; m, multiplet.
Note that in the Examples the numbers of compounds, such as 1 or 2, are different and separate from the compounds represented by numbers in parenthesis above and in the claims, such as (1) or (2), just to clarify paradigmatically.
Example 1: Synthesis of (2R,4S)-4-amino-5-([1,1′-biphenyl]-4-yl)-2-methyl-pentanoic Acid chlorohydrate
Figure US10385004-20190820-C00050
Example of catalyst includes (catalysts commercially available or reported in literature)
Figure US10385004-20190820-C00051
Figure US10385004-20190820-C00052
a) 1-(biphenyl-4-yl)-2-nitroethanol (Compound 2) from biphenyl-4-carbaldehyde (2)
Figure US10385004-20190820-C00053
To a solution of 4-biphenyl carboxaldehyde (Sigma-Aldrich Corporation St. Louis, Mo., USA) (25 g, 137 mmol) and nitromethane (7.3 mL, 137 mmol) in methanol (125 mL), sodium hydroxide (6.25 g, 164 mmol) in water (21 mL) was added dropwise by maintaining the internal temperature at 0° C. The reaction mixture was stirred at 0° C. for 5 h. The progress of the reaction was monitored by HPLC. The reaction mixture was diluted with ice-cold water (150 mL) and stirred for 15 min at 0° C. The resultant reaction mixture was acidified with 6 N HCl (250 mL) at 0° C. and stirred for 30 min. The yellow solid precipitated out was filtered, washed with water and dried under vacuum to get a yellow solid (23 g). Analysis revealed that the isolated material is a mixture of compounds 2 and 3. This material has been used for the next step without any further purification.
b) 4-[2-nitroethenyl]biphenyl (Compound 3) from 1-(biphenyl-4-yl)-2-nitroethanol (3)
Figure US10385004-20190820-C00054
To a solution of the above mixture (23 g, 94.5 mmol, considered as 1 eq.) in dichloromethane (230 mL) acetic anhydride (18 mL, 189 mmol) and triethylamine (26 mL, 189 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water (100 mL) at 0° C. and concentrated under reduced pressure to remove dichloromethane completely. The brown solid was precipitated out from the resultant aqueous layer. It was washed with excess of water, filtered and dried under vacuum to get compound 3 as a yellow solid (18 g), used for the next step without further purification.
c) 4-(2-nitroethyl)biphenyl (Compound 4) from 4-[2-nitroethenyl]biphenyl (4)
Figure US10385004-20190820-C00055
To a solution of compound 3 (10 g, 44.4 mmol) in dimethylsulfoxide (35 mL) was added acetic acid (5 mL, 88.8 mmol) followed by sodium borohydride (0.51 g, 13.3 mmol) portionwise (3 lots) at 0° C. and stirred for 90 min. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) at 0° C. and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water (2×100 mL) and saturated brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography on silica-gel using 6% ethyl acetate in hexane as an eluent to afford compound 4 as a pale yellow solid. Yield: 6 g (26.4 mmol, 34%, over 3 steps).
1H-NMR (300 MHz, CDCl3) δ 1.58 (s, 1H), 3.37 (t, 2H, J=8 Hz), 4.65 (t, 2H, J=7.5 Hz), 7.263-7.384 (m, 2H), 7.423 (m, 1H), 7.448-7.472 (m, 2H), 7.55-7.59 (m, 2H).
13C-NMR (100 MHz, CDCl3) δ 33.0, 76.14, 127.0, 127.4, 127.6, 128.8, 129.0, 134.7, 140.3, 140.5
d) 4-(2-nitroallyl)-1,1′-biphenyl (5)
Figure US10385004-20190820-C00056
To a solution of compound 4 (10 g, 44.0 mmol) in THF (100 mL) a solution of NaOH (10%, w/w) was added, followed by a 37% aqueous solution of formaldehyde (37.5 g, 46.2 mmol) added dropwise at 0° C. The resulting mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. Brine was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was dissolved (6 g of target compound estimated) in toluene and N-ethyl-N-isopropylpropan-2-amine (diisopropylamine) was added (13.2 ml, 76.96 mmol). To the resulting stirring solution 2,2,2-trifluoroacetic anhydride (3.73 g, 26.8 mmol) was added dropwise at 0° C. and the mixture stirred for 3 h at room temperature. the resulting solution was purified by flash chromatography (gradient Hex→Hex:EtOAc, 8:2, v/v) to obtain 5.8 g (24.24 mmol, 55%) of compound 5
1H-NMR (300 MHz, CDCl3) δ 3.94 (s, 2H), 5.53 (psd, 1H), 6.56 (psd, 1H), 7.30-7.38 (m, 3H), 7.44-7.47 (t, 2H), 7.57-7.60 (m, 4H).
13C-NMR (100 MHz, CDCl3) δ 36.1, 119.0, 127.1, 127.4, 127.6, 128.8, 129.4, 134.5, 140.3, 140.6, 157.5.
e) (2R,4S)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-nitropentanal (5)
Figure US10385004-20190820-C00057
Screening conditions: To a solution of 4-(2-nitroallyl)-1,1′-biphenyl (5) (50 mg, 0.21 mmol) in toluene or DMF (1 ml), propionaldehyde (37 Dl, 0.522 mmol) 4-nitrobenzoic acid (8.8 mg, 0.0525 mmol) and catalyst (0.021 mmol, 10 mol %) were added at 10° C. The mixture was stirred at 10° C. for 48 h.
By using (S)-(−)-α,α-Diphenyl-2-pyrrolidinemethanol tert-butyldimethylsilyl ether as catalyst a mixture of isomers enriched in compound 6 (96% solution yield; 33% (2R,4S); 28% (2S,4R); 20% (2S,4S); 17% (2R,4R)), was obtained.
f) Compound 6 as 2R4S Isomer
1H-NMR (400 MHz, CDCl3) δ 1.19 (d, 3H, J=7.5 Hz), 1.98-2.06 (m, 1H), 2.21 (ddd, 1H, J1=3.3, J2=9.8, J3=14.8 Hz), 2.43-2.53 (m, 1H), 3.12 (dd, 1H, J1=5.5, J2=14.3 Hz), 3.31 (dd, 1H, J1=8.8, J2=14.3 Hz), 4.89-4.96 (m, 1H), 7.25 (psd, 2H), 7.33-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H), 9.56 (s, 1H).
13C-NMR (100 MHz, CDCl3) δ 14.2, 33.9, 40.0, 42.9, 87.8, 126.9, 127.3, 127.5, 128.7, 129.2, 133.9, 140.4, 140.4, 202.3.
LC-MS: [MH3O]+=315.2 m/z
Chiral HPLC, 9.00 (2R,4S), 10.17 (2S,4S) 12.65 (2R,4R), 14.89 min (2S,4R); Column Chiralpak ID 4.6 mm ø×250 mm, 5 μm Daicel Corporation, Osaka, Japan
25° C.; Hept:EtOAc:CH3CN, 90:8:2
g) (2R,4S)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-nitropentanoic Acid
Figure US10385004-20190820-C00058
To a solution of compound 6 (492 mg, 1.72 mmol) in a mixture of EtOAc/tBuOH/H2O (1:2:1.5 v/v/v, 20 ml) was added 2-methyl-2-butene (361 mg, 5.15 mmol). The resulting mix was stirred for 1 min and KH2PO4 (750 mg, 5.15 mmol) and NaClO4 (311 mg, 3.44 mmol) were added. The mixture was stirred 2 h at room temperature. HCl 3 M (25 ml) was added and the product was extracted with EtOAc (3*30 ml) and the combined organic phases were filtered on a pad of MgSO4, and dried in vacuum, to obtain 508 mg (1.62 mmol, crude yield 94%) of acid 7. Compound 7 was consider pure enough and has been used for the next step without any further purification.
Compound 7 as 2R4S Isomer
1H-NMR (400 MHz, CDCl3) δ 1.27 (d, 3H, J=7.5 Hz), 2.12-2.22 (m, 2H), 2.51-2.57 (m, 1H), 3.12 (dd, 1H, J1=5.5, J2=14.3 Hz), 3.30 (dd, 1H, J1=8.8, J2=14.3 Hz), 4.92-4.97 (m, 1H), 7.25 (psd, 2H), 7.34-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H).
13C-NMR (100 MHz, CDCl3) δ 18.1, 36.0, 36.7, 40.1, 88.0, 127.0, 127.3, 127.5, 128.8, 129.3, 130.8, 140.0, 179.3.
h) (2R,4S)-4-amino-5-([1,1′-biphenyl]-4-yl)-2-methyl-pentanoic Acid chlorohydrate
Figure US10385004-20190820-C00059
Compound 6 (considered 508 mg, 1.62 mol) was dissolved in MeOH (5 ml), and Nickel Raney (30 mg) was added (washed with MeOH 4 time). The hydrogenation was carried out in endeavour biotage equipment (4 bar, 35° C., 2 h) and the mixture was filtered on a pad of celite and washed with MeOH. To this solution was bubbled HCl(g), in turn generated in a separated flask from NaCl and H2SO4. After 10 min the mixture was dried in vacuum, washed with DCM/Hexane 1:4 (v/v), to obtain (475 mg, 1.48 mmol) of solid in 92% yield; Analytical data have been compared and found consistent with those reported into PCT Int. Appl. WO 2008/083967.
Example 2: Alternative Synthesis of (2R,4S)-4-amino-5-([1,1′-biphenyl]-4-yl)-2-methyl-pentanoic Acid chlorohydrate
Figure US10385004-20190820-C00060
Examples of catalysts are:
Figure US10385004-20190820-C00061
Figure US10385004-20190820-C00062
Figure US10385004-20190820-C00063
Figure US10385004-20190820-C00064
Figure US10385004-20190820-C00065
Figure US10385004-20190820-C00066
Figure US10385004-20190820-C00067
a) 4-(2-nitroethyl)biphenyl (Compound 4)
This compound is synthesized as described in Example 1.
b) (2R,4S)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-nitropentanal (5)
Figure US10385004-20190820-C00068
To a solution of 4-(2-nitroethyl)-1,1′-biphenyl (600 mg, 2.64 mmol) in toluene 6 ml, methacroleine (462.6 mg, 6.6 mmol) and catalyst (116 mg, 0.264 mmol, 10 mol %) were added. The solution was stirred 8 h at 10° C. The crude material was purified by column chromatography on silica-gel using 20% ethyl acetate in heptane to afford 492 mg (1.76 mmol, 65% yield) of a mixture of isomers enriched in compound 5 (65% yield; 59% (2R,4S); 17% (2S,4R); 15% (2S,4S); 8% (2R,4R)), as white solid.
Compound 5 as 2R4S isomer
1H-NMR (400 MHz, CDCl3) δ 1.19 (d, 3H, J=7.5 Hz), 1.98-2.06 (m, 1H), 2.21 (ddd, 1H, J1=3.3, J2=9.8, J3=14.8 Hz), 2.43-2.53 (m, 1H), 3.12 (dd, 1H, J1=5.5, J2=14.3 Hz), 3.31 (dd, 1H, J1=8.8, J2=14.3 Hz), 4.89-4.96 (m, 1H), 7.25 (psd, 2H), 7.33-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H), 9.56 (s, 1H).
13C-NMR (100 MHz, CDCl3) δ 14.2, 33.9, 40.0, 42.9, 87.8, 126.9, 127.3, 127.5, 128.7, 129.2, 133.9, 140.4, 140.4, 202.3.
LC-MS: [MH3O]+=315.2 m/z
Chiral HPLC: 9.00 (2R,4S), 10.17 (2S,4S) 12.65 (2R,4R), 14.89 min (2S,4R); Column Chiralpak ID (Daicel Corporation, Osaka, Japan) 4.6 mm ø×250 mm, 5 μm; 25° C.; Hept:EtOAc:CH3CN, 90:8:2
c) (2R,4S)-4-amino-5-([1,1′-biphenyl]-4-yl)-2-methyl-pentanoic Acid chlorohydrate
(2R,4S)-5-([1,1′-biphenyl]-4-yl)-2-methyl-4-nitropentanoic acid 7 and (2R,4S)-4-amino-5-([1,1′-biphenyl]-4-yl)-2-methyl-pentanoic acid chlorohydrate 8 were then synthesized as described in Example 1, step i) and step h).
Analytical data have been compared and found consistent with those reported into PCT Int. Appl. WO 2008/083967.
Enantiomer Characterization:
X-ray data available for the ester analogues:
Compound Structure X-RAY HPLC rt (min)a
E1
Figure US10385004-20190820-C00069
 		confirmed  9.6
E2
Figure US10385004-20190820-C00070
 		confirmed  5.8
E3
Figure US10385004-20190820-C00071
 		NO X-ray availlable  6.4
E4
Figure US10385004-20190820-C00072
 		confirmed 13.3
aheptanes/IPA/EtOH 85:10:5 (v/v/v), flow: 1 ml/min, isocratic, column: chiralcel OD-H, 4.6 × 250 mm
Example 3: Preparation of the Nitroester Isomers
Figure US10385004-20190820-C00073
Ethyl 5-([1,1′-biphenyl]-4-yl)-2-methyl-4-nitropentanoate (9)
To a solution of compound 8 and ethyl methacrylate (1.3 equiv.) in toluene, DBU (1 equiv.) was added dropwise and the mixture was stirred at room temperature for 48 h. NH4Cl(ss) was added and the mix stirred for 5 min. The phases were separated ant the aqueous was extracted with EtOAc. The combined organic phases were dried over MgSO4 and the solvent was removed under vacuum and submitted to flash chromatography.
The fractions containing the four isomers of compound 9 were further purified by preparative chromatography, (Thar SFC200) (Waters Corporation, Milford, Mass., United States of America), mobile phase: A: scCO2; B: MeOH, flow: 200 g/min, conditions: 5% B isocratic column: chiralpak AD-H, 50×250 mm P (Daicel Corporation, Osaka, Japan). The enantio-enriched compounds E1, E2, E3 and E4 have also been tested for their chiral purity with chiral HPLC, mobile phase: heptanes/IPA/EtOH 85:10:5 (v/v/v), flow: 1 ml/min, conditions: isocratic column: chiralcel OD-H, 4.6×250 mm (Daicel Corporation, Osaka, Japan) (rt=E1: 9.6 min, E2: 5.8 min, E3: 6.4 min, E4: 13.3 min).
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:
Temperature 100(2) K
Wavelength 1.54178 Å
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a = 5.448(2) Å □ = 90°
b = 8.286(2) Å □ = 90°
c = 40.777(12) Å □ = 90°
Volume 1840.8(10) Å3
Z 4
Density (calculated) 1.232 g/cm3
Absorption coefficient 0.696 mm−1
F (000) 728
Crystal size 0.21 × 0.11 × 0.04 mm3
Theta range for data collection 2.17 to 66.57°
Index ranges −6 <= h <= 5, −9 <= k <= 9,
−48 <= I <= 48
Reflections collected 53449
Independent reflections 3246 [R(int) = 0.0429]
Completeness to theta = 66.57° 99.5%
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.9727 and 0.8676
Refinement method Full-matrix least-squares on F2
Data/restraints/parameters 3246/0/229
Goodness-of-fit on F2 1.112
Final R indices [I > 2sigma(I)] R1 = 0.0324, wR2 = 0.0826
R indices (all data) R1 = 0.0332, wR2 = 0.0831
Absolute structure parameter 0.0(2)
Extinction coefficient 0.0042(3)
Largest diff, peak and hole 0.166 and −0.158 e · Å−3
Example 4: Manufacture of AHU377 (Sacubitril)
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).
Alternatively, AHU377 can be manufactured as described in WO 2008/083967.
Example 5: Synthesis of Thiourea Catalysts
The following catalysts were synthesized as described below:
Figure US10385004-20190820-C00074
Figure US10385004-20190820-C00075
Figure US10385004-20190820-C00076
Figure US10385004-20190820-C00077
Figure US10385004-20190820-C00078
Figure US10385004-20190820-C00079
The members of series 1 can be prepared as follows:
Compounds 110a, 111a (Scheme A) and, 112a (Scheme B), were prepared by reacting a THF solution of the chiral amine with an equimolar amount of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (119). This is followed by chromatography purification of target products 110a, 111a and 112a obtained in good to excellent yield.
Figure US10385004-20190820-C00080
Figure US10385004-20190820-C00081
Compounds 113a and 114a, can easily be prepared from the common precursor 122. 113a obtained by reacting 122 with isothiocyanate 120, followed by acid hydrolysis of the tert-butyl carbonate protecting group and basic work-up (Scheme C).
Figure US10385004-20190820-C00082
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).
Figure US10385004-20190820-C00083
The synthesis of the catalysts belonging to series 2 is reported in Schemes E and F. The monoprotected chiral diamines 124 and 126 were initially submitted to reductive amination by treatment with formaldehyde and sodium cyanoborohydride. Compounds 125 and 127 thus obtained were deprotected by acid hydrolysis, while the thiourea function was introduced by reaction with isothiocyanate 120 using THF as solvent. The corresponding derivatives 111b and 112b were obtained after flash chromatography in good yield (Scheme 17).
Figure US10385004-20190820-C00084
The synthesis of 114b was performed by a similar procedure, while 113b required a different approach. First, it was reacted with 120 in THF, and subsequently the Boc protecting group was removed by acid hydrolysis with HCl 6 N. The intermediate 128 was submitted to reductive amination by treatment with formaldehyde and sodium cyanoborohydride to obtain the product 113b in good overall yield (Scheme G).
Figure US10385004-20190820-C00085
Series 3
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 pKa values (pKa˜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 preparation of this series is reported in Scheme H. Starting from the benzylic protected chiral diamine 129, the first step involves of the alkylation of the free amine with the alkyl halide in water/organic mixture at 120° C. This is followed by deprotection of the protecting group with HCl 6N at 120° C., leading to compound 130. Both reactions were performed in a microwave apparatus. The last step is the reaction with isothiocyanate 120. The pure catalysts 110c-g were obtained by precipitation from an hexane/EtOAc mixture.
Figure US10385004-20190820-C00086
Series 4
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).
Figure US10385004-20190820-C00087
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).
Figure US10385004-20190820-C00088
Figure US10385004-20190820-C00089
In the following, details for the synthesis of catalysts are provided:
General Methods
All used commercial chemicals were supplied by Sigma-Aldrich, Merck or Fluka, and all these reagents were used without further purification. All reaction were monitored by analytical thin layer chromatography (TLC), performed on Merck silica gel 60 F254 precoated aluminum or glass sheets (0.2 mm) and visualized with UV irradiation (254 nm). NMR were recorded on 400 MHz instruments. Chemical shift are given in δ (ppm) relative to TMS, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br=broad), relative integral, and coupling constants J (Hz). General laboratory equipment and materials like Rotavapor (Büchi), flash-chromatography systems (Biotage). Analytical high performance liquid chromatography (HPLC) and Analytic reverse phase high-performance liquid chromatography (RP-HPLC) were carried out on Agylent instruments, using chiral or RP-18 columns (see Appendix A for HPLC methods). LC-MS were performed in Acquity UPLC/ESI MS.
Synthesis of the Catalysts
1. General Procedure for 110a, 111a and 112a
Isothiocyanato-3,5-bis(trifluoromethyl)benzene (2.95 mmol, 1 eq) was added via syringe pump (0.5 ml/min) to a stirred solution of the (1R,2R)-cyclohexane-1,2-diamine (2.95 mmol, 1 eq) in dry THF (15 mL) over a period of 30 min at 0° C., the reaction was stirred for additional 15 h at room temperature. The solvent was removed and the residue was purified by flash chromatography on biotage apparatus.
110a—1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea
Figure US10385004-20190820-C00090
Prepared according to the general procedure 1. Purification by flash column chromatography on silica gel (DCM:MeOH, from 100:0 to 93:7, v/v) to afford 900 mg of pure product. (Purity estimated by HPLC≥99%). The product was obtained as yellow solid in 80% yield
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.25-1.34 (m, 4H), 1.76-1.81 (m, 2H), 1.95 (m, 1H), 1.97-2.03 (m, 1H), 2.07 (m, 1H), 2.66-2.73 (m, 1H), 3.39 (m, 1H), 6.63 (s, 1H), 7.58 (s, 1H), 8.02 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 24.3, 31.7, 59.4, 118.6, 121.3, 124, 132.2-133.2, 138.6, 180.4.
LCMS (ESI): exact mass calculated for [M+H]+ (C15H18F6N3S) requires m/z 386.11, found m/z 386.2.
111a—1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea
Figure US10385004-20190820-C00091
Prepared according to the general procedure 1. Purification by flash column chromatography on silica gel (DCM:MeOH, from 100:0 to 93:7, v/v) to afford 490 mg of pure product (Purity estimated by HPLC≥95%). The product was obtained in 90% yield, yellow solid.
1H NMR (400 MHz, DSMO): d (ppm) δ 4.38 (d, 1H, J=8 Hz), 5.50 (d, 1H, J=8 Hz), 7.20-7.45 (m, 10H), 7.71 (s, 1H), 8.32 (s, 2H), 10.58 (s, 1H). 13C NMR (100 MHz, DMSO): (ppm) δ 59.9, 63.7, 116.3, 121.5, 122.3, 125.0, 127.3, 127.4, 127.5, 128.4, 128.6, 130.5, 141.4, 142.5, 143.4, 180.6.
LCMS (ESI): exact mass calculated for [M+H]+ (C23H19F6N3S) requires m/z 483.47, found m/z 484.2.
112a—(R)-1-(2′-amino-[1,1′-binaphthalen]-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea
Figure US10385004-20190820-C00092
Prepared according to the general procedure 1. Purification by flash column chromatography on silica gel apparatus (Hex:EtOAc, from 100:0 to 75:25, v/v) to afford 990 mg of pure product (Purity estimated by HPLC≥93%). The product was obtained in 68% yield, yellow solid.
1H NMR (400 MHz, CDCl3): d (ppm) δ 6.87 (dd, 1H, J1=1.1 Hz, J2=8.3 Hz), 7.04 (d, 1H, J=8.8 Hz), 7.16 (ddd, 1H, J1=1.5 Hz, J2=6.8 Hz, J3=8.3 Hz), 7.23 (ddd, 1H, J1=1.3 Hz, J2=6.8 Hz, J1=8.1 Hz), 7.39-7.35 (m, 2H), 7.59-7.53 (m, 3H), 7.62 (s, 1H), 7.72 (d, 2H, J=3.0 Hz), 7.81-7.74 (m, 2H), 8.00 (dt, 1H, J1=1.0 Hz, J2=8.3 Hz), 8.13-8.05 (m, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 76.7, 77.0, 77.2, 77.3, 11.9, 118.2, 119.7, 121.4, 122.9, 123.0, 124.1, 124.7, 124.9, 126.1, 126.9, 127.4, 127.5, 128.2, 128.4, 128.5, 129.7, 130.4, 132.2 (q), 132.7, 132.9, 133.2, 133.8, 138.7, 141.9, 180.1.
LCMS (ESI): exact mass calculated for [M+H]+ (C29H19F6N3S) requires m/z 555.2, found m/z 556.2.
110d—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(piperidin-1-yl)cyclohexyl)thiourea
Figure US10385004-20190820-C00093
Prepared according to the general procedure 1. Purification by flash column chromatography on silica gel (DCM:MeOH, from 100:0 to 9:1, v/v) to afford 900 mg of pure product. (Purity estimated by HPLC 97%). The product was obtained as yellow solid in 76% yield.
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.49-1.07 (m, 10H), 1.78 (d, 1H, J=8.1 Hz), 1.85 (d, 1H, J=8.1 Hz), 1.95 (d, 1H, J=8.1 Hz), 2.36 (td, 3H, J1=3.9 Hz, J2=11.1 Hz), 2.62 (t, 2H, J=8.2 Hz), 2.73 (s, 1H), 3.75 (td, 1H, J1=4.0 Hz, J2=10.5 Hz), 7.73 (s, 1H), 7.84 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 32.6, 49.6, 56.3, 68.9, 118.8, 119.0, 119.1, 119.2, 121.5, 124.3, 124.6, 127.0, 132.6 (q), 139.7, 182.
LCMS (ESI): exact mass calculated for [M+H]+ (C20H25F6N3S) requires m/z 453.5, found m/z 454.3.
113a—1-((1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl) thiourea
Figure US10385004-20190820-C00094
To a solution of 890 mg of 121 in 15 ml THF, a solution of isothiocyanate (1.069 g, 3.94 mmol) in 5 ml of THF at 0° C., was added drop-wise via syringe pump (0.5 ml/min), stirring 5 h (until room temperature). The crude was concentrated under reduced pressure. It was suspended on 5 ml H2O, HCl 6 N (10 ml) was added and stirred overnight. The suspension was dissolved, heating (reflux), stirred 1 h. White crystals were formed from the solution at room temperature, and they were filtered. iPr2O (10 ml) were added to remove lipophilic impurities, and the solid was filtered. Saturated solution of sodium bicarbonate (20 ml) and ethyl acetate were added, stirred 3 h. Aqueous phase was than extracted with EtOAc (2*20), and the organic phases were collected and dried with MgSO4 and concentrated under reduced pressure. 1.15 g of pure product were obtained (69% yield), analized by NMR, HPLC and LC-MS.
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.98 (dd, 1H, J1=10.1 Hz, J2=15.3), 3.43 (dd, 1H, J1=15.1 Hz, J2=8.3 Hz), 4.32-4.17 (m, 1H), 4.41 (d, 1H, J=7.9 Hz), 6.96 (s, 1H), 7.45-7.22 (m, 4H), 7.65 (s, 1H), 8.19 (s, 2H), 12.72 (s, 1H),
13C NMR (100 MHz, CDCl3): (ppm) δ 36.5, 64.5, 65.3, 121.8, 123.0, 123.5, 124.8, 128.1, 128.7, 131.7 (q), 137.9, 141.7, 143.1, 182.6.
LCMS (ESI): exact mass calculated for [M+H]+ (C20H25F6N3S) requires m/z 419.4, found m/z 420.2.
115a—1-((1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl)-3-(3,5-bis(trifluoromethyl)phenyl) thiourea
Figure US10385004-20190820-C00095
To a solution of 121 (1.0 g, 4.03 mmol) in 10 ml of dichloromethane, 0.62 ml (0.669 mg, 6.5 mmol) acetic anhydride and bismuth triflate (118 mg, 0.2 mmol) were added. The solution turn from red to brown, stirred for 2 h. HPLC showed the formation of a product, quantitative. HCl 3N was added and stirred overnight. NaOH 2N (30 ml) was added to the aqueous phase which extracted with EtOAc (3*40 ml). The organic phase was dried with MgSO4, filtered and concentrated under reduced pressure. 800 mg of product were obtained as yellow solid. It has been used directly for the step 2 and the product from step 1 was dissolved on 15 ml of THF. A solution of isothiocyanate (1.092 mg, 4.03 mmol) in 5 ml of THF was added drop wise and stirred 2 h. 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. The solid was dissolved in NaOH (50 ml), and the solution was extracted with EtOAc (50*3), dried with MgSO4 and concentrated under reduced pressure to obtain 710 mg of white powder (overall yield 42%). Product was analyzed by HPLC, NMR and LC-MS.
1H NMR (400 MHz, CDCl3): δ (ppm) δ 2.69 (dd, 1H, J1=9.3 Hz, J2=15.6), 3.40 (dd, 1H, J1=8.2 Hz, J2=15.8 Hz), 3.67 (q, 1H, J=8.5 Hz), 5.06-4.85 (m, 1H), 6.67 (s, 1H), 7.16-7.08 (m, 1H), 7.41-7.22 (m, 2H), 7.55 (s, 1H), 8.09 (s, 2H), 12.37 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 41.9, 62.9, 67.3, 117.9, 123.0, 123.3, 124.9, 128.03, 129.3, 131.8, 138.3, 139.8, 141.8, 182.6.
LCMS (ESI): exact mass calculated for [M+H]+ (C18H15F6N3S) requires m/z 419.3, found m/z 420.1.
2. General Procedure for 111b and 112b
SM (3.93 mmol, 1 eq) was suspended in CH3CN (20 ml), stirred 15 min, and aqueous HCOH (19.6 mmol, 5 eq) was added and stirred 15 min. The suspension became a solution and NaCNBH3 (7.86 mmol, 2 eq) was added, stirring 5 h. AcOH (2 ml) was added and after 2 h of magnetic stirring the solution was dilute with 2% MeOH-DCM (50 ml), washed with NaOH 1 N (3*40 ml) and dried by MgSO4 and concentrated under reduced pressure. A brownish oil was obtained and it was used directly for the step 2. It was dissolved in EtOH (15 ml) and HCl 6 N (5 ml) was added in a microwave vial (20 ml). The solution was heated at 120° C. for 3 h. NaOH 2 N (40 ml) was added and the solution was extracted with EtOAc (3*30 ml), dried by MgSO4 and concentrated under reduced pressure to obtain a brownish oil which was employed directly for the Step 3. To a solution of crude in THF (20 ml), under nitrogen atmosphere, and stirring 10 min as suspension, isothiocyanate (3.93 mmol, 1 eq) was added. After stirring 1 h, a yellow solution was obtained. The reaction mixture was concentrated under reduced pressure, to obtain a yellow oil.
111b—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)-1,2-diphenylethyl) thiourea
Figure US10385004-20190820-C00096
Prepared according to the general procedure 2. The crude was dissolve in EtOAc:Hex (20 ml), 2:3, v/v, stirring 1 h, until the formation of a fine precipitate which has been filtered. The liquid phase was purified by flash chromatography (biotage apparatus) (Hex:DCM from 100:0 to 8:2) to obtain 695 mg of product 111b (overall yield 36%). The reaction product was analyzed by HPLC (≥99%), NMR and LC-MS
1H NMR (400 MHz, CDCl3): δ (ppm) δ 2.13 (s, 1H), 3.76 (d, 1H, J=10.9 Hz), 5.20 (s, 2H), 5.34 (s, 1H), 6.99 (dd, 2H, J1=2.4 Hz, J2=6.7 Hz), 7.05 (s, 5H), 7.17-7.14 (m, 2H), 7.59 (s, 1H), 7.66 (s, 2H), 8.35 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 40.5, 53.4, 59.4, 74.0, 119.0, 121.6, 123.6, 124.3, 127.8, 128.6, 129.9, 131.3, 132.4, 139.1, 180.5.
LCMS (ESI): exact mass calculated for [M+H]+ (C25H23F6N3S) requires m/z 511.5, found m/z 513.2.
112b—(R)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(2′-(dimethylamino)-[1,1′-binaphthalen]-2-yl) thiourea
Figure US10385004-20190820-C00097
Prepared according to the general procedure 2. Hex:DCM from 100:0 to 8:2 to obtain 702 mg of product C2 (overall yield 36%). The reaction product was analyzed by HPLC (≥97%), NMR and LC-MS
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.47 (s, 6H), 5.21 (s, 2H), 6.82 (d, 1H, J=8.5 Hz), 7.02 (ddd, 1H, J1=1.4 Hz, J2=6.6 Hz, J3=8.3 Hz), 7.23-7.13 (m, 2H), 7.34-7.25 (m, 2H), 7.51-7.38 (m, 5H), 7.64 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.90 (t, 2H, J=8.0 Hz), 7.99 (d, 1H, J=8.6 Hz), δ 8.27 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 43.1, 52.4, 117.8, 117.9, 120.5, 121.9, 122.9, 123.0, 123.2, 123.9, 125.8, 126.2, 126.5, 127.4, 127.5, 128.9, 129.0, 129.5, 130.2, 130.6, 130.9, 131.0, 131.2, 131.9, 132.2, 132.3, 133.0, 138.6, 149.0, 178.8.
LCMS (ESI): exact mass calculated for [M+H]+ (C31H23F6N3S) requires m/z 583.59, found m/z 585.2.
113b—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-1-(dimethylamino)-2,3-dihydro-1H-inden-2-yl)thiourea
Figure US10385004-20190820-C00098
To a solution of SM (4.0 g, 16 mmol) in THF (50 ml), a solution of isothiocyanate (4.8 g, 17.7 mmol) in THF (10 ml) at 0° C. was added drop-wise via syringe pump (0.5 ml/min). The solution was stirred 30 min until room temperature was reached. The crude was concentrated under reduced pressure and employed directly for the step 2. The crude from was suspended on H2O (20 ml) and dissolved at reflux. HCl 6 N (10 ml) was added stirring overnight. White crystals were formed from the solution at room temperature, and they were filtered. NaOH 2 N (30 ml) solution and EtOAc (20 ml) were added; the biphasic system was stirred 30 min. Aqueous phase was than extracted with EtOAc (3*20 ml) and all organic phases were dried with MgSO4 and concentrated under reduced pressure. 6,450 g of pure product were obtained The solid obtained from step 2 was suspended on CH3CN (100 ml) and stirred 15 min. Aqueous HCOH (37%) (2.42 g, 80.5 mmol) was added, stirred 15 min and the suspension became a solution. NaCNBH3 (2.025 g, 32.2 mmol) were added, stirs 6 h, and AcOH (5 ml) was added drop-wise and stirred 20 min. The reaction was dilute with 2% MeOH-DCM (100 ml), washed with NaOH 1 N (3*50 ml), dried by MgSO4 and concentrated under reduced pressure. A yellowish solid (5.68 g) were obtained; it was dissolved on MeOH (10 ml) and precipitated as yellowish product (1,958 g, Purity≥97%; 2,562 g≥75% and 1.130 g≥40% (by HPLC)).
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.67 (s, 6H), 2.90 (dd, 1H, J1=9.3 Hz, J2=15.7 Hz), 3.47 (dd, 1H, J1=8.8 Hz, J2=15.7 Hz), 4.50-4.36 (m, 1H), 4.52 (d, 1H, J=7.4 Hz), 6.83-6.68 (m, 1H), 7.45-7.28 (m, 4H), 7.65 (s, 1H), 8.12 (s, 2H), 13.05 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 36.7, 41.4, 60.0, 117.9, 121.8, 123.1, 124.5, 125.5, 127.2, 128.8, 131.7, 136.9, 139.3, 141.9, 182.6
LCMS (ESI): exact mass calculated for [M+H]+ (C20H19F6N3S) requires m/z 447.4, found m/z 448.2.
114b—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl)thiourea
Figure US10385004-20190820-C00099
To a solution of SM (1.5 g, 6.04 mmol) in CH3CN (30 ml), aqueous formaldehyde (37%) (3 ml) was added at room temperature, stirring 15 min. NaBH3CN (760 mg, 12.08 mmol) was added to the solution and it was stirred 2 h. AcOH (2 ml) was added and the solution was stirred for 2 h. Afterwards, the reaction was diluted with 2% MeOH-DCM (80 ml), washed with NaOH 1 N (3*50) and dried by MgSO4 and concentrated under reduced pressure. Brownish oil was obtained and it was employed directly for the step 2. 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. To a solution of crude from step 2 in THF (10 ml), under nitrogen atmosphere, and stirring 10 min as suspension, isothiocyanate (1.64 g, 6.04 mmol) was added. After stirring 30 min, a yellow solution was obtained. The 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%)
The reaction product was analyzed by HPLC (≥97%), NMR and LC-MS
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.45 (s, 6H), 3.11-2.89 (m, 2H), 3.69 (q, 1H, J=8.5 Hz), 5.14 (dd, 1H, J1=4.5 Hz, J2=7.6 Hz), 6.59 (d, 1H, J=4.0 Hz), 7.20-7.23 (m, 2H), 7.26-7.29 (m, 2H), 7.40-7.32 (m, 1H), 7.55 (t, 1H, J=1.5 Hz), 8.03 (d, 2H, J=1.7 Hz), 12.71 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 25.5, 40.9, 53.4, 62.6, 75.6, 117.8, 122.8, 123.5, 125.7, 128.0, 129.5, 131.7, 137.6, 139.9, 142.0, 182.5.
3. General Procedure for Series 3
128 (4.58 mmol, 1 eq), R-X (11.9 mmol, 2.5 eq), K2CO3 (11.9 mmol, 2.5 eq) and water (18 ml) were added in a microwave vial. The reaction tube was placed in a microwave synthesis system and operated at 120° C. for 35 min. After completion of the reaction (monitored by HPLC and LC-MS), the organic portion was extracted into EtOAc (3*20 ml) and the solvent was removed under reduced pressure to obtain a yellowish solid, which was employed directly for the step 2 The crude and HCl 6 N (10 ml) were added in a microwave vial (10-20 ml). The reaction tube was placed in a microwave synthesis system and operated at 150° C. for 1 h. After completion of the reaction (monitored by HPLC and LC-MS), the organic portion was extracted into DCM (3*10 ml) (HPLC showed the presence of benzoic acid). The organic phase was wash with HCl 2 N (3*10 ml) and the aqueous phase (3*15 ml) was concentrate under reduced pressure and washed with MeOH, to obtain yellowish oil, which was used directly for the step 3. To the crude from step 2, THF (30 ml) and Et3N (1.5 ml) were added to obtain a white suspension and let stir for 30 min. 3,5-bis-trifluoromethyl-isothiocianate (4.58 mmol, 1 eq) in THF (15 ml) was added drop-wise and stirred 2 h. 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.
110c—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(pyrrolidin-1-yl)cyclohexyl)thiourea
Figure US10385004-20190820-C00100
Prepared according to the general procedure 3. Purification by flash column chromatography on silica gel apparatus, DCM:MeOH from 100:0 to 95:5, to obtain 921 mg of final product. Overall yield 46%. (Purity≥98%, estimated by HPLC). The reaction has been monitored by NMR and LC-MS.
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 1.37-1.14 (m, 4H), 1.53-1.38 (m, 1H), 1.70-1.57 (m, 1H), 1.85-1.70 (m, 5H), 1.97-1.87 (m, 1H), 2.14-2.02 (m, 1H), 2.89 (s, 4H), 4.39 (s, 1H), 7.72 (s, 1H), 8.27 (s, 2H), 8.50 (s, 1H), 10.51 (s, 1H).
13C NMR (100 MHz, DMSO-d6): (ppm) δ 34.5, 47.2, 53.3, 118.4, 119.1, 119.2, 119.4, 121.7, 125.2, 127.1, 127.5, 132.4, 138.6, 182.
LCMS (ESI): exact mass calculated for [M+H]+ (C19H23F6N3S) requires m/z 439.5, found m/z 441.2.
110e—1-((1R,2R)-2-(bis(2-hydroxyethyl)amino)cyclohexyl)-3-(3,5-bis(trifluoromethyl) phenyl)thiourea
Figure US10385004-20190820-C00101
Prepared according to the general procedure 3. Purification by flash column chromatography on silica gel apparatus Hep:EtOAc from 100:0 to 8:2, to obtain 633 mg of final product. Overall yield 30% (Purity≥95%, estimated by HPLC). The reaction has been monitored by NMR and LC-MS.
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 1.30-1.04 (m, 4H), 1.67-1.55 (m, 1H), 1.80-1.68 (m, 1H), 1.92-1.82 (m, 1H), 2.30 (s, 1H), 2.74-2.56 (m, 3H), 3.47-3.33 (m, 4H), 4.26 (s, 2H), 7.73 (s, 1H), 7.83 (s, 1H), 8.27 (s, 2H), 10.00 (s, 1H).
13C NMR (100 MHz, DMSO-d6): (ppm) δ 24.5, 25.5, 32.5, 53.4, 55.6, 61.0, 116.4, 122.4, 125.1, 130.7, 142.5, 179.8.
LCMS (ESI): exact mass calculated for [M+H]+ (C19H25F6N302S) requires m/z 473.2, found m/z 474.3.
110f—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(2,5-dimethylpyrrolidin-1-yl)cyclohexyl) thiourea
Figure US10385004-20190820-C00102
Prepared according to the general procedure 3. Purification by flash column chromatography on silica gel apparatus, DCM:MeOH from 100:0 to 95:5, to obtain 921 mg of final product. Overall yield 46%. Overall yield 30% (Purity≥98%, estimated by HPLC). The reaction has been monitored by NMR and LC-MS.
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 0.89 (s, 3H), 0.91 (s, 3H), 1.04-1.23 (m, 4H), 1.26-1.42 (m, 3H), 1.71-1.82 (m, 4H), 2.02 (m, 1H), 2.75 (dt, J1=7.5 Hz, J2=28.2 Hz, 1H), 2.82-2.91 (m, 1H), 3.19 (m, 2H), 3.96 (dt, J1=7.5 Hz, J2=26.9 Hz, 1H), 7.74 (s, 3H)
13C NMR (100 MHz, DMSO-d6): (ppm) δ 19.9, 24.7, 26.0, 27.3, 31.1, 32.8, 57.0, 58.9, 120.3, 122.1, 124, 9, 125.0, 133.9, 139.5, 181.5.
110g—1-(3,5-bis(trifluoromethyl)phenyl)-3-((I R,2R)-2-(isoindolin-2-yl)cyclohexyl)thiourea
Prepared according to the general procedure 3. Purification by flash column chromatography on silica gel DCM:MeOH from 100:0 to 95:5, to obtain 521 mg of final product. Overall yield 24% (Purity≥96%, estimated by HPLC). The reaction has been monitored by NMR and LC-MS.
Figure US10385004-20190820-C00103
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 1.40-1.13 (m, 5H), 1.55-1.40 (m, 1H), 1.71-1.58 (m, 1H), 1.77 (d, J=9.1 Hz, 1H), 1.90 (d, 1H), 2.18 (d, J=97.5 Hz, 1H), 3.03-2.77 (m, 1H), 4.23-3.91 (m, 4H), 4.33 (s, 1H), 7.22 (ddd, J1=3.2 Hz, J2=5.6 Hz, J3=22.4, 4H), 7.67 (s, 1H), 8.17 (s, 2H), 8.29 (d, J=7.8 Hz, 1H), 10.03 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 23.8, 27.1, 25.7 32.7, 53.6, 55.3, 61.4, 119.9, 121.1, 127.5, 128.6, 132.1, 133.2, 139.9, 180.7.
LCMS (ESI): exact mass calculated for [M+H]+ (C23H23F6N3S) requires m/z 487.5, found m/z 489.2.
110h—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dibenzylamino)cyclohexyl)thiourea
Figure US10385004-20190820-C00104
Prepared according to the general procedure 3. Purification by flash column chromatography on silica gel Hep:EtOAc from 100:0 to 8:2, to obtain 988 mg of final product. Overall yield 39% (Purity≥95%, estimated by HPLC). The reaction has been monitored by NMR and LC-MS.
1H NMR (400 MHz, CDCl3): d (ppm) δ 0.88 (qd, 1H, J1=3.9 Hz, J2=13.3 Hz), 1.08 (qt, 1H, J1=3.6 Hz, J2=13.1 Hz), 1.34-1.23 (m, 2H), 1.63 (d, 1H, J=13.4, 3.2 Hz), 1.79 (d, 1H, J=12.0 Hz), 2.04 (d, 1H, J=12.2 Hz), 2.33 (td, 1H, J1=3.3 Hz, J2=11.3 Hz), 2.55 (d, 1H, J=11.8 Hz), 3.25 (d, 2H, J=13.1 Hz), 3.68 (d, 2H, J=13.2 Hz), 4.13-3.99 (m, 1H), 6.16-6.00 (m, 1H), 7.04-6.94 (m, 4H), 7.15-7.04 (m, 6H), 7.61 (s, 2H), 7.65 (s, 1H),
13C NMR (100 MHz, CDCl3): (ppm) δ 23.2, 24.5, 25.3 32.3, 53.3, 55.8, 61.0, 119.3, 121.4, 124.0, 127.2, 128.4, 129.8, 132.5, 132.8, 133.5, 139.5, 180.7.
LCMS (ESI): exact mass calculated for [M+H]+ (C29H29F6N3S) requires m/z 565.8, found m/z 568.3.
4. General Procedure for 110k and 111k
110a (5 mmol, 1 eq) was dissolved in ACNL (10 ml) and stirred 15 min. Reagent 130 (1.2 eq) was dissolved in ACNL (12 ml) and added drop-wise at −10° C., stirring for 3 h. NaOH (2 eq) in water (20 ml), and EtOAc (30 ml) were added and stirred 10 min. The organic phase was dried over MgSO4 and concentrated under reduced pressure.
130—N-(chloro(dimethylamino)methylene)-N-methylmethanaminium chloride
Figure US10385004-20190820-C00105
The synthesis of the guanidine-based organocatalysts was performed preparing first the reagent 130 under Vilsmeyer's condition, and it was then employed in synthesis of A12 and B12. To a solution of tetramethylurea (0.71 mmol, 1 eq) in Et2O (5 ml), stirred 5 min, oxalylcloride (3.55 mmol, 5 eq) dissolved in Et2O (5 ml) was added drop-wise. The solution was stirred overnight and the product precipitated as white solid. The solid has been washed with Et20 (3*15 ml), without getting dry.
110k—1-((1R,2R)-2-((bis(dimethylamino)methylene)amino)cyclohexyl)-3-(3,5-bis (trifluoromethyl)phenyl)thiourea
Figure US10385004-20190820-C00106
Prepared according to the general procedure 4. The crude was purified by RP-flash chromatography (H2O:ACNL, from 8:2 to 1:1) To obtain 262 mg of 110k in 78% yield (purity>93% estimated by HPLC)
1H NMR (400 MHz, CDCl3): δ (ppm) δ 1.25-1.34 (m, 4H), 1.76-1.81 (m, 2H), 1.95 (m, 1H), 1.97-2.03 (m, 1H), 2.07 (m, 1H), 2.72 (m, 12H), 3.39 (m, 1H), 6.63 (s, 1H), 7.58 (s, 1H), 8.02 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 24.3, 31.7, 39.2, 59.4, 118.6, 121.3, 124, 132.2-133.2, 138.6, 180.4.
111k—1-((1R,2R)-2-((bis(dimethylamino)methylene)amino)-1,2-diphenylethyl)-3-(3,5-bis (trifluoromethyl)phenyl)thiourea
Figure US10385004-20190820-C00107
Prepared according to the general procedure 4. The crude was purified by RP-flash chromatography (H2O:ACNL, from 8:2 to 1:1) To obtain 149 mg of 110k in 63% yield (purity>96% estimated by HPLC)
1H NMR (400 MHz, DMSO): d (ppm) δ 2.65 (s, 12H), 4.38 (d, 1H, J=8 Hz), 5.50 (d, 1H, J=8 Hz), 7.20-7.45 (m, 10H), 7.71 (s, 1H), 8.32 (s, 2H), 10.58 (s, 1H).
13C NMR (100 MHz, DMSO): (ppm) δ 34.4, 59.9, 63.7, 116.3, 121.5, 122.3, 125.0, 127.3, 127.4, 127.5, 128.4, 128.6, 130.5, 141.4, 142.5, 143.4, 180.6.
5. General Procedure 110l and 111l
To a solution of 110a (0.4 mmol, 1 eq) dissolved in DCM (20 ml) 2-azido-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (0.46 mmol, 1.15 eq) and triethylamine (2 mmol, 5 eq) were added and the solution was stirred 30 min. The reaction was quenched with NaHCO3 (20 ml), then extracted with DCM (3*20 ml), washed with water, saturated brine, and dried over MgSO4. The organic phase has been concentrated, without reaching dryness. Et2O (5 ml) was added and a solution was formed. Triphenylphosphine (0.4 mmol, 1 eq) was dissolved in Et2O (5 ml) and added drop-wise to the reaction. The solid formed was dissolved in MeOH and purified by SFC.
110l 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((triphenylphosphoranylidene)amino) cyclohexyl)thiourea
Figure US10385004-20190820-C00108
Prepared according to the general procedure 5.
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.08-0.90 (m, 1H), 1.40-1.15 (m, 4H), 1.59-1.41 (m, 3H), 1.75-1.63 (m, 1H), 2.11-1.98 (m, 1H), 2.94-2.79 (m, 1H), 3.84-3.67 (m, 1H), 7.38-7.31 (m, 1H), 7.76-7.43 (m, 18H),
13C NMR (100 MHz, CDCl3): (ppm) δ 24.2, 25.0, 32.8, 37.5, 62.1, 66.0, 115.6, 121.9, 124.6, 128.4, 130.9, 131.9, 132.9, 144.0, 183.2
LCMS (ESI): exact mass calculated for [M+H]+ (C33H30F6N3PS) requires m/z 645.6, found m/z 646.5.
110l—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-1,2-diphenyl-2-((triphenylphosphoranylidene)amino)ethyl)thiourea
Figure US10385004-20190820-C00109
Prepared according to the general procedure 5.
1H NMR (400 MHz, CDCl3): δ (ppm) δ 4.43 (dd, 1H, J1=8.8 Hz, J2=15.7 Hz), 5.06 (d, 1H, J=8.6 Hz), 7.01-6.84 (m, 7H), 7.22-7.05 (m, 5H), 7.63-7.37 (m, 25H), 8.23 (s, 1H)
13C NMR (100 MHz, CDCl3): (ppm) δ 60.7, 69.2, 116.5, 123.2, 123.7, 124.6, 125.6, 126.4, 128.4, 128.6, 128.7, 129.2, 131.9, 133.0, 140.4, 144.1, 157.2, 178.2.
LCMS (ESI): exact mass calculated for [M+H]+ (C41H32F6N3PS) requires m/z 747.7, found m/z 748.9.
110m—1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-guanidinocyclohexyl)thiourea
Figure US10385004-20190820-C00110
SM (1 g, 2.595 mmol) and DIPEA (0.671 g, 5.19 mmol) were dissolved in DCM (25 ml), stirred 10 min. 1,3-Bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.5 g, 5.19 mmol) were dissolved in DCM (25 ml) and added drop-wise to the mixture and stirred 16 h, reflux. The crude has been washed with water, dried with MgSO4, and concentrated under reduced pressure. The intermediate 1 was dissolved in EtOH (15 ml) and HCl 6 N (10 ml) were added, stirring 3 h, reflux. NaOH 2 N (60 ml) was added and stir 10 min. The mixture was extracted with EtOAc (3*40 ml), washed with brine, dried with MgSO4 and concentrated under reduced pressure. The mixture was purified by flash chromatography to obtain 935 mg of product in 84% overall yield (Purity estimated by HPLC>97%).
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.06-1.18 (m, 1H), 1.26-1.42 (m, 2H), 1.50-1.65 (m, 5H), 3.7-3.75 (m, 1H), 3.82-3.89 (m, 1H), 7.95 (s, 1H), 8.01 (s, 2H)
13C NMR (100 MHz, CDCl3): (ppm) δ 29.3, 29.8, 55.5, 56.9, 118.9, 119.9, 121.6, 122.6, 124.3, 126.9, 131.9, 139.6, 156.7, 179.3.
LCMS (ESI): exact mass calculated for [M+H]+ (C16H19F6N5S) requires m/z 427.4, found m/z 429.1.

Claims (16)

The invention claimed is:
1. A compound of formula (1), or a salt thereof,
Figure US10385004-20190820-C00111
wherein R1 is hydrogen or C1-C6-alkyl.
2. The compound of the formula (1) according to claim 1 represented by formula (1-a),
Figure US10385004-20190820-C00112
wherein R1 is hydrogen or C1-C6-alkyl.
3. A compound of formula (2),
Figure US10385004-20190820-C00113
4. The compound of formula (2) according to claim 3 represented by formula (2-a),
Figure US10385004-20190820-C00114
5. A compound of formula (7),
Figure US10385004-20190820-C00115
6. A process for the manufacture of a compound of formula (1),
Figure US10385004-20190820-C00116
wherein R1 is hydrogen, or a salt thereof, comprising, oxidizing a compound of formula (2),
Figure US10385004-20190820-C00117
in the presence of an oxidant.
7. The process according to claim 6, further comprising the step of simultaneously or separately esterifying the obtained compound of formula (1), or a salt thereof, wherein R1 is hydrogen, with a C1-C6-aliphatic alcohol, to yield a compound of formula (1) wherein R1 is C1-C6-alkyl.
8. A process for the manufacture of a compound of Formula (2),
Figure US10385004-20190820-C00118
comprising, reacting a compound of formula (3),
Figure US10385004-20190820-C00119
with methacrolein, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
Figure US10385004-20190820-C00120
Figure US10385004-20190820-C00121
Figure US10385004-20190820-C00122
Figure US10385004-20190820-C00123
Figure US10385004-20190820-C00124
Figure US10385004-20190820-C00125
Figure US10385004-20190820-C00126
9. A process for the manufacture of a compound of formula (2),
Figure US10385004-20190820-C00127
comprising, reacting of a compound of formula (7),
Figure US10385004-20190820-C00128
with propionaldehyde, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
Figure US10385004-20190820-C00129
Figure US10385004-20190820-C00130
Figure US10385004-20190820-C00131
Figure US10385004-20190820-C00132
Figure US10385004-20190820-C00133
Figure US10385004-20190820-C00134
Figure US10385004-20190820-C00135
10. The process according to claim 8, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
Figure US10385004-20190820-C00136
11. A process for the manufacture of a compound of formula (7),
Figure US10385004-20190820-C00137
comprising, reacting a compound of formula (3),
Figure US10385004-20190820-C00138
with formaldehyde, or a reactive derivative thereof.
12. The process according to claim 8, further comprising a process for the manufacture of the compound of formula (3),
Figure US10385004-20190820-C00139
the process comprising, hydrogenating a compound of formula (4),
Figure US10385004-20190820-C00140
in the presence of an alkali metal borohydride capable of selectively reducing the double bond.
13. The process according to claim 12, further comprising a process for the manufacture of the compound of formula (4),
Figure US10385004-20190820-C00141
the process comprising, reacting a compound of formula (5),
Figure US10385004-20190820-C00142
with a dehydrating agent.
14. The process according to claim 13, further comprising a process for the manufacture of the compound of formula (5) or a mixture of the compound of formula (5) and the compound of formula (4), the process comprising reacting an aldehyde compound of formula (6),
Figure US10385004-20190820-C00143
or a reactive derivative thereof, with nitromethane.
15. A process for the manufacture of a compound of formula (8),
Figure US10385004-20190820-C00144
wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, and R1 is hydrogen or C1-C6-alkyl, comprising hydrogenating a compound of formula (1), or a salt thereof,
Figure US10385004-20190820-C00145
wherein R1 is hydrogen or C1-C6-alkyl, in the presence of Raney Nickel and optionally including or followed by the introduction of a nitrogen protecting group; and
wherein the obtained compound of formula (8) is optionally further reacted with succinic acid, or a derivative thereof to form a compound of formula (10),
Figure US10385004-20190820-C00146
wherein R1 is hydrogen or C1-C6-alkyl, thereof.
16. The process according to claim 9, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
Figure US10385004-20190820-C00147
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 2015-02-13
EP15155147 2015-02-13
EP15155147.0 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 (en)
EP (1) EP3256444B1 (en)
JP (1) JP6665193B2 (en)
CN (1) CN107250100B (en)
TW (1) TW201632493A (en)
WO (1) WO2016128924A1 (en)

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 (en) * 2018-07-30 2020-08-14 湖北大学 Quaternary phosphonium salt supported chiral amino-thiourea and preparation method and application thereof
CN113121342B (en) * 2019-12-31 2022-05-31 浙江医药股份有限公司新昌制药厂 Preparation method and application of shakubiqu intermediate
CN114957043B (en) * 2022-04-29 2023-09-08 凯特立斯（深圳）科技有限公司 Sabobiqu intermediate, preparation method and application thereof

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
AR064842A1 (en) 2007-01-12 2009-04-29 Mazzucco Gavieiro Maria Belen PIRROLIDIN-2-ONAS, AND ITS USE IN THE PREPARATION OF NEP INHIBITORS
WO2011035569A1 (en) 2009-09-23 2011-03-31 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Process for manufacture of n-acylbphenyl alanine
CN101774941A (en) 2009-01-13 2010-07-14 浙江九洲药业股份有限公司 Method for preparing and splitting 2-acyl amino-3-biphenylyl propionic acid
RU2564024C2 (en) 2010-01-22 2015-09-27 Новартис Аг Intermediate products for producing neutral endopeptidase inhibitors and method for production thereof
KR101476937B1 (en) 2010-08-23 2014-12-24 노파르티스 아게 Process for the preparation of intermediates for the manufacture of nep inhibitors
BR112013004179A2 (en) 2010-08-23 2016-05-10 Novartis Ag process for the preparation of intermediates useful for the manufacture of nep inhibitors
AR092278A1 (en) 2012-08-31 2015-04-08 Novartis Ag PROCESS FOR OBTAINING N-ACILIC DERIVATIVES OF BIFENYL-ALANINE AND RELATED INTERMEDIARIES

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 (en) 2008-01-17 2011-01-19 诺瓦提斯公司 Process and intermediates for the preparation of 5-biphenyl-4-yl-2-methylpentanoic acid derivatives
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
WO2016128924A1 (en) 2016-08-18
CN107250100A (en) 2017-10-13
JP2018506541A (en) 2018-03-08
EP3256444A1 (en) 2017-12-20
TW201632493A (en) 2016-09-16
CN107250100B (en) 2019-12-06
US20180022690A1 (en) 2018-01-25
EP3256444B1 (en) 2019-03-27
JP6665193B2 (en) 2020-03-13

Similar Documents

Publication Publication Date Title
US10385004B2 (en) Process and intermediates for the preparation of NEP inhibitors
US20220098200A1 (en) Synthesis of a bruton&#39;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 (en) Process for the preparation of intermediates for the manufacture of nep inhibitors
US9278972B2 (en) Synthesis of triazolopyrimidine compounds
US11434192B2 (en) Process and intermediates
CN109415308B (en) Novel method for early-stage sabcomet intermediate
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
US20220009952A1 (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
WO2012165268A1 (en) Process for producing ester compound
JPWO2005026108A1 (en) Process for producing N, N&#39;-dialkoxy-N, N&#39;-dialkyloxamide
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 (en) Method for producing phenylalanine derivatives

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