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WO2016135751A1 - Nouveau procédé pour la préparation de sacubitril et de ses intermédiaires - Google Patents

Nouveau procédé pour la préparation de sacubitril et de ses intermédiaires Download PDF

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WO2016135751A1
WO2016135751A1 PCT/IN2016/050065 IN2016050065W WO2016135751A1 WO 2016135751 A1 WO2016135751 A1 WO 2016135751A1 IN 2016050065 W IN2016050065 W IN 2016050065W WO 2016135751 A1 WO2016135751 A1 WO 2016135751A1
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Prior art keywords
formula
process according
sacubitril
group
solvent
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Inventor
Siva Ram Prasad Vellanki
Arabinda Sahu
Nitin Ashok Shimpi
Siva Koteswara Rao Prathi
Lakshmana Rao AMPOLU
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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    • 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
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates generally to a process for the preparation of pharmaceutical active ingredients and more specifically tosacubitril. Intermediates formed during the process for preparing sacubitril are also disclosed. The present invention further relates to crystalline sacubitril.
  • Sacubitril is chemically known as 3-[(lS,3R)-l-[(biphenyl-4-yl) methyl]-3-ethoxycarbonyl-l- butylcarbamoyl] propionic acid and has the structure shown in Formula-I. Sacubitril is an inhibitor of neprilysin and is often included and administered with valsartan. A combination of sacubitril and valsartanis marketed as ENTRESTO® by Novartis pharmaceuticals and is indicated for the treatment of heart failure.
  • the present invention provides a process for the preparation of sacubitril as well as intermediates formed during the preparation of sacubitril.
  • One aspect of the present invention provides a process for the preparation of sacubitril, which may be carried out by the following steps: a) hydrolyzing Formula- VIII in the presence of a base and a solvent to prepareFormula-XI;
  • Ri and R 2 are independently hydrogen or an amine protecting group and "X" is a halide selected from the group consisting of -F, -CI, -Br, and -I.
  • the base used in the hydrolyzing step may be an organic base or an inorganic base.
  • suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • suitable alkaline metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the solvent used in the hydrolyzing step may an alcohol solvent, an ethereal solvent, or mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, n-propanol, isopropanol, and mixtures thereof.
  • the conversion ofFormula-XII into Formula-XIII may be carried out in the presence of phenylboronic acid, a metal catalyst, and a solvent.
  • suitable metal catalysts include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone) palladium(0)tris(dibenzylideneacetone)palladium(0), palladium(II) acetate, copper, cuprous bromide, cuprous iodide, and ( ⁇ )-2,2'-bis(diphenylphosphino)-l,l'-binaphtalene (rac-BINAP).
  • the solvent may bean ethereal solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • Formula-XIII may be converted into Formula-XIV or its salt by esterification of the carboxylic acid group and deprotection of the amine.
  • the esterification reaction may be carried out in the presence of a halogenation reagent and an alcohol solvent.
  • the halogenation reagent may be, for example, phosphorous oxychloride, phosphorous pentachloride, and thionyl chloride.
  • the alcohol solvent is ethanol.
  • Formula-XIV may be optionally converted into a salt form of Formula-XIV.
  • Another aspect of the present invention provides a process for the preparation of sacubitril,which may include the following steps: a) converting Formula-XII into Formula-XVII;
  • Ri and R 2 are independently hydrogen or an amine protecting group and "X" is a halide is -F, -CI, -Br, and -I.
  • Formula-XII may be converted to Formula-XIII by esterification of the acid group and deprotection of the amine group.
  • the esterification reaction may be carried out in the presence of a halogenation reagent and an alcoholsolvent.
  • suitable halogenation reagent includephosphorous oxychloride, phosphorous pentachloride, and thionyl chloride.
  • the alcohol solvent is ethanol.
  • the reacting ofFormula-XVII with Formula-XV may be carried out in the presence of a base and a halogenated solvent.
  • the base may be an inorganic base or an organic base.
  • examples of particularly useful organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine.
  • the halogenated solvent may be, for example, dichloromethane, trichloroethylene, carbon tetrachloride, methyl chloroform, or mixtures thereof.
  • the step of converting of Formula-XVI into sacubitril may be carried out in the presence of phenylboronic acid, a metal catalyst, and a solvent.
  • suitable metal catalysts include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone) palladium(0)tris(dibenzylideneacetone)palladium(0), palladium(II) acetate j copper, cuprous bromide, cuprous iodide, and ( ⁇ )-2,2'-bis(diphenylphosphino)-l, l'-binaphtalene (rac-BINAP).
  • Suitablesolventsin include ethereal solvents, hydrocarbon solvents, water, and mixtures thereof.
  • Formula-XVII may be converted into a salt form of Formula-XVII.
  • Another aspect of the present invention provides solid sacubitril, which, may, in some embodiments be in crystalline form.
  • solid crystalline sacubitril may be characterized by a powder X-ray diffraction pattern having significant peaks at 18.8, 19.4, 19.8, 20.6, and 21.3 ( ⁇ ) 0.2° 2- theta.
  • Solid crystalline sacubitril may befurther characterized by the powder X-ray diffraction pattern in Figure 1.
  • One aspect of the present invention provides processes for the preparation of sacubitril.
  • One embodiment provides a method for the preparation of Formula-XII, which may be carried out by the following steps: a) hydrolyzing Formula- VIII into Formula-XI; and
  • the "Ri” and “R 2 " moieties are independently hydrogen or an amine protecting group.
  • the "X" moiety is a halo group, for example, -F, -CI, -Br, or -I.
  • amine protecting group is well known and familiar to one of skill in the art. Suitable protecting groups as well as conditions for use and removal can be found in standard works, for example, 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", Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in “Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol.
  • R p is a -C(R P1 ) 3 , wherein each R P1 is hydrogen or optionally substituted aryl, provided that at least one R P1 is not hydrogen;
  • R° is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein each alkyl, aryl, and heteroaryl group is optionally substituted.
  • Optionally substituted as used herein means the reference group may be substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(Ci_ 3 alkyl)silyl (e.g., trimethylsilyl).
  • groups e.g., 1 to 5, or 1 to 3, or 1 to 2 groups or 1 group
  • amine protecting groups include, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p- methoxybenzylcarbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • aryl as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring.
  • Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thia groups.
  • aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
  • halo or halogen as used herein means -F, -CI, -Br, or -I.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O.
  • monocyclic and bicyclicheteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,triazinyl.
  • benzimidazolyl benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydroquinolin-yl.
  • heteroarylalkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
  • examples of particularly suitable amine protecting groups includecarboxybenzyl (Cbz), tert-butyloxycarbonyl (BOC), benzyl, and trityl groups.
  • Formula- VIII may be hydrolyzed into Formula-XI. This reaction may be carried out in the presence of an inorganic base and a solvent.
  • inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • alkaline metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • alkaline metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkaline metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkaline alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and potassium propoxide.
  • the solvent may be, for example, an alcohol solvent, an ethereal solvent, or mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, n-propanol,isopropanol, and mixtures thereof.
  • suitable ethereal solvent include tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof.
  • Formula-XI may bereduced to Formula-XII.
  • a reducing agent a chiral ligand, and a solvent.
  • suitable reducing agents includeborane, sodium borohydride, lithiumborohydride, sodiumcyanoborohydride, sodiumtriacetoxyborohydride, bis(dibenzylideneacetone) palladium(0),tris(dibenzylideneacetone)palladium(0) i palladium(ll) acetate , copper, cuprous bromide, cuprous iodide, and ( ⁇ )-2,2'-bis(diphenylphosphino)-l, -binaphtalene (rac-BINAP), and diiodo(p-cymene)ruthenium(II) dimer.
  • diiodo(p- cymene)ruthenium(II) dimer is used as a reducing agent.
  • Suitable chiral ligands includeMandyphos ligands, Walphos ligands, Josiphosligands, and Solphos ligands.
  • Mandyphos ligands are used as chiral ligands.
  • solventsin examples includealcoholsolvents, ethereal solvents, and mixtures thereof.
  • alcohol solvents examples include methanol, ethanol, n-propanol, isopropanol, and mixtures thereof.
  • ethereal solvents examples includetetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof.
  • methanol is used as a solvent.
  • Formula-XII may be formed as an intermediate in the preparation of sacubitril.
  • Another aspect of the present invention provides methods for converting Formula-XII to sacubitril.
  • Formula-XII can be converted to sacubitril by the following steps: a) converting Formula-XII into Formula-XIII;
  • amine protecting groups are well known in the art and one of skill in the art will be familiar with a variety of amine protecting groups that will be suitable in this embodiment.
  • a carboxybenzyl (Cbz), atert- butyloxycarbonyl (BOC), a benzyl group, or a trityl group is used as a protecting group.
  • the "X" moiety is a halo group, for example, -F, -CI, -Br, or -I.
  • Formula-XII may be converted into Formula-XIII. This may be carried out by reacting Formula-XII with phenylboronic acid in the presence of a metal catalyst, a buffer, and a solvent.
  • a metal catalyst examples includetetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(ll) dichloride, bis(dibenzylideneacetone)palladium(0)tris(dibenzylideneacetone)palladium(0), palladium(II) acetate j copper, cuprous bromide, cuprous iodide, and ( ⁇ )-2,2'- bis(diphenylphosphino)-l,l'-binaphtalene (rac-BINAP).
  • palladium acetate was used as a metal catalyst.
  • Suitable buffersin include phosphate bufferssuch as sodiumphosphate buffers and potassium phosphate buffers.
  • phosphate buffers such as sodiumphosphate buffers and potassium phosphate buffers.
  • One of skill in the art will be familiar with the use and preparation of these and other well-known suitable buffer solutions that would be useful in the context of this step of this embodiment.
  • the solvent may be, for example, an ethereal solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • suitable ethereal solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • suitable hydrocarbon solvents includetoluene, xylene, and mixtures thereof.
  • water was used as a solvent.
  • Formula-XIII may then be converted into Formula-XIV byesterification of the carboxylic acid moietyand deprotection of the amine group.
  • the esterification of the carboxylic acid moiety may be carried out by procedures well known in art.
  • the carboxylic acid group may first be converted to an acidhalide through a halogenation reaction and the acid halide may then be reacted with ethanol.
  • Halogenation may be carried out using well-known reagents such as phosphorous oxychloride, phosphorous pentachloride,or thionyl chloride.
  • Deprotection of the amine group may also be carried out by methods well known to one of skill in the art, who will be familiar with and knowledgeable regarding suitable deprotection conditions for the variety of protecting groups that may be used within the context of the present embodiment. For example, many protecting groups may be removed by hydrogenolysis or through the use of an acid or a base. In some embodiments, deprotection may occur during esterification, for example, while halogenating using reagents such as phosphorous oxychloride, phosphorous pentachloride,or thionyl chloride.
  • Formula-XIV may be optionally converted into a salt of Formula-XIV.
  • Conversion of Formula-XIV into its salt may increase the purity of the product formed which, in turn, may increase yields and purity of subsequent products of subsequent reactions, including the final sacubitril product.
  • Methods for converting compounds into their salt forms are well known in the art, and may be carried out, for example, by reacting a free base moiety on a molecule with a suitable acid reagent.
  • Formula-XIV can be reacted to obtain a salt of Formula-XIV.
  • the hydrochloride salt of Formula-XIV is formed.
  • Formula-XIV or a salt thereof,may then bereacted with Formula- XV to get sacubitril.
  • Methods for obtaining sacubitril from Formula-XIV are well-known in the art, for example,by following procedures disclosed in US 5,217,996, which is hereby incorporated by reference.
  • this reaction may becarried out in the presence of a base and a halogenated solvent.
  • the base may be an organic base or an inorganic base.
  • suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • alkaline metal hydroxides include sodium hydroxide and potassium hydroxide.
  • alkaline metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkaline metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkaline alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, and potassium tert- butoxide.
  • suitable organic bases include pyridine, triethylamine, and N,N- diisopropylethylamine.
  • suitable halogenated solvent includedichloromethane, trichloroethylene, carbon tetrachloride, methyl chloroform, and mixtures thereof.
  • Formula-XII may be converted to sacubi trilby the following steps: a) converting Formula-XII into Formula-XVII or its salt;
  • the "Ri” and “R 2 " moieties are independently hydrogen or an amine protecting group and the "X" moiety is a halo group, for example, -F, -CI, -Br, or -I.
  • amine protecting groups are well known in the art and one of skill in the art will be familiar with a variety of amine protecting groups that will be suitable in this embodiment.
  • a carboxybenzyl (Cbz), atert- butyloxycarbonyl (BOC), a benzyl group, or a trityl group is used as a protecting group.
  • Formula-XII may be converted into Formula-XVIIby esterification of the carboxylic acid moiety and deprotection of the amine group.
  • the esterification of the carboxylic acid moiety may be carried out by procedures well known in art.
  • the carboxylic acid group may first be converted to an acid halide through a halogenation reaction and the acid halide may then be reacted with ethanol.
  • Halogenation may be carried out using well-known reagents such as phosphorous oxychloride, phosphorous pentachloride, or thionyl chloride.
  • Deprotection of the amine group may also be carried out by methods well known to one of skill in the art, who will be familiar with and knowledgeable regarding suitable deprotection conditions for the variety of protecting groups that may be used within the context of the present embodiment. For example, many protecting groups may be removed by hydrogenolysis or through the use of an acid or a base. In some embodiments, deprotection may occur during esterification, for example, while halogenating using reagents such as phosphorous oxychloride, phosphorous pentachloride, or thionyl chloride.
  • Formula-XVII may be optionally converted into a salt of Formula-XVII.
  • Conversion of Formula-XVII into a salt may increase the purity of the product formed which, in turn, may increase yields and purity of subsequent products of subsequent reactions, including the final sacubitril product.
  • Methods for converting compounds into their salt forms are well known in the art, and may be carried out, for example, by reacting a free base moiety on a molecule with a suitable acid reagent.
  • Formula-XVII or a salt thereof,may be reacted with Formula-XV to get Formula-XVI.
  • this reaction may be carried outin the presence of a base and a halogenated solvent.
  • the base may be an organic base or an inorganic base.
  • suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • alkaline metal hydroxides include sodium hydroxide and potassium hydroxide.
  • alkaline metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkaline metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkaline alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine.In some embodiments, triethylamine is used as a base.
  • suitable halogenated solvent includedichloromethane, trichloroethylene, carbon tetrachloride, methyl chloroform, and mixtures thereof.
  • this reaction may be further carried out in the presence of a catalytic amount of 4-dimethylaminopyridine.
  • Formula-XVI may then be converted into sacubitril.
  • This reaction may be carried out by reacting Formula-XVI with phenylboronic acid in the presence of a metal catalyst, a buffer, and a solvent.
  • suitable metal catalyst include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone)palladium(0)tris(dibenzylideneacetone)palladium(0), palladium(II) acetate , copper, cuprous bromide, cuprous iodide, and ( ⁇ )-2,2'-bis(diphenylphosphino)-l,l'- binaphtalene (rac-BINAP).
  • bis(triphenylphosphine)palladium(II) dichloride is used as a metal catalyst.
  • suitable buffers include phosphate buffers, for example, such as sodium phosphate buffers and potassium phosphate buffers.
  • phosphate buffers for example, such as sodium phosphate buffers and potassium phosphate buffers.
  • the solvent may be, for example, an ethereal solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • suitable ethereal solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and mixtures thereof.
  • suitable hydrocarbon solvents includetoluene, xylene, and mixtures thereof.
  • a mixture of 1 ,2-dimethyoxyethane and water is used as a solvent.
  • Another aspect of the present invention provides another method for the preparation of sacubitril, which may be carried out by the following steps: a) reacting Formula-IV with Formula-V to get Formula- VI;
  • Formula-IV Formula- VI b) converting Formula- VI to Formula- Vlin the presence of a reducing agent
  • Ri and R 2 " moieties are independently hydrogen or an amine protecting group, as previously described above.
  • suitable amine protecting groups include carboxybenzyl (Cbz), tert- butyloxycarbonyl (BOC), benzyl groups, and trityl groups.
  • the "X" moiety is a halo group, for example, -F, -CI, -Br, or -I.
  • Formula-IV may be reacted with Formula-V in the presence of a suitable reagent and a solventto get Formula- VI.
  • suitable reagents include coupling agents such as ⁇ , -carbonyldiimidazole, dicyclohexylcarbodiimide, and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimideHCl.
  • the solvent may be, for example, dichloromethane, acetone, dimethylacetamide, dimethyl formamide, acetonitrile, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof.
  • 1,1'- carbonyldiimidazole is used to carry out this reaction and dimethyl formamide is used as a solvent.
  • Forma-VI may be converted into Formula- VII in the presence of a reducing agent.
  • suitable reducing agents include lithium aluminum hydride, sodium hydride, DIBAL-H, and sodium bis(2-methyoxyethoxy)aluminumhydride (vitride).
  • the reaction may be carried out in the presence of a suitable solvent, for example, a hydrocarbon solvent.
  • suitable hydrocarbon solvents includetoluene,ethers such as tetrahydrofuran and 1,4-dioxane, and mixtures thereof.
  • sodium bis(2-methyoxyethoxy)aluminumhydride is used as a reducing agent and toluene is used as a solvent.
  • Formmula-VII may then beconverted toFormula-VIII. This may be carried out in the presence of a Wittig reagent and a suitable solvent.
  • a Wittig reagent examples include those shown below asFormula-a, Formula-b and Formula-c.
  • wherin R 4 is selected from alkyl and aryl
  • Suitable solvents include dichloromefhane, dimethylacetamide, dimethyl formamide, acetonitrile, tetrahydrofuran, and mixtures thereof.
  • Formula- VIII may be converted into Formula-IX. This may be carried out by reacting Formula- VIII with phenylboronic acid in the presence of a metal catalyst, a base, and a suitable solvent.
  • a metal catalyst useful with the context of this embodiment include tetrakis(triphenylphosphine) palladium and bis(triphenylphosphine) palladium(II) dichloride.
  • suitable solvents include ethereal solvents, hydrocarbon solvents, and mixtures thereof.
  • Suitable ethereal solvents include 1,4-dioxane, diethyl ether, ethyl tert- butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • suitable hydrocarbon solvents include toluene, xylene, and mixtures thereof.
  • bis(triphenylphosphine) palladium(II) dichloride is used as a metal catalyst and toluene is used as a solvent.
  • suitable bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • alkaline metal hydroxides include sodium hydroxide and potassium hydroxide.
  • alkaline metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkaline metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkaline alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • Formula-IX may then be converted to Formula-X by deprotecting of Formula-X, if necessary, and by reducing Formula-IX. If both Ri and R 2 are hydrogen, no deprotection is necessary.
  • the conditions required for deprotection of the amine group depend on the protecting group and one of skill in the art will be familiar and recognize suitable conditions for carrying out this reaction.
  • Formula-IX (wherein Ri and R 2 are benzyl) may be reduced and deprotectedusing a metal catalyst, such as Pd/C, in the presence of a hydrogen source and asolvent.
  • suitable solvents include methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, and mixtures thereof.
  • the chiral purity of Formula-X may optionally be increased. This may be carried out byforming an acid addition salt of Formula-X. Within the context of this invention, this step may increase the purity of the "2S, 4R" enantiomer of Formula-X (where Formula-X is chemically named (2S, 4R)-ethyl 5-(biphenyl-4-yl)-4-(amino)-2-methylpentanoate).
  • the conversion of Formula-X to an acid addition salt may be carried out by reacting Formula-X with an inorganic or an organic acid.
  • suitable inorganic acids include hydrochloric acid andhydrobromic acid.
  • suitable organic acids include acetic acid, fumaric acid, succinic acid, citric acid, mandelic acid, and tartaric acid.
  • Formula-X may be further converted into sacubitril. This may be carried out by methods well-known in the art, for example, by those disclosed in US 5,217,996.
  • Formula-X may be reacted with succinic anhydride in the presence of a base and a halogenated solvent.
  • the base may be an inorganic base oraninorganic base.
  • suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides.
  • alkaline metal hydroxides include sodium hydroxide and potassium hydroxide.
  • alkaline metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkaline metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkaline alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine.
  • suitable halogenated solvent includedichloromethane, trichloroethylene, carbon tetrachloride, and methyl chloroform.
  • sacubitril Prior art processes for the preparation of sacubitril result, such as those in US 5,217,996, provide a final sacubitril product as an oil. In contrast, by practicing the methods disclosed herein below, sacubitril may be obtained as a solid. Thus, another aspect of the present invention provides a novel crystalline form of sacubitril.
  • the solid crystalline sacubitril prepared by methods disclosed herein be characterized by their powder X-ray diffraction (PXRD) pattern.
  • PXRD powder X-ray diffraction
  • the PXRD pattern of the crystalline sacubitrilobtained by methods disclosed herein was measured on a PANalyticalX'pert pro powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and X'celerator detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • crystalline sacubitril may be characterized by a PXRD pattern having characteristic peaks at 18.8, 19.4, 19.8, 20.6, and 21.3 ( ⁇ ) 0.2° 2-theta.
  • Crystalline sacubitril may be further characterized by powder X-ray diffraction having characteristic peaks at 16.5, 17.8, 18.8, 19.4, 19.8, 20.6, 21.3, 22.0, and 22.8 and 21.3 ( ⁇ ) 0.2° 2- theta.
  • the crystalline sacubitril maybe further characterized by the PXRD pattern as depicted in Figure 1.
  • Another aspect of the present invention provides processes for the preparation of crystallinesacubitril.
  • crystalline sacubitril may be prepared by the following steps: a) dissolving sacubitril in a solvent;
  • sacubitril may be first dissolved in a solvent.
  • the sacubitril may be in any form, for example, an oil such as disclosed above.
  • the solvent may be, for example, an alcohol solvent, a ketone solvent, anester solvent, a nitrile solvent, or mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, n-propanol, isopropanol, and mixtures thereof.
  • suitable ketone solvents include acetone, methylethyl ketone, methyhsobutyl ketone, and mixtures thereof.
  • suitableester solvents include methyl acetate, ethyl acetate, isopropyl acetate,tert-butyl acetate, and mixtures thereof.
  • a suitable nitrile solvent may be, for example, acetonitrile.
  • the solvent may be removed. This may be carried out by methods well-known in the art, for example, by distillation or evaporation.
  • a non-polar solvent may then be added.
  • the non-polar solvent may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • adding a non-polar solvent may cause a precipitate to form.
  • Suitable ether solvent examples include tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4- dioxane, methyl tert-butyl ether, and mixtures thereof.
  • suitablehydrocarbon solvents include pentane, hexane,cyclohexane, and mixtures thereof.
  • crystalline sacubitril may be isolated. This may be carried out by methods well-known in the art, for example, by filtering the solution and drying the obtained solid to result in crystalline sacubitril.
  • crystalline sacubitril may be prepared by the following steps: a) dissolving sacubitril in a polar solvent;
  • sacubitril may be first dissolved in a polar solvent.
  • suitable polar solvent include alcohol solvents, ketone sol vents, ester solvents, and mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, n-propanol, isopropanol, and mixtures thereof.
  • suitable ketone solvents include acetone, methylethyl ketone, methylisobutyl ketone, and mixtures thereof.
  • suitable ester solvents include methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, and mixtures thereof.
  • a non-polar solvent may then be added.
  • the non-polar solvent may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • Suitable ether solvents include tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4- dioxane, methyl tert-butyl ether, and mixtures thereof.
  • suitable hydrocarbon solvents include pentane, hexane, cyclohexane, and mixtures thereof.
  • the non-polar solvent may optionally be added at an elevated temperature, for example, from about 35 °C to about 60 °C. In certain embodiments, the non-polar solvent is added at a temperature of about 40°C to about 50 °C.
  • the solution may then be cooled, for example, to a temperature of about 5 °C to about 30 °C. In certain embodiments, the solution is cooled to about 20 °C to about 30 °C.
  • a solid may be formed upon addition of the non- polar solvent. Solid may also be formed during the optional steps of heating then cooling the solution. In some embodiments, the optional heating and cooling of the solution as described above may facilitate formation of a solid.
  • Crystalline sacubitril may then be isolated. Isolation of solid crystalline sacubitril may be carried out by methods well known in the art, for example, by filtering the solution and drying the obtained solid.
  • the sacubitril disclosed herein may be used in preparation of trisodiumsacubitril valsartanand may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. Dosage forms that include thesacubitril may be useful for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. Dosage forms may, in some embodiments, contain additional active pharmaceutical ingredients, such as valsartan.
  • the oral dosage forms containing sacubitril may further comprise one or more additional pharmaceutically acceptable excipients such as, for example, microcrystalline cellulose, hydroxypropyl cellulose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide, and mixtures thereof.
  • Capsules or tablets containing sacubitril disclosed herein may include a coating that contains one or more excipients, artificial flavorings, artificial colorings, or mixtures thereof.
  • the coatings may contain hypromellose, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide black, iron oxide yellow, or mixtures thereof.
  • excipients that would be useful for creating suitable coatings for a final dosage form of that contains sacubitril.
  • dosage forms containing sacubitril disclosed herein may have between about 24 mg to about 97 mg of sacubitril per dose.
  • Particularly useful embodiments of the present invention contain 24 mg sacubitril, 49 mg sacubitril, or 97 mg sacubitril.
  • Example2 Process for the preparation of tert-butyl [(2R)-l-(4-bromophenyl)-3- hydroxypropan-2-yl] carbamate (Formula-XII)
  • reaction mass was stirred at 75-85 °C for 2 hours.
  • the pH of the reaction mass was adjusted to 4.5-5.0 with an aqueous acetic acid solution and the reaction mass was stirred at 75-85 °C for 1 hour before cooling the mass to 0-5 °C.
  • the solution was filtered to obtained a solid, which was washed with ethanol to get (2E, 4R)-5-(4-bromophenyl)- 4-[(tert-butoxycarbonyl) amino-2-methylpent-2-enoic acid solid (Formula-XI, 15.5 g).
  • reaction mass was stirred at 55-65 °C for 7 hours, after which the reaction completion mass was cooled to ambient temperature.
  • the solution was then treated with CECAactivated carbon and the aqueous and organic layers were separated.
  • the organic layer was concentrated completely under vacuum to get a solid, which were dissolved in ethyl acetate (30 mL) at 45-55 °C.
  • Hexane (100 mL) was added at 45-55 °C and the mass was stirred for 30 minutes at 45-55 °C after which the reaction mass was cooled to ambient temperature.
  • Ethyl (2R,4S)-4-amino-5-(4-bromophenyl)-2-methylpentanoate hydrochloride (hydrochloride salt of Formula-XVII,0.6 g) was dissolved in dichloromethane (12 mL) and the mass wascooled to 0-5 °C. A catalytic amount of 4-dimethylaminopyridine and succinic anhydride (Formula- XV, 0.2 g) were then added. Triethylamine (0.26 g) was added and the reaction mass was stirred at 25-35 °C for 3 hours, after which the organic layer was washed with a IN HC1 solution and 10%brine solution.
  • Example7 Process for the preparation of 4- ⁇ [(2S, 4R)-l-(biphenyl-4-yl)-5-ethoxy-4-methyl- 5-oxopentan-2-yl] amino ⁇ -4-oxobutanoic acid (sacubitril)
  • reaction mass was filtered, concentrated, and purified by column chromatography to get (2R, 4S)-ethyl 5-(4-bromophenyl)-4-(dibenzylamino)-2-methylpentanoate (0.8 g).
  • Examplel3 Process for the preparation of (S)-3-(4-bromophenyl)-2-(dibenzylamino) propanoic acid
  • Examplel4 Process for the preparation of (S)-3-(4-bromophenyl)-2-(dibenzylamino) propanal (Formula- VII)
  • N, N-dibenzyl-L-bromo tyrosine (Formula-IV, 20 g) was dissolved in dimethylformamide (100 mL). Carbonyldiimidazole (9.2 g) was added and the reaction mass was stirred for 2 hours. ⁇ , ⁇ -dimethylhydroxylamine HCl(Formula-V, 6 g) and pyridine(4.4 g) were then added. The reaction mass was stirred for 12-15 hours and quenched into a mixture of water (100 mL) and methyl tert-butyl ether (MTBE, 100 mL). The layers were separated and the organic layer was washed with dilute HCl solution followed by concentration.
  • MTBE methyl tert-butyl ether
  • Examplel5 Process for the preparation of (S, Z)-ethyl 5-(4-bromophenyl)-4- (dibenzylamino) -2-methylpent-2-enoate (Formula- VIII)
  • Examplel6 Process for the preparation of (S, Z)-ethyl 5-(biphenyl-4-yl)-4- (dibenzylamino) -2-methylpent-2-enoate (Formula-IX)
  • Examplel7 Process for the preparation of (2S, 4R)-ethyl 5-(biphenyl-4-yl)-4-(amino)-2- methylpentanoate (Formula-X)
  • Example 19 Process for the preparation of 4- ⁇ [(2S, 4R)-l-(biphenyl-4-yl)-5-ethoxy-4- methyl-5-oxopentan-2-yl] amino ⁇ -4-oxobutanoic acid (sacubitril)

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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé pour la préparation de sacubitril et de ses intermédiaires. Les procédés de l'invention permettent d'obtenir une forme solide de sacubitril. L'invention concerne également une forme cristalline de sacubitril.
PCT/IN2016/050065 2015-02-25 2016-02-25 Nouveau procédé pour la préparation de sacubitril et de ses intermédiaires Ceased WO2016135751A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
CN106699604A (zh) * 2017-01-09 2017-05-24 四川同晟生物医药有限公司 一种沙库比曲及其中间体的制备方法
WO2017098430A1 (fr) 2015-12-10 2017-06-15 Novartis Ag Nouveau procédé et composés intermédiaires
CN106966926A (zh) * 2017-04-01 2017-07-21 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
WO2018069833A1 (fr) * 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
CN108203396A (zh) * 2016-12-19 2018-06-26 江西东邦药业有限公司 一种脑啡肽酶抑制剂的合成
CN108299226A (zh) * 2017-01-12 2018-07-20 南京红杉生物科技有限公司 一种ahu377钙盐的合成方法
EP3272734A4 (fr) * 2015-03-20 2018-11-21 Crystal Pharmatech Co., Ltd. Forme cristalline de ahu377, procédé de préparation et utilisation de cette dernière
CN109456212A (zh) * 2018-12-03 2019-03-12 康化（上海）新药研发有限公司 一种沙库比曲中间体的合成方法
JP2020503257A (ja) * 2016-10-28 2020-01-30 バイオコン・リミテッド アモルファスサクビトリルバルサルタン三ナトリウムおよびその調製のためのプロセス
CN113121342A (zh) * 2019-12-31 2021-07-16 浙江医药股份有限公司新昌制药厂 一种沙库必曲中间体的制备方法及应用
CN117447341A (zh) * 2023-09-06 2024-01-26 杭州国瑞生物科技有限公司 一种沙库巴曲缬沙坦钠中间体的精制方法
WO2024169071A1 (fr) * 2023-02-15 2024-08-22 瑞博(苏州)制药有限公司 Procédé de préparation d'un composé de sacubitril par hydrogénation catalytique asymétrique

Citations (5)

* 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
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2012025502A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Nouveau procédé de préparation d'intermédiaires utilisés pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2012025501A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Procédé de préparation d'intermédiaires pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2016029828A1 (fr) * 2014-08-27 2016-03-03 上海翰森生物医药科技有限公司 Acide crystallin libre, sel hemicalcique et sel d'alpha-phényléthylamine de ahu-377 et son procédé de préparation et son application

Patent Citations (5)

* 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
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2012025502A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Nouveau procédé de préparation d'intermédiaires utilisés pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2012025501A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Procédé de préparation d'intermédiaires pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2016029828A1 (fr) * 2014-08-27 2016-03-03 上海翰森生物医药科技有限公司 Acide crystallin libre, sel hemicalcique et sel d'alpha-phényléthylamine de ahu-377 et son procédé de préparation et son application

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"The Peptides", vol. 3, 1981, ACADEMIC PRESS
GARY M KSANDER ET AL: "Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 38, no. 10, 1 May 1995 (1995-05-01), pages 1689 - 1700, XP008154341, ISSN: 0022-2623, Retrieved from the Internet <URL:http://pubs.acs.org/journals/jmcmar/index.html> [retrieved on 19950501], DOI: 10.1021/JM00010A014 *
H.-D. JAKUBKE; H. JESCHEIT: "Aminosauren, Peptide, Proteine", 1982, VERLAGCHEMIE
HOUBEN-WEYL: "Methoden der organischenChemie", vol. 15/1, 1974, GEORG THIEMEVERLAG
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
JOCHEN LEHMANN: "Chemie der Kohlenhydrate: Monosaccharide und Derivate", 1974, GEORG THIEMEVERLAG
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY

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EP3272734A4 (fr) * 2015-03-20 2018-11-21 Crystal Pharmatech Co., Ltd. Forme cristalline de ahu377, procédé de préparation et utilisation de cette dernière
US11434192B2 (en) 2015-12-10 2022-09-06 Novartis Ag Process and intermediates
WO2017098430A1 (fr) 2015-12-10 2017-06-15 Novartis Ag Nouveau procédé et composés intermédiaires
CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
US11318116B2 (en) 2016-10-10 2022-05-03 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
WO2018069833A1 (fr) * 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
US10857132B2 (en) 2016-10-10 2020-12-08 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
JP2020503257A (ja) * 2016-10-28 2020-01-30 バイオコン・リミテッド アモルファスサクビトリルバルサルタン三ナトリウムおよびその調製のためのプロセス
JP7022747B2 (ja) 2016-10-28 2022-02-18 バイオコン・リミテッド アモルファスサクビトリルバルサルタン三ナトリウムおよびその調製のためのプロセス
CN108203396A (zh) * 2016-12-19 2018-06-26 江西东邦药业有限公司 一种脑啡肽酶抑制剂的合成
CN106699604B (zh) * 2017-01-09 2019-01-01 四川同晟生物医药有限公司 一种沙库比曲及其中间体的制备方法
CN106699604A (zh) * 2017-01-09 2017-05-24 四川同晟生物医药有限公司 一种沙库比曲及其中间体的制备方法
CN108299226A (zh) * 2017-01-12 2018-07-20 南京红杉生物科技有限公司 一种ahu377钙盐的合成方法
CN106966926B (zh) * 2017-04-01 2018-10-19 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
CN106966926A (zh) * 2017-04-01 2017-07-21 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
CN109456212A (zh) * 2018-12-03 2019-03-12 康化（上海）新药研发有限公司 一种沙库比曲中间体的合成方法
CN113121342A (zh) * 2019-12-31 2021-07-16 浙江医药股份有限公司新昌制药厂 一种沙库必曲中间体的制备方法及应用
CN113121342B (zh) * 2019-12-31 2022-05-31 浙江医药股份有限公司新昌制药厂 一种沙库必曲中间体的制备方法及应用
WO2024169071A1 (fr) * 2023-02-15 2024-08-22 瑞博(苏州)制药有限公司 Procédé de préparation d'un composé de sacubitril par hydrogénation catalytique asymétrique
CN117447341A (zh) * 2023-09-06 2024-01-26 杭州国瑞生物科技有限公司 一种沙库巴曲缬沙坦钠中间体的精制方法

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