US20090326066A1 - Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors - Google Patents

Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors Download PDF

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US20090326066A1
US20090326066A1 US12/438,798 US43879807A US2009326066A1 US 20090326066 A1 US20090326066 A1 US 20090326066A1 US 43879807 A US43879807 A US 43879807A US 2009326066 A1 US2009326066 A1 US 2009326066A1
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process according
formula
mandyphos
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David Hook
Bernhard Wietfeld
Matthias Lotz
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Novartis Pharmaceuticals Corp
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    • 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
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • 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
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or 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
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a process for producing a compound according to formula (i),
  • R1 and R1′ are independently hydrogen or an amine protecting group, and R2 is a carboxyl group or an ester group, comprising reacting a compound according to formula (ii),
  • R1, R1′ and R2 are defined as above, with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table.
  • the invention relates to products obtainable by said process and to their use in the production of NEP inhibitors. Moreover, the invention relates to the use of transition metal catalyst in the preparation NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • Atrial natriuretic peptides also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals.
  • ANF peptides are metabolically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), also responsible for e.g. the metabolic inactivation of enkephalins.
  • NEP inhibitors are known which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals by inhibiting the degradation thereof to less active metabolites.
  • NEP inhibitors are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (EC 3.4.24.11), particularly cardiovascular disorders such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
  • Processes for preparing NEP-inhibitors are known. Those processes usually comprise a hydrogenation step with a palladium catalyst on carbon:
  • U.S. Pat. No. 5,217,996 describes biaryl substituted 4-amino-butyric acid amide derivatives which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals.
  • NEP neutral endopeptidase
  • U.S. Pat. No. 5,217,996 discloses N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester as a preferred embodiment.
  • N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester 1(ii-a) (4.2 g) is hydrogenated in the presence of palladium on charcoal to give N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers 1(i-a):1(i-b).
  • U.S. Pat. No. 5,250,522 describes phosphonomethyl-biaryl substituted amino acid derivatives which show NEP inhibitor activity.
  • a preferred embodiment is (S)-5-(Biphenyl-4-yl)-4-[(dimethylphosphonomethyl)-amino]-2-pentenoic acid ethyl ester.
  • NEP dicarboxylic acid dipeptide neutral endopeptidase
  • the hydrogenation step preferably has a high yield and preferably leads to products having a high purity degree, preferably products in a diasteromeric ratio higher than 88:12
  • the objects of the present invention can be achieved by using a specific catalyst and a specific chiral ligand in a hydrogenation step in the production of an NEP inhibitor, in particular a NEP inhibitor comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • a specific catalyst and a specific chiral ligand are used in a hydrogenation reaction of compounds according to formula (ii), or salts thereof, particularly in a hydrogenation reaction of compounds according to formula (ii-a), or salts thereof,
  • R1, R1′ and R2 are defined as above.
  • R1, R1′ and R2 are defined as above.
  • the subject-matter of the present invention is a process for producing a compound according to formula (i),
  • R1 and R1′ independently are hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group, comprising reacting a compound according to formula (ii),
  • R1, R1′ and R2 are defined as above, with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table.
  • the term represents a covalent bond, wherein the stereochemistry of the bond is determined, as either (S) configuration or as (R) configuration of such a chiral centre.
  • compounds according to formula (ii), or salts thereof are chiral compounds and refer to compounds according to formula (ii-a), or salts thereof, or compounds according to formula (ii-b), or salts thereof.
  • compounds according to formula (i), or salts thereof are chiral compounds and refer to compounds according to formulae (i-a), (i-b), (i-c) and (i-d), or salts thereof.
  • the present invention relates to a process for diastereoselectively hydrogenating a compound of formula (ii) with hydrogen in the presence of a transition metal catalyst and a chiral ligand.
  • the starting material of formula (ii) is chiral, therefore the chirality of both the substrate and the ligand affect the diasteoselectivity in a phenomenon termed “double diastereodifferentiation”, (“matched” and “mistmatched” double asymmetric induction).
  • the degree of facial selectivity observed in the hydrogenation of a chiral compound of formula (ii) in the absence of any other chiral element is the degree of substrate control.
  • the facial selectivity of the substrate matches the facial selectivity of the ligand (“matched” double asymmetric induction)
  • the diastereoselectivity of the hydrogenation with hydrogen in the presence of a transition metal catalyst and a chiral ligand would be expected to increase.
  • the facial selectivity of the substrate does not match the facial selectivity of the ligand (“mismatched” double asymmetric induction)
  • high diastereoselectivity would not be expected.
  • the hydrogenation of a compound of formula (ii) can be achieved in high diastereoselectivity regardless of the degree of substrate control. Therefore, even when the degree of substrate control is high (for example a diasteromeric ratio of up to 80 to 20), the process of the present invention provides means to obtain any of the possible diasteromeric products with high diastereoselectivity.
  • the present invention allows the stereocontrolled hydrogenation of compounds of formula (ii) regardless of the stereochemistry of the starting compound of formula (ii).
  • the process described herein can thus provide any of (i-a), (i-b), (i-c) and (i-d) with high diastereomeric excess.
  • the hydrogenation of a compound of formula (ii-a) can lead to both (i-a) and (i-b) with high diastereomeric excess.
  • the hydrogenation of a compound of formula (ii-b) can lead to both (i-c) and (i-d) with high diastereomeric excess.
  • the compounds of formula (i) have a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid backbone.
  • NEP inhibitors which have a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid backbone, such as N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid. Therefore, the present invention provides a novel asymmetric approach towards the preparation of NEP inhibitors. More importantly, the approach proceeds with high stereocontrol.
  • R1 and R1′ are independently hydrogen or an amine protecting group.
  • R1 is an amine protecting group. It is further preferred that R1′ is hydrogen. That means, in a preferred embodiment R1 is one of the below explained preferred amine protecting groups and R1′ is hydrogen. Alternatively, R1 and R1′ can together form a cyclic ring structure (and thus form a bifunctional cyclic amine protecting group).
  • amine protecting group comprises any group which is capable of reversibly protecting the amino functionality. Suitable amine protecting groups are conventionally used in peptide chemistry and are described e.g. in standard reference works such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Fourth edition, Wiley, New York 2007, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, and in “ Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974.
  • Preferred protecting groups comprise, for example, C 1 -C 2 -alkyl which is mono-, di- or trisubstituted by phenyl, such as benzyl, (or) benzhydryl or trityl, wherein the phenyl ring is unsubstituted or substituted by one or more, e.g. two or three, residues e.g.
  • C 1 -C 7 -alkyl those 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 ; phenyl-C 1 -C 2 -alkoxycarbonyl; and allyl or cinnamyl.
  • benzyloxycarbonyl Cbz
  • 9-fluorenylmethyloxycarbonyl Fmoc
  • benzyloxymethyl BOM
  • pivaloyl-oxy-methyl POM
  • trichloroethxoycarbonyl Troc
  • 1-adamantyloxycarbonyl Adoc
  • the protecting group can also be silyl, like trialkylsilyl, especially trimethylsilyl, tert.-butyl-dimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilylethoxymethyl (SEM), and can also be sulfonyl, such as methanesulfonyl, trifluoromethanesulfonyl and benzylsulfonyl, or sulfenyl, such as benzenesulfenyl.
  • silyl like trialkylsilyl, especially trimethylsilyl, tert.-butyl-dimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilylethoxymethyl (SEM), and can also be sulfonyl, such as methanesulfonyl, trifluoromethanesulfonyl and benzylsulfon
  • R1 and/or R1′ can also be a succinimidyl group or an acetal group.
  • R1 and/or R1′ further include C 1-10 alkenyloxy carbonyl, C 6-10 aryl-C 1-6 alkyl, and C 1-6 alkyl-carbonyl, C 6-10 aryl-carbonyl, C 1-6 alkoxy-carbonyl, and C 6-10 aryl-C 1-6 alkoxycarbonyl.
  • R1 is C 6-10 aryl-C 1-6 alkoxycarbonyl, C 1-6 alkoxy-carbonyl, allyloxycarbonyl or C 6-10 aryl-C 1-6 alkyl such as benzyl, t-butoxycarbonyl (BOC).
  • R1 is t-butoxycarbonyl (BOC). More preferred is that R1 is t-butoxycarbonyl (BOC) and R1′ is hydrogen.
  • R1 and/or R1′ are independently hydrogen or selected from a benzyl group, a succinimdyl group, an acetal group, a silyl group or an oxycarbonyl group.
  • R1 and/or R1′ are independently hydrogen or an amine protective group selected from the group consisting of C 1-6 alkyl which is mono-, di- or trisubstituted by C 6-10 aryl, wherein the aryl ring is unsubstituted or substituted by one, two or three, residues selected from the group consisting of C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, nitro, cyano and CF 3 ; C 6-10 aryl-C 1-6 alkyl, cumyl, phenyl-C1-C2-alkoxycarbonyl, allyl, cinnamyl, 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), C 1-10 alkenyloxycarbonyl, sily
  • ester group comprises any ester of a carboxyl group generally known in the art; for example groups —COOR3, wherein R3 is selected from the group consisting of: C 1-6 alkyl, such as methyl, ethyl or t-butyl, C 1-6 alkoxyC 1-6 alkyl, heterocyclyl, such as tetrahydrofuranyl, C 6-10 aryloxyC 1-6 alkyl, such as benzyloxymethyl (BOM), silyl, such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, cinnamyl, allyl, C 1-6 alkyl which is mono-, di- or trisubstituted by halogen, silyl, cyano or C 1-6 aryl, wherein the aryl ring is unsubstituted or substituted by one, two or three, residues selected
  • R2 is —COOR3, wherein R3 is a C 1-6 alkyl residue.
  • R3 is an ethyl group.
  • R2 is COOH
  • R1 is t-butoxycarbonyl. In another preferred embodiment R1 is t-butoxycarbonyl. In both preferred embodiments R1′ preferably is hydrogen.
  • R1, R1′ and R2 also apply to formulae (i-a), (i-b), (i-c), (i-d), (ii-a) and (ii-b).
  • the reaction of the compound according to formula (ii), or salt thereof, with hydrogen is carried out in the presence of a transition metal catalyst, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table. Therefore, the transition metal catalyst comprises, for example, Manganese (Mn), Rhenium (Re), Iron (Fe), Ruthenium (Ru), Osmium (Os), Cobalt (Co), Rhodium (Rh) and/or Iridium (Ir).
  • the transition metal catalyst comprises rhodium, iridium or ruthenium. In a more preferred embodiment the transition metal catalyst comprises rhodium or ruthenium. In a particular preferred embodiment the transition metal catalyst comprises ruthenium.
  • the transition metal catalyst is an organometallic complex, comprising one or more of the above-mentioned metal atoms and suitable ligands.
  • Suitable ligands for the organometallic complex generally are ⁇ -donor ligands, ⁇ -donor/ ⁇ -acceptor ligands or ⁇ , ⁇ -donor/ ⁇ -acceptor ligands.
  • suitable kind of ligands are among others carbon monoxide, halides, phosphines, alkenyls, alkinyls, aryls and mixtures thereof.
  • ligands for the organometallic complex are: norbornadiene (nbd), cyclooctadiene (cod), cymene, in particular p-cymene, and iodide.
  • the complexes can comprise a single transition metal.
  • the complexes can comprise two or more transition metals, optionally comprising a metal-metal bond.
  • two metal atoms are bridged via two halides.
  • transition metal catalysts examples include [RuI 2 (p-cymene)] 2 , [Rh(nbd) 2 BF 4 ] and [Ir(cod) 2 Cl] 2 . More preferred are [RuI 2 (p-cymene)] 2 and [Rh(nbd) 2 BF 4 ].
  • chiral ligand comprises any ligand that is suitable to build organometallic complexes and that comprises a chiral centre.
  • the chiral ligand comprises a chiral phosphine.
  • the chiral ligand comprises a chiral ferrocene. It is also preferred that the chiral ligand comprises a ferrocene structure wherein the Cp-ligand of the ferrocene is substituted with a chiral group.
  • the chiral ligand is selected from Josiphos ligand, Walphos ligand, Taniaphos ligand, Solphos ligand, Mandyphos ligand, Butiphane ligand or mixtures thereof.
  • Josiphos ligands, Walphos ligands, Taniaphos ligands and Mandyphos ligands are of the formulae:
  • R and R′ are as described in WO2006/003196, EP-B1-612758, WO2006/017045, WO2006/117369 and in particular as shown in examples herein.
  • Suitable chiral ligands are:
  • Ligand (S)—C4-TunaPhos is described in J. Org. Chem., 2000, 65, 6223 (Example 4).
  • Ligand (R)-(+)-BINAP can be purchased from commercial sources such as Aldrich. All other above-mentioned ligands (Mandyphos, Josiphos, Walphos, Solphos, etc.) are commercially available from Solvias AG (Basel, Switzerland).
  • Preferred chiral ligands are:
  • More preferred chiral ligands are:
  • transition metal catalyst and chiral ligand are preferred: rhodium catalyst and a Mandyphos, a Walphos, a Josiphos or a Solphos ligand; more preferably Rh(nbd) 2 BF 4 and a Mandyphos, a Walphos, a Josiphos or a Solphos ligand; yet more preferably rhodium catalyst and Mandyphos SL-M004-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-W001-2, Walphos SL-W003-1, Walphos SL-W008-1 or Solphos SL-A001-1; even more preferably Rh(nbd) 2 BF 4 and Mandyphos SL-M004-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-W001-2, Walpho
  • transition metal catalyst and chiral ligand are preferred: rhodium catalyst and Walphos SL-W008-1; even more preferably Rh(nbd) 2 BF 4 and Walphos SL-W008-1.
  • rhodium catalyst and Walphos SL-W008-1 even more preferably Rh(nbd) 2 BF 4 and Walphos SL-W008-1.
  • transition metal catalyst and chiral ligand are preferred: rhodium catalyst and Mandyphos SL-M004-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-W001-2, Walphos SL-WO03-1 or Solphos SL-A001-1; even more preferably Rh(nbd) 2 BF 4 and Mandyphos SL-M004-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-WO01-2, Walphos SL-W003-1 or Solphos SL-A001-1.
  • transition metal catalyst and chiral ligand by reacting a compound of formula (ii-a), or salt thereof, a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced, wherein the molar ratio of (i-b) to (i-a) is at least 65:35, more preferably at least 73:27.
  • transition metal catalyst and chiral ligand are preferred: rhodium catalyst and a Mandyphos or a Walphos ligand; more preferably [Rh(nbd) 2 BF 4 ] and a Mandyphos or a Walphos ligand as well as rhodium catalyst and SL-M004-2 or SL-W008-1; most preferably [Rh(nbd) 2 BF 4 ] and SL-M004-2 or [Rh(nbd) 2 BF 4 ] and SL-W008-1.
  • transition metal catalyst and chiral ligand are preferred: ruthenium catalyst and a Mandyphos or a Josiphos ligand; more preferably [RuI 2 (p-cymene)] 2 and a Mandyphos or a Josiphos ligand; even more preferably ruthenium catalyst and SL-M001-1, SL-M002-1, SL-M004-1, SL-M004-2 or SL-J002-1; yet more preferably [RuI 2 (p-cymene)] 2 and SL-M001-1, SL-M002-1, SL-M004-1, SL-M004-2 or SL-J002-1.
  • transition metal catalyst and chiral ligand are preferred: ruthenium catalyst and Mandyphos SL-M004-2 or SL-M002-1; preferably [RuI 2 (p-cymene)] 2 and Mandyphos SL-M004-2 or SL-M002-1.
  • transition metal catalyst and chiral ligand by reacting a compound of formula (ii-a), or salt thereof, a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced, wherein the molar ratio of (i-b) to (i-a) is at least 65:35, more preferably at least 73:27, most preferably at least 94:6.
  • the combination of transition metal catalyst and chiral ligand is: ruthenium catalyst and Mandyphos SL-M001-1, Mandyphos SL-M004-1 or Josiphos SL-J002-1; preferably [RuI 2 (p-cymene)] 2 and Mandyphos SL-M001-1, Mandyphos SL-M004-1 or Josiphos SL-J002-1.
  • the combination of transition metal catalyst and chiral ligand is: ruthenium catalyst and Mandyphos SL-M004-1; preferably [RuI 2 (p-cymene)] 2 and Mandyphos SL-M004-1.
  • transition metal catalyst and chiral ligand by reacting a compound of formula (ii-b), or salt thereof, a composition comprising compounds according to formulae (i-c) and (i-d), or salts thereof, is produced, wherein the molar ratio of (i-c) to (i-d) is at least 88:12, more preferably at least 92:8.
  • transition metal catalyst and chiral ligand are preferred: ruthenium catalyst and a Mandyphos or a Josiphos ligand; more preferably [RuI 2 (p-cymene)] 2 and a Mandyphos or a Josiphos ligand as well as ruthenium catalyst and SL-M001-1, SL-M004-1 or SL-J002-1; most preferably [RuI 2 (p-cymene)] 2 and SL-M001-1, SL-M004-1 or SL-J002-1.
  • reaction conditions of the process of the present invention are preferably chosen such that the reaction is carried out as a homogenous catalysis.
  • homogenous catalysis describes a catalysis where the catalyst is in the same phase (e.g. solid, liquid and gas) as the reactants.
  • heterogeneous catalysis describes a catalysis where the catalyst is in a different phase to the reactants. Heterogeneous catalysts usually provide a surface for the chemical reaction to take place on.
  • solvents generally known in the art can be used.
  • a solvent is used which is able to dissolve the transition metal catalyst and the chiral ligand.
  • a polar solvent is used, e.g. a monovalent alcohol. More preferably, the solvent is methanol or ethanol. More preferably, ethanol is used.
  • the amount of solvent employed may be such that the concentration of reactant is in a the range of from 1 to 30% w/v (weight/volume), preferably of from 3 to 25% w/v, more of from 10 to 25% w/v, most preferably of from 20 to 25% w/v.
  • the hydrogenation is carried out at a temperature between 0° C. and 80° C., preferably between room temperature and 80° C., more preferably between room temperature and 60° C., even more preferably between room temperature and 45° C., most preferably between room temperature and 35° C.
  • the hydrogenation usually is carried out at a temperature between 0° C. and 60° C., preferably between 30° C. and 50° C., more preferably between 35° C. and 45° C.
  • the applied hydrogen pressure usually ranges between 5 bar and 30 bar, preferably between 10 bar to 25 bar, more preferably between 12 bar and bar.
  • the reaction time usually ranges between 1 hour and 25 hours, more preferably between 6 hours and 24 hours, yet more preferably between 5 hours and 20 hours. Most preferably, the reaction time usually ranges from 1 hour to 25 hours, preferably from 5 hours to 20 hours.
  • the hydrogen pressure ranges from of 5 bar to bar, preferably from of 5 bar to 20 bar, more preferably from of 10 bar to 20 bar, yet more preferably from of 15 to 20 bar, most preferably the hydrogen pressure is 20 bar.
  • the amount of transition metal catalyst to substrate (ii), typically employed in the process may be in the range of from 0.001 to 5% mol, preferably of from 0.001 to 1% mol, more preferably of from 0.003 to 0.3% mol, yet more preferably of from 0.005 to 0.1% mol, most preferably of from 0.01 to 0.05% mol.
  • the upper limit of the S/C ratio is 25 000, more preferably 30 000.
  • substrate to catalyst ratio refers to the molar ratio of starting compounds according to formula (ii), or salts thereof, to “active catalyst” (formed by mixing the transition metal catalyst and the chiral ligand).
  • the active catalyst is formed by mixing 0.9 to 1.2, preferably 1.0 to 1.1, more preferably 1.0 to 1.05 mole of chiral ligand with 1.0 mole of transition metal atoms comprised in the transition metal catalyst.
  • the active catalyst is formed by mixing 0.9 to 1.2, preferably 1.0 to 1.1, more preferably 1.0 to 1.05 mole of chiral ligand with 1.0 mole of transition metal atoms comprised in the transition metal catalyst.
  • a dimer transition metal catalyst is employed, preferably two moles of chiral ligand are reacted with one mole of transition metal catalyst in order to form the “active catalyst”.
  • the chiral ligand is typically added to the reaction mixture in a solution prepared with the same solvent used for the reaction.
  • R1, R1′ and R2 are defined as above, or according to formula (ii-b), or salt thereof,
  • R1, R1′ and R2 are defined as above, can be used as starting compound.
  • compound (ii-a), or salt thereof is used as starting compound.
  • the synthesis of the starting compound (ii), or salt thereof, wherein R1 is BOC, R1′ is hydrogen and R2 is COOEt is known in the art.
  • R1, R1′ and R2 are defined as above, can be obtained.
  • R1, R1′ and R2 are defined as above, can be obtained.
  • the ratio of compounds according to formula (i-a) to (i-b) and (i-c) to (i-d), respectively, or salts thereof, usually depends on the chosen reaction conditions, e.g. on the transition metal catalyst, on the chiral ligand, on the S/C-ratio and/or on the solvent.
  • a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein the molar ratio of compounds according to formula (i-a), or salts thereof, to compounds according to formula (i-b), or salts thereof, is at least 88:12, preferably from 90:10, more preferably from 99 to 1. Most preferably the molar ratio of compounds according to formula (i-a), or salts thereof, to compounds according to formula (i-b), or salts thereof, is at least 88:12, preferably from 90:10 to 99.9:0.1.
  • the process of the present invention provides compounds according to formulae (i-a) and (i-b), or salts thereof, wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is COOH.
  • a further subject of the present invention is a composition
  • a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, wherein the molar ratio (i-a) to (i-b) is at least 88:12, preferably from 90:10, more preferably from 99:1.
  • the composition comprises compounds according to formulae (i-a) and (i-b), or salts thereof, wherein the molar ratio (i-a) to (i-b) is at least 88:12, preferably from 90:10 to 99.9:0.1.
  • the composition comprises compounds according to formulae (i-a) and (i-b), or salts thereof, wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is COOH.
  • composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein:
  • composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein:
  • composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein:
  • composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein:
  • composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced wherein:
  • composition comprising compounds according to formulae (i-c) and (i-d), or salts thereof is produced wherein:
  • composition comprising compounds according to formulae (i-d) and (i-c), or salts thereof, is produced wherein:
  • the process of the present invention can comprise an additional optional step wherein the compounds according to formula (i-a), or salts thereof, are separated from the above-described composition by means of crystallisation.
  • a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, [preferably having a molar ratio of (i-a) to (i-b) of at least 88:12] is dissolved in a suitable polar first solvent, e.g. a monovalent alcohol, preferably ethanol or an ester, preferably isopropylacetate.
  • a suitable polar first solvent e.g. a monovalent alcohol, preferably ethanol or an ester, preferably isopropylacetate.
  • a suitable less polar second solvent may be added.
  • hydrocarbons e.g. heptane is used as a second solvent.
  • a preferred system comprising a first and a second solvent is isopropylacetate/heptane.
  • the crystallisation step yields compounds according to formula (i-a), or salts thereof, in crystalline form. Therefore, the subject-matter of the present invention are compounds, or salts thereof, according to formula (i-a) in crystalline form. Additionally, also compounds, or salts thereof, according to formulae (i-b), (i-c) and (i-d) in crystalline form are subject of the present invention.
  • the crystalline products of the invention comprise a monoclinic crystal system. Further preferred, the crystalline products of the invention comprise the space group P21. In a preferred embodiment the crystalline products of the invention comprise the following unit cell dimensions, measured at a temperature of 100 K:
  • R2 is COOH or RCOOEt, in particular wherein R2 is COOH.
  • R1 preferably is BOC and R1′ is preferably hydrogen.
  • R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group, provided that R2 is not COOEt if R1 is BOC and R1′ is hydrogen.
  • R2 is COOH.
  • the subject-matter of the present invention is compounds according to formulae (i-b), (i-c) and/or (i-d), or salts thereof, wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group.
  • R2 is COOH or COOEt; more preferably R2 is COOH.
  • the products of the process of the present invention can be used in the synthesis of NEP inhibitors or prodrugs 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).
  • prodrug describes a pharmacological substance which is administered in an inactive (or less active) form. Once administered, the prodrug is metabolised in the body in vivo into the active compound.
  • an embodiment of the process of the present invention comprises one or more additional steps wherein the compound according to formula (i), or salt thereof, is further reacted to obtain a NEP-inhibitor or a prodrug thereof, in particular a NEP-inhibitor or a prodrug thereof comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • NEP-inhibitor or “NEP-inhibitors prodrug” relates to the substances as such or to salts thereof, preferably pharmaceutically acceptable salts thereof. Examples are sodium, potassium, magnesium, calcium or ammonium salts. Calcium salts are preferred.
  • NEP-inhibitor or a prodrug thereof is further reacted to obtain a NEP-inhibitor or a prodrug thereof, in particular a NEP-inhibitor or a prodrug thereof comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • a NEP-inhibitor or a prodrug thereof comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • R1 is BOC
  • R1′ is hydrogen
  • R2 is COOH.
  • a compound according to formula (i-a), or salt thereof is further reacted to obtain the NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (known in the art as AHU 377) or a salt thereof.
  • the present invention comprises any pharmaceutically acceptable salt of N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methyl-butanoic acid ethyl ester, wherein the calcium salt is preferred.
  • NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester optionally is further reacted to obtain the active NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)methylbutanoic acid.
  • the synthesis of N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester starts from a compound according to formula (i-a), or salt thereof, preferably, the synthesis starts from the compound of formula (i-a) wherein R1 is preferably BOC, R1′ is preferably hydrogen and R2 is preferably COOH.
  • said reaction comprises the following steps:
  • the inventive process can be used in the synthesis of NEP inhibitors or prodrugs thereof, in particular NEP-inhibitors, or prodrugs thereof, comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • NEP-inhibitors or prodrugs thereof, comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • a further subject of the present invention is the use of a transition metal catalyst and a chiral ligand in the synthesis of a NEP inhibitor or a prodrug thereof, in particular a NEP-inhibitor comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table.
  • the transition metal catalyst and the chiral ligand are used in a hydrogenation step in the synthesis of a NEP inhibitor, in particular a NEP-inhibitor, or prodrug thereof, comprising a ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid, or acid ester, backbone.
  • the hydrogenation step gives two diastereomers having a diastereomeric ratio of at least 88:12, more preferably from 90:10 to 99.9:0.1.
  • the hydrogenation step yields two diastereomers according to formulae (i-a) and (i-b) having a diastereomeric ratio of at least 88:12, more preferably from 90:10 to 99.9:0.1.
  • the hydrogenation step yields two diastereomers of compounds according to formulae (i-a) and (i-b), or salts thereof, wherein R1 and R1′ are as defined above, having a diastereomeric ratio of at least 88:12, preferably at least 90:10, more preferably at least 99:1.
  • the transition metal catalyst and the chiral ligand, as defined above are used in the synthesis of the NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or a salt thereof.
  • Alkyl being a radical or part of a radical is 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
  • Aryl 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.
  • 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 22 (more preferably 3 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 substitutents mentioned above for cycloalkyl.
  • the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
  • Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo.
  • 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.
  • 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 7 -alkanoyl and is, for example, acetyl [—C( ⁇ O)Me], propionyl, butyryl, isobutyryl or pivaloyl.
  • C 2 -C 5 -Alkanoyl is preferred, especially acetyl.
  • Acetyl is —C( ⁇ O)C 1 -C 7 alkyl, preferably —C( ⁇ O)Me.
  • Alkoxyalkyl may be linear or branched.
  • the alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms.
  • Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.
  • Silyl is —SiRR′R′′, wherein R, R′ and R′′ are independently of each other C 1-7 alkyl, aryl or phenyl-C 1-4 alkyl.
  • Sulfonyl is C 1 -C 7 -alkylsulfonyl, such as methylsulfonyl, (phenyl- or naphthyl)-C 1 -C 7 -alkylsulfonyl, such as phenylmethanesulfonyl, [C 1 -C 7 -alkyl-, phenyl-, halo-C 1 -C 7 -alkyl-, halo, oxo-C 1 -C 7 -alkyl-, C 1 -C 7 -alkyloxy-, phenyl-C 1 -C 7 -alkoxy-, halo-C 1 -C 7 -alkyloxy-, phenoxy-, C 1 -C 7 -alkanoylamino-, C 1 -C 7 -alkylsulfonyl, cyano and/or C 1 -C 7 -alkylsulfony
  • 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.
  • Alkenyl may be linear or branched alkyl containing a double bond and comprising preferably 2 to 12 C atoms, 2 to 8 C atoms being especially preferred. Particularly preferred is a linear C 2-4 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.
  • allyl is preferably allyl.
  • Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, where salts are not 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-di-sulfonic acid, benzenesulfonic 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
  • 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.
  • FIG. 1 shows the structure of crystalline (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid measured by x-ray diffraction.
  • the crystals comprise the following unit cell dimensions, measured by 100 K:
  • the solution is degassed using vacuum and a pressure of 5.5 bar hydrogen is applied.
  • the mixture is heated to 60° C. and stirred at this temperature for 5 days.
  • the vessel is then purged with nitrogen.
  • the solvent is removed in vacuo.
  • the resulting solid is dissolved in isopropyl acetate (34 ml) and heated to reflux.
  • An heptane fraction (68 ml) is added and the mixture is cooled to room temperature.
  • the solid is collected by filtration and washed with an heptane-isopropyl acetate 2:1 mixture (20 ml).
  • the solid is dried overnight at 50° C.
  • Recrystallization 94.5 g of a 80:20 mixture of 3(i-d):3(i-c) is suspended in isopropyl acetate (190 ml) and heated to reflux to give a solution. Heptane fraction (378 ml) is added and the mixture is cooled to room temperature. The material is collected by filtration and washed with 180 ml Heptane/Isopropyl acetate (2:1) to give a 91.7:8.3 mixture of 3(i-d):3(i-c). This mixture is suspended again in isopropyl acetate (280 ml) and heated to reflux. Heptane fraction (560 ml) is added and the mixture cooled to room temperature.

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* Cited by examiner, † Cited by third party
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CN106065006B (zh) * 2015-04-22 2020-06-05 深圳信立泰药业股份有限公司 一种中性内肽酶抑制剂盐晶型及其制备方法
CN106187808A (zh) * 2015-05-08 2016-12-07 苏州鹏旭医药科技有限公司 Ahu-377的制备方法、ahu-377中间体及ahu-377中间体的制备方法
CN104860894B (zh) * 2015-06-10 2017-05-17 北京博全健医药科技有限公司 一种抗心衰药lcz696的制备方法
US11786498B2 (en) 2015-07-02 2023-10-17 Novartis Ag Sacubitril calcium salts
WO2017009784A1 (en) 2015-07-14 2017-01-19 Cadila Healthcare Limited Solid state forms of trisodium salt of valsartan/sacubitril complex and sacubitril
CN105061263B (zh) * 2015-08-11 2017-03-15 苏州楚凯药业有限公司 一种nep抑制剂中间体的制备方法
CN105085322B (zh) * 2015-08-15 2017-10-03 浙江永宁药业股份有限公司 Ahu‑377中间体的制备方法及其中间体和中间体的制备方法
CN105168205A (zh) * 2015-08-18 2015-12-23 泰力特医药（湖北）有限公司 一种血管紧张素ii受体和脑啡肽酶受体双重抑制剂lcz696的制备方法
WO2017033128A1 (en) * 2015-08-25 2017-03-02 Novartis Ag Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors
CN105152980B (zh) * 2015-09-11 2017-03-29 浙江永宁药业股份有限公司 N‑叔丁氧羰基‑（4s）‑（对苯基苯基甲基）‑4‑氨基‑（2r）‑甲基丁酸的手性制备方法
WO2017051326A1 (en) 2015-09-23 2017-03-30 Novartis Ag New processes and intermediates useful in synthesis of nep inhibitors
CN105348209B (zh) 2015-12-09 2017-12-26 浙江天宇药业股份有限公司 一种抗心衰药lcz696的制备方法
CN105523964B (zh) * 2015-12-09 2017-05-24 苏州楚凯药业有限公司 一种抗心衰药物中间体的制备方法
JP7001597B2 (ja) * 2015-12-10 2022-01-19 ノバルティス アーゲー 新規なプロセスおよび中間体
MX2018007129A (es) 2015-12-11 2018-11-09 Zentiva Ks Formas solidas de ester etilico del acido (2r,4s)-5-(bifenil-4-il) -4-[(3-carboxipropionil)amino]-2-metil-pentanoico, sus sales y un metodo de preparacion.
CN106977415B (zh) * 2016-01-15 2021-03-26 广东东阳光药业有限公司 一种沙库必曲的中间体及其制备方法
WO2017141193A1 (en) * 2016-02-16 2017-08-24 Sun Pharmaceutical Industries Limited Process for the preparation of sacubitril or salts thereof
CN105924355B (zh) * 2016-05-11 2018-08-17 浙江宏元药业有限公司 沙库比曲中间体及沙库比曲中间体和沙库比曲的制备方法
WO2018007919A1 (en) 2016-07-05 2018-01-11 Novartis Ag New process for early sacubitril intermediates
JP6945619B2 (ja) 2016-08-17 2021-10-06 ノバルティス アーゲー Ｎｅｐ阻害剤合成のための新規な方法および中間体
CN106380421B (zh) * 2016-08-26 2017-12-08 中国科学院上海有机化学研究所 沙库必曲的合成方法
US10857132B2 (en) 2016-10-10 2020-12-08 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
CN106631903A (zh) * 2016-12-16 2017-05-10 重庆市碚圣医药科技股份有限公司 一种lcz‑696关键中间体的制备方法
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CN111269148B (zh) * 2020-04-08 2022-02-08 台州职业技术学院 一种沙库比曲中间体的制备方法
JP7064527B2 (ja) * 2020-05-01 2022-05-10 ノバルティス アーゲー サクビトリルカルシウム塩
CN112745246A (zh) * 2020-12-30 2021-05-04 重庆市碚圣医药科技股份有限公司 一种沙库必曲中间体的纯化方法

Citations (6)

* 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
US5250522A (en) * 1992-10-09 1993-10-05 Ciba-Geigy Corporation Phosphono/biaryl substituted amino acid derivatives
US5550119A (en) * 1995-03-02 1996-08-27 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives as ECE inhibitors
US6214763B1 (en) * 1997-05-20 2001-04-10 Firmenich Sa Ruthenium catalysts and their use in the asymmetric hydrogenation of weakly coordinating substrates
US20040220049A1 (en) * 2000-11-03 2004-11-04 Hems William Patrick Catalyst
US20050101643A1 (en) * 2003-09-25 2005-05-12 Blazecka Peter G. Amino acids with affinity for the alpha2delta-protein

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3020128B2 (ja) * 1994-03-08 2000-03-15 高砂香料工業株式会社 光学活性カルボン酸の製造法
TR200400953T4 (tr) 2000-01-27 2004-07-21 Warner Lambert Company Pregabalinin asimetrik sentezi.
AR043515A1 (es) * 2003-03-19 2005-08-03 Merck & Co Inc Procedimiento para preparar derivados quirales beta aminoacidos mediante hidrogenacion asimetrica
US20050033384A1 (en) 2003-08-04 2005-02-10 Sacha Mike K. Cochlear ear implant
ES2293596T3 (es) * 2004-07-05 2008-03-16 Solvias Ag 1,1'-difosfinoferrocenos con restos quirales o aquirales enlazados en la posicion 2,2'.
GB0418046D0 (en) * 2004-08-12 2004-09-15 Prosidion Ltd Eantioselective process
WO2006057904A1 (en) * 2004-11-23 2006-06-01 Merck & Co., Inc. Stereoselective preparation of 4-aryl piperidine amides by asymmetric hydrogenation of a prochiral enamide and intermediates of this process
AT501193B1 (de) * 2004-12-27 2007-03-15 Dsm Fine Chem Austria Gmbh Verfahen zur übergangsmetall - katalysierten asymmetrischen hydrierung von acrylsäurederivaten

Patent Citations (6)

* 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
US5250522A (en) * 1992-10-09 1993-10-05 Ciba-Geigy Corporation Phosphono/biaryl substituted amino acid derivatives
US5550119A (en) * 1995-03-02 1996-08-27 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives as ECE inhibitors
US6214763B1 (en) * 1997-05-20 2001-04-10 Firmenich Sa Ruthenium catalysts and their use in the asymmetric hydrogenation of weakly coordinating substrates
US20040220049A1 (en) * 2000-11-03 2004-11-04 Hems William Patrick Catalyst
US20050101643A1 (en) * 2003-09-25 2005-05-12 Blazecka Peter G. Amino acids with affinity for the alpha2delta-protein

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835668B2 (en) 2010-08-23 2014-09-16 Novartis Ag Process for the preparation of intermediates for the manufacture of NEP inhibitors
WO2016037098A1 (en) 2014-09-04 2016-03-10 Concert Pharmaceuticals, Inc. Deuterated sacubitril
CN111748590A (zh) * 2019-03-29 2020-10-09 台州保灵药业有限公司 转氨酶在制备Sacubitril中间体中的应用

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