WO2017141193A1 - Process for the preparation of sacubitril or salts thereof - Google Patents

Process for the preparation of sacubitril or salts thereof Download PDF

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Publication number
WO2017141193A1
WO2017141193A1 PCT/IB2017/050890 IB2017050890W WO2017141193A1 WO 2017141193 A1 WO2017141193 A1 WO 2017141193A1 IB 2017050890 W IB2017050890 W IB 2017050890W WO 2017141193 A1 WO2017141193 A1 WO 2017141193A1
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formula
compound
process according
group
solvent
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PCT/IB2017/050890
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French (fr)
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Siddamal Reddy PUTAPATRI
Bhushan Balasaheb KHAIRNAR
Gyanendra Pandey
Kaptan Singh
Mohan Prasad
Ashok Kumar
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Sun Pharmaceutical Industries Limited
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Publication of WO2017141193A1 publication Critical patent/WO2017141193A1/en

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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
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton

Definitions

  • the present invention provides processes for the preparation of sacubitril or salts thereof.
  • the present invention further provides intermediates of Formula IV, V and VI and their use for the preparation of sacubitril or salts thereof.
  • U.S. Patent No. 5,217,996, PCT Publication Nos. WO 2007/056546, WO 2008/031567, WO 2008/083967, WO 2009/090251, WO 2012/025502, WO 2012/025501, WO 2013/026773, and WO 2014/032627 provides processes for the preparation of sacubitril of Formula I or salts thereof. These applications are incorporated by reference into this application for their disclosure of processes for preparing sacubitril.
  • the present invention provides processes for the preparation of sacubitril or salts thereof.
  • the present invention further provides intermediates of Formula IV, V and VI and their use for the preparation of sacubitril or salts thereof.
  • ambient temperature refers to the temperature in the range of 25°C to 35°C.
  • treating includes combining, mixing, triturating, suspending, contacting, or a combination thereof.
  • Ci-6 alkyl refers to straight or branched aliphatic hydrocarbon, or cyclic aliphatic hydrocarbon, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • a first aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a second aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a third aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a fourth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a fifth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a sixth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a seventh aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
  • An eighth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a ninth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
  • a tenth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • An eleventh aspect of the present invention provides a process for the preparation of a sacubitril of Formula I or a salt thereof,
  • a twelfth aspect of the present invention provides a process for the preparation of a compound of Formula III,
  • a thirteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
  • a fourteenth aspect of the present invention provides a process for the preparation a compound of Formula V,
  • a fifteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a sixteenth aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a seventeenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • An eighteenth aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a nineteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a twentieth aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a twenty first aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a twenty second aspect of the present invention provides a process for the preparation of a compound of Formula VI,
  • a twenty third aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a twenty fourth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
  • a twenty fifth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a twenty sixth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
  • a twenty seventh aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a twenty eighth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a twenty ninth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
  • a thirtieth aspect of the present invention provides a compound of Formula VI.
  • a thirty first aspect of the present invention provides a compound of Formula V.
  • a thirty second aspect of the present invention provides a compound of Formula
  • a thirty third aspect of the present invention provides use of a compound of
  • a thirty forth aspect of the present invention provides use of a compound of Formula V for the preparation of Sacubitril or a salt thereof.
  • a thirty fifth aspect of the present invention provides use of a compound of Formula IV for the preparation of sacubitril or a salt thereof.
  • the compound of Formula IX is prepared by any method known in the art, for example, European Patent No. 0,462,531 B, and U.S. Patent No. 7,375,231, both of which are incorporated by reference in this application for the methods for preparing the compound of Formula IX.
  • the compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII in the presence of a base in a solvent.
  • the trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
  • the base is selected from the group consisting of an organic and an inorganic base.
  • an organic base include ethylamine, propyl amine, isopropyl amine, and triethyl amine.
  • an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent at a temperature of about -10°C to about 55°C, for example, at about 0°C to about 45°C.
  • the compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent for about 1 hour to about 5 hours, for example, for about 1 hour to about 2 hours.
  • the compound of Formula VIII may be isolated by methods including
  • the compound of Formula VIII is reduced to the compound of Formula VII in the presence of a buffer and a reducing agent in a solvent.
  • the buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
  • the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula VIII is reduced to the compound of Formula VII at a temperature of about 10°C to about 55°C, for example, at about 20°C to about 45°C.
  • the compound of Formula VIII is reduced to the compound of Formula VII for about 1 hour to about 5 hours, for example for about 2 hours to about 4 hours.
  • the compound of Formula VII may be isolated by methods including
  • concentration concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula VII is oxidized to the compound of Formula VI in the presence of an oxidizing agent and a base in a solvent.
  • the oxidizing agent is selected from the group consisting of sodium
  • hypochlorite/2,2,6,6-tetramethylpiperidinooxy TEMPO
  • potassium permanganate potassium dichromate
  • PCC pyridinium chlorochromate
  • DMP dess-martin periodinane
  • DMSO oxalyl chloride/dimethyl sulfoxide
  • chromium oxide/pyridine The base is selected from the group consisting of an organic and an inorganic base. Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethyl amine.
  • Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula VII is oxidized to the compound of Formula VI at a temperature of about -10°C to about 45°C, for example, at about -10°C to about 25°C.
  • the compound of Formula VII is oxidized to the compound of Formula VI for about 0.5 hour to about 5 hours, for example, for about 1 hour to about 3 hours.
  • the compound of Formula VI may be used as such in the next step or may be isolated from the mixture by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate to obtain the compound of Formula V in a solvent.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate at a temperature of about 20°C to about 45°C, for example, at about 20°C to about 25 °C.
  • the compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate for about 10 hours to about 20 hours, for example, for about 15 hours to 18 hours.
  • the compound of Formula V may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula V is hydrogenated to the compound of Formula IV in the presence of a hydrogenating agent in a solvent.
  • the hydrogenating agent is selected from the group consisting of transition metal/ carbon, and an organometallic complex optionally in the presence of a chiral ligand.
  • the transition metal is selected from the group consisting of palladium, manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, and iridium.
  • the chiral ligand is selected from the group consisting of carbon monoxide, halides, phosphines, naphthols, l, l'-bi-2-naphthol (BINOL), 2,2'-bis(diphenylphosphino)- ⁇ , ⁇ -binaphthyl (BINAP), a,a,a,a-tetraaryl-l,3-dioxolane-4,5-dimethanols (TADDOL), 2,3-0-isopropylidene-2,3-dihydroxy-l,4-bis(diphenylphosphino)butane (DIOP), bis(oxazoline) ligands (BOX) and DuPhos (a phosphine ligand), cymene and mixtures thereof.
  • BINOL 2,2'-bis(diphenylphosphino)- ⁇ , ⁇ -binaphthyl
  • TADDOL 2,3-0-is
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula V is hydrogenated to the compound of Formula IV at a temperature of about 20°C to about 45°C, for example, at about 20°C to about 25°C.
  • the compound of Formula V is hydrogenating to the compound of Formula IV for about 1 hour to about 10 hours, for example, for about 2 hours to about 5 hours.
  • the compound of Formula IV may be isolated by methods including
  • concentration concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula IV is reacted with phenylboronic acid to obtain the compound of Formula III in the presence of a coupling agent and a base in a solvent.
  • the coupling agent is selected from the group consisting of
  • the base is selected from the group consisting of an organic and an inorganic base.
  • Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethylamine.
  • Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula IV is reacted with phenylboronic acid at a temperature of about 20°C to about 100°C, for example, at about 20°C to about 85°C.
  • the compound of Formula IV is reacted with phenylboronic acid for about 1 hour to about 10 hours, for example, for about 2 hours to about 5 hours.
  • the compound of Formula III may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula III is deprotected to obtain the compound of Formula II in the presence of a deprotecting agent in a solvent.
  • the deprotecting agent is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, sulfuric acid, p-toluene sulfonic acid, and methane sulfonic acid
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbons include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula III is deprotected to the compound of Formula II at a temperature of about 20°C to about 75°C, for example, at about 30°C to about 70°C.
  • the compound of Formula III is deprotected to the compound of Formula II for about 0.5 hours to about 4 hours, for example, for about 1 hour to about 2 hours.
  • the compound of Formula II may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the compound of Formula II is reacted with succinic anhydride to obtain sacubitril of Formula I in the presence of a base in a solvent.
  • the base is selected from the group consisting of an organic and an inorganic base.
  • an organic base include ethylamine, propyl amine, isopropyl amine, and triethylamine.
  • an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
  • the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • aromatic hydrocarbon include toluene or benzene.
  • ketones include acetone or methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
  • ethers include methyl i-butyl ether or tetrahydrofuran.
  • alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane.
  • polar aprotic solvents include ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
  • the compound of Formula II is reacted with succinic anhydride at a temperature of about 5°C to about 30°C, for example, at about 5°C to about 20°C.
  • the compound of Formula II is reacted with succinic anhydride for about 1 hour to about 10 hours, for example, for about 1 hour to about 5 hours.
  • Sacubitril of compound of Formula I may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • Sacubitril of Formula I may be further converted to its salt or to a solid form of sacubitril and an angiotensin receptor antagonist, for example, valsartan, irbesartan, telmisartan, in their salt form or their hydrates, by the analogous methods provided in PCT Publication No. WO 2007/056546 and U.S. Patent No. 7,468,390, which are incorporated herein by reference, or process as described herein.
  • angiotensin receptor antagonist for example, valsartan, irbesartan, telmisartan
  • salts include monovalent salt or bivalent salt.
  • the monovalent salt includes lithium, sodium, potassium, rubidium, cesium, or NPv4 + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt includes barium, magnesium, calcium, zinc, and strontium salt.
  • the salt of sacubitril of compound of Formula I also includes benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine salt.
  • the reaction mixture was cooled to 10°C to 15°C and the pH was adjusted to 5.0 to 5.5 by adding IN hydrochloric acid (15 mL) at 10°C to 15°C.
  • the reaction mixture was stirred for 15 minutes and the layers obtained were separated.
  • the ethyl acetate (360 mL) obtained was recovered from the reaction mixture under 190 mm to 9 mm of Hg pressure at 40°C to 45°C for 40 minutes to obtain the title compound.
  • Dichloromethane (840 mL) was added to a compound of Formula VII (105.0 g; example 2) at 20°C to 25°C.
  • De-ionized water (262.5 mL) was added and the reaction mixture was cooled to -10°C to -5°C.
  • Sodium bromide (13.5 g), sodium bicarbonate (44.1 g) and TEMPO (2.99 g) were added to the reaction mixture at -10°C to -5°C.
  • a solution of 7% sodium hypochlorite (475 mL) was added to the reaction mixture at -10°C to -5°C and stirred for 1 hour.
  • dichloromethane solution (900 mL) of a compound of Formula VI (example 3) at 20°C to 25°C and stirred for 16 hours.
  • Dichloromethane (900 mL) was recovered under 400 mm to 10 mm of Hg pressure at 40°C to 45°C.
  • the solid obtained was purified using silica gel column using ethyl acetate: hexane solvent system as 5:95 (10 L) to obtain the title compound.
  • Toluene (240 mL) was added to the compound of Formula IV (24.0 g; example 5) at 20°C to 25°C.
  • Phenylboronic acid (12.1 g), potassium carbonate (13.7 g) and tetrakistriphenylphospine palladium(O) (1.72 g) were added sequentially to the mixture at 20°C to 25°C.
  • the reaction mixture was degassed by purging with nitrogen gas for 10 minutes.
  • the reaction mixture was heated to 80°C to 85°C and stirred for 2 hours.
  • the reaction mixture was cooled to 20°C to 25 °C and filtered through celite.
  • Toluene layer was washed with aqueous sodium hydroxide solution (5%, 100 mL), IN hydrochloric acid (100 mL) and de-ionized water (100 inL) sequentially.
  • Toluene (290 mL) was recovered from the reaction mixture under 150 mm to 9 mm of Hg pressure at 40°C to 45°C to obtain the solid material (27.0 g).
  • the solid material (27.0 g) was purified using silica gel column using ethyl acetate: hexane solvent system as 5: 95 (3 L) to obtain the title compound.
  • a solution of hydrochloric acid in ethanol (10%, 32 mL) was added to the compound of Formula III (16.0 g; example 6) at 20°C to 25°C.
  • the reaction mixture was heated to 65°C to 70°C and stirred for 1 hour.
  • the reaction mixture was further cooled to 20°C to 25°C.
  • Ethanol (80 mL) was recovered from the reaction mixture under 150 mm to 9 mm of Hg at 40°C to 45°C.
  • the solid material (20 g) obtained was dissolved in toluene (64 mL) and water (48 mL) and the reaction mixture was cooled to 5°C to 10°C.
  • the pH was adjusted to 9 by adding aqueous sodium hydroxide solution (10%, 15 mL) at 5°C to 10°C and the reaction mixture was stirred for 15 minutes. The layers obtained were separated at 20°C to 25°C. The toluene layer (48 mL) was collected and used as such in the next step.
  • Succinic anhydride (5.0 g) and diisopropyl ethyl amine (4.0 mL) were added to toluene (32 mL) at 5°C to 10°C.
  • a solution of the compound of Formula II in toluene (64.0 mL; example 7) was added to the reaction mixture at 5°C to 10°C.
  • the reaction mixture was stirred at 5°C to 10°C for 1 hour.
  • Water (30 mL) was added to the reaction mixture and the pH of the solution was adjusted to 2.0 by adding IN hydrochloric acid (15 mL) at 5°C to 10°C.
  • the reaction mixture was stirred at 5°C to 10°C for 10 minutes.
  • the layers obtained were separated and the toluene (90 mL) was recovered from the organic layer under 400 mm to 9 mm of Hg pressure for 40 minutes to obtain the title compound.
  • Sacubitril 130.0 g was added to methanol (520 mL) and the reaction mixture was cooled to 5°C to 10°C.
  • a solution of sodium hydroxide (12.26 g in 30 mL of water) was added to the reaction mixture at 5°C to 10°C and the reaction mixture was stirred for 2 hours.
  • Methanol and water 530 mL were recovered from the reaction mixture under reduced 200 mm to 10 mm of Hg pressure at 40°C to 45°C.
  • Acetone (390 mL) was added to the reaction mixture at 40°C to 45 °C and the mixture was stirred for 15 minutes.
  • Acetone (390 mL) was recovered from the reaction mixture under reduced 300 mm to 10 mm of Hg pressure at 40°C to 45°C.
  • Cyclohexane (390 mL) was added to the reaction mixture and stirred for 30 minutes at 20°C to 25°C.
  • the reaction mixture was filtered and washed with cyclohexane (130 mL) to obtain the solid material (135 g) and dried under vacuum at 650 mm to 680 mm of Hg at 40°C to 45°C for 20 hours to obtain the title compound.

Abstract

The present invention provides processes for the preparation of sacubitril or salts thereof. The present invention further provides intermediates of Formula IV, V and VI and their use for the preparation of sacubitril or salts thereof.

Description

PROCESS FOR THE PREPARATION OF SACUBITRIL OR SALTS THEREOF
Field of the Invention
The present invention provides processes for the preparation of sacubitril or salts thereof. The present invention further provides intermediates of Formula IV, V and VI and their use for the preparation of sacubitril or salts thereof.
Background of the Invention
U.S. Patent No. 5,217,996, PCT Publication Nos. WO 2007/056546, WO 2008/031567, WO 2008/083967, WO 2009/090251, WO 2012/025502, WO 2012/025501, WO 2013/026773, and WO 2014/032627 provides processes for the preparation of sacubitril of Formula I or salts thereof. These applications are incorporated by reference into this application for their disclosure of processes for preparing sacubitril.
Figure imgf000002_0001
Formula I
Summary of the Invention
The present invention provides processes for the preparation of sacubitril or salts thereof. The present invention further provides intermediates of Formula IV, V and VI and their use for the preparation of sacubitril or salts thereof.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to the temperature in the range of 25°C to 35°C. The term "treating," "reacting," or "converting," includes combining, mixing, triturating, suspending, contacting, or a combination thereof.
The term "Ci-6 alkyl," as used herein, refers to straight or branched aliphatic hydrocarbon, or cyclic aliphatic hydrocarbon, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
A first aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000003_0001
Formula I
wherein the process comprises
a) reacting a compound of Formula IX,
Figure imgf000003_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000004_0001
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000004_0002
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000004_0003
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V.
Figure imgf000004_0004
Formula V e) hydrogenating the compound of Formula V to obtain a compound of Formula IV,
Figure imgf000005_0001
Formula IV
f) reacting the compound of Formula IV with phenylboronic acid to obtain a
compound of Formula III,
Figure imgf000005_0002
Formula III
g) deprotecting the compound of Formula III to obtain a compound of Formula II, and
Figure imgf000005_0003
Formula II
h) reacting the compound of Formula II with succinic anhydride to obtain sacubitril of Formula I or a salt thereof. A second aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000006_0001
Formula IV
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000006_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000006_0003
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000007_0001
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000007_0002
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V, and
Figure imgf000007_0003
Formula V
e) hydrogenating the compound of Formula V to obtain the compound of Formula IV.
A third aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000008_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000008_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000008_0003
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000009_0001
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000009_0002
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosph
propionate to obtain a compound of Formula V,
Figure imgf000009_0003
Formula V
e) hydrogenating the compound of Formula V to obtain a compound of Formula IV, and
Figure imgf000010_0001
Formula IV
f) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof.
A fourth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000010_0002
Formula IV
wherein the process comprises hydrogenating a compound of Formula V,
Figure imgf000010_0003
Formula V
A fifth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000011_0001
Formula I
wherein the process comprises:
a) hydrogenating a compound of Formula V
Figure imgf000011_0002
Formula V
to obtain a compound of Formula IV, and
Figure imgf000011_0003
Formula IV
b) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof. A sixth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000012_0001
Formula IV
wherein the process comprises:
a) reacting a compound of Formula VI
Figure imgf000012_0002
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V, and
Figure imgf000012_0003
Formula V
b) hydrogenating the compound of Formula V to obtain the compound of Formula IV. A seventh aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
Figure imgf000013_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula VI
Figure imgf000013_0002
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V,
Figure imgf000013_0003
Formula V
b) hydrogenating the compound of Formula V to obtain a compound of Formula IV, and
Figure imgf000014_0001
Formula IV
c) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof.
An eighth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000014_0002
Formula IV
wherein the process comprises:
a) oxidizing a compound of Formula VII
Figure imgf000014_0003
Formula VII
a compound of Fonnula VI,
Figure imgf000015_0001
Formula VI
b) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V, and
Figure imgf000015_0002
Formula V
c) hydrogenating the compound of Formula V to obtain the compound of Formula IV.
A ninth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
Figure imgf000015_0003
Formula I
wherein the process comprises:
a) oxidizing a compound of Formula VII
Figure imgf000016_0001
Formula VII
to obtain a compound of Formula VI,
Figure imgf000016_0002
Formula VI
b) reacting the compound of Formula VI with ethyl 2-(triphenylphosph
propionate to obtain a compound of Formula V,
Figure imgf000016_0003
Formula V
c) hydrogenating the compound of Formula V to obtain a compound of Formula IV, and
Figure imgf000017_0001
Formula IV
d) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof.
A tenth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000017_0002
Formula IV
wherein the process comprises:
a) reducing a compound of Formula VIII
Figure imgf000017_0003
Formula VIII
to obtain a compound of Formula VII,
Figure imgf000018_0001
Formula VII
b) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000018_0002
Formula VI
c) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V, and
Figure imgf000018_0003
Formula V
d) hydrogenating the compound of Formula V to obtain the compound of Formula IV.
An eleventh aspect of the present invention provides a process for the preparation of a sacubitril of Formula I or a salt thereof,
Figure imgf000019_0001
Formula I
wherein the process comprises:
a) reducing a compound of Formula VIII
Figure imgf000019_0002
Formula VIII
to obtain a compound of Fonnula VII,
Figure imgf000019_0003
Formula VII
oxidizing the compound of Fonnula VII to obtain a compound of Formula VI.
Figure imgf000020_0001
Formula VI
c) reacting the compound of Formula VI with ethyl 2-(triphenylphosph
propionate to obtain a compound of Formula V,
Figure imgf000020_0002
Formula V
d) hydrogenating the compound of Formula V to obtain a compound of Formula IV, and
Figure imgf000020_0003
Formula IV
e) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof.
A twelfth aspect of the present invention provides a process for the preparation of a compound of Formula III,
Figure imgf000021_0001
Formula III
wherein the process comprises reacting a compound of Formula IV with phenylboronic acid.
Figure imgf000021_0002
Formula IV
A thirteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof
Figure imgf000021_0003
Formula I
wherein the process comprises: a) reacting a compound of Formula IV
Figure imgf000022_0001
Formula IV
with phenylboronic acid to obtain a compound of Formula III, and
Figure imgf000022_0002
Formula III
b) converting the compound of Formula III to sacubitril of Formula I or a salt thereof.
A fourteenth aspect of the present invention provides a process for the preparation a compound of Formula V,
Figure imgf000022_0003
oso2CF3 Formula V
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000023_0001
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000023_0002
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000023_0003
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI, and
Figure imgf000023_0004
Formula VI d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain the compound of Formula V.
A fifteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000024_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000024_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000024_0003
Formula VIII b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000025_0001
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000025_0002
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V, and
Figure imgf000025_0003
Formula V
e) converting the compound of Formula V to sacubitril of Formula I or a salt thereof.
A sixteenth aspect of the present invention provides a process for the preparation of a compound of Formula V,
Figure imgf000026_0001
Formula V
wherein the process comprises:
a) reducing a compound of Formula VIII
Figure imgf000026_0002
Formula VIII
to obtain a compound of Formula VII,
Figure imgf000026_0003
Formula VII
b) oxidizing the compound of Formula VII to obtain a compound of Fonnula VI, and
Figure imgf000026_0004
Formula VI c) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain the compound of Formula V.
A seventeenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000027_0001
Formula I
wherein the process comprises:
a) reducing a compound of Formula VIII
Figure imgf000027_0002
Formula VIII
to obtain a compound of Formula VII,
Figure imgf000027_0003
Formula VII b) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000028_0001
Formula VI
c) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V. and
Figure imgf000028_0002
Formula V
d) converting the compound of Formula V to sacubitril of Formula I or a salt thereof.
An eighteenth aspect of the present invention provides a process for the preparation of a compound of Formula V,
Figure imgf000028_0003
Formula V
wherein the process comprises:
a) oxidizing a compound of Formula VII
Figure imgf000029_0001
Formula VII
to obtain a compound of Formula VI, and
Figure imgf000029_0002
Formula VI
b) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain the compound of Formula V.
A nineteenth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000029_0003
Formula I
wherein the process comprises:
a) oxidizing a compound of Formula VII
Figure imgf000030_0001
Formula VII
to obtain a compound of Formula VI,
Figure imgf000030_0002
Formula VI
b) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl)
propionate to obtain a compound of Formula V, and
Figure imgf000030_0003
Formula V
c) converting the compound of Formula V to sacubitril of Formula I or a salt thereof.
A twentieth aspect of the present invention provides a process for the preparation of a compound of Formula V,
Figure imgf000031_0001
Formula V
wherein the process comprises reacting a compound of Formula VI
Figure imgf000031_0002
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate.
A twenty first aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000031_0003
Formula I
wherein the process comprises:
a) reacting a compound of Formula VI
Figure imgf000032_0001
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V, and
Figure imgf000032_0002
Formula V
converting the compound of Fomiula V to sacubitril of Formula I or a salt thereof. A twenty second aspect of the present invention provides a process for the preparation of a compound of Formula VI,
Figure imgf000032_0003
Formula VI
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000033_0001
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIIL
Figure imgf000033_0002
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII, and
Figure imgf000033_0003
Formula VII
c) oxidizing the compound of Formula VII to obtain the compound of Formula VI.
A twenty third aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000034_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000034_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII.
Figure imgf000034_0003
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000035_0001
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI, and
Figure imgf000035_0002
Formula VI
d) converting the compound of Formula VI to sacubitril of Fonnula I or a salt
A twenty fourth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
Figure imgf000035_0003
Formula VI
vherein the process comprises:
a) reducing a compound of Formula VIII
Figure imgf000036_0001
Formula VIII
a compound of Formula VII, and
Figure imgf000036_0002
Formula VII
b) oxidizing the compound of Fonnula VII to obtain the compound of Fonnula VI.
A twenty fifth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000036_0003
Formula I
wherein the process comprises:
a) reducing a compound of Fonnula VIII,
Figure imgf000037_0001
Formula VIII
to obtain a compound of Fonnula VII
Figure imgf000037_0002
Formula VII
b) oxidizing the compound of Fonnula VII to obtain a compound of Fonnula VI, and
Figure imgf000037_0003
Formula VI
c) converting the compound of Fonnula VI to sacubitril of Fonnula I or a salt
A twenty sixth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
Figure imgf000038_0001
Formula VI
wherein the process comprises oxidizing a compound of Formula VII.
Figure imgf000038_0002
Formula VII
A twenty seventh aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000038_0003
Formula I
wherein the process comprises:
a) oxidizing a compound of Formula VII
Figure imgf000039_0001
Formula VII
to obtain a compound of Formula VI, and
Figure imgf000039_0002
Formula VI
b) converting the compound of Formula VI to sacubitril of Formula I or a salt A twenty eighth aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000039_0003
Formula IV
wherein the process comprises:
a) reacting a compound of Formula VI
Figure imgf000040_0001
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V, and
Figure imgf000040_0002
Formula V
b) hydrogenating the compound of Formula V to obtain the compound of Formula IV.
A twenty ninth aspect of the present invention provides a process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000040_0003
Formula I
wherein the process comprises:
a) reacting a compound of Formula VI
Figure imgf000041_0001
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V,
Figure imgf000041_0002
Formula V
b) hydrogenating the compound of Formula V to obtain a compound of Formula IV, and
Figure imgf000041_0003
Formula IV
c) converting the compound of Formula IV to sacubitril of Formula I or a salt thereof.
A thirtieth aspect of the present invention provides a compound of Formula VI.
Figure imgf000042_0001
Formula VI
A thirty first aspect of the present invention provides a compound of Formula V.
Figure imgf000042_0002
Formula V
A thirty second aspect of the present invention provides a compound of Formula
IV.
Figure imgf000042_0003
Formula IV
A thirty third aspect of the present invention provides use of a compound of
Formula VI for the preparation of Sacubitril or a salt thereof.
Figure imgf000043_0001
Formula VI
A thirty forth aspect of the present invention provides use of a compound of Formula V for the preparation of Sacubitril or a salt thereof.
Figure imgf000043_0002
Formula V
A thirty fifth aspect of the present invention provides use of a compound of Formula IV for the preparation of sacubitril or a salt thereof.
Figure imgf000043_0003
Formula IV
The compound of Formula IX is prepared by any method known in the art, for example, European Patent No. 0,462,531 B, and U.S. Patent No. 7,375,231, both of which are incorporated by reference in this application for the methods for preparing the compound of Formula IX. The compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII in the presence of a base in a solvent.
The trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
The base is selected from the group consisting of an organic and an inorganic base. Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethyl amine. Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent at a temperature of about -10°C to about 55°C, for example, at about 0°C to about 45°C.
The compound of Formula IX is reacted with trifluoromethyl sulfonyl containing reagent for about 1 hour to about 5 hours, for example, for about 1 hour to about 2 hours.
The compound of Formula VIII may be isolated by methods including
concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried. The compound of Formula VIII is reduced to the compound of Formula VII in the presence of a buffer and a reducing agent in a solvent.
The buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
The reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula VIII is reduced to the compound of Formula VII at a temperature of about 10°C to about 55°C, for example, at about 20°C to about 45°C.
The compound of Formula VIII is reduced to the compound of Formula VII for about 1 hour to about 5 hours, for example for about 2 hours to about 4 hours.
The compound of Formula VII may be isolated by methods including
concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula VII is oxidized to the compound of Formula VI in the presence of an oxidizing agent and a base in a solvent.
The oxidizing agent is selected from the group consisting of sodium
hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess-martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO), and chromium oxide/pyridine. The base is selected from the group consisting of an organic and an inorganic base. Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethyl amine. Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula VII is oxidized to the compound of Formula VI at a temperature of about -10°C to about 45°C, for example, at about -10°C to about 25°C.
The compound of Formula VII is oxidized to the compound of Formula VI for about 0.5 hour to about 5 hours, for example, for about 1 hour to about 3 hours.
The compound of Formula VI may be used as such in the next step or may be isolated from the mixture by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate to obtain the compound of Formula V in a solvent.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate at a temperature of about 20°C to about 45°C, for example, at about 20°C to about 25 °C.
The compound of Formula VI is reacted with ethyl 2-(triphenylphosphoranyl) propionate for about 10 hours to about 20 hours, for example, for about 15 hours to 18 hours.
The compound of Formula V may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula V is hydrogenated to the compound of Formula IV in the presence of a hydrogenating agent in a solvent.
The hydrogenating agent is selected from the group consisting of transition metal/ carbon, and an organometallic complex optionally in the presence of a chiral ligand.
The transition metal is selected from the group consisting of palladium, manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, and iridium.
The chiral ligand is selected from the group consisting of carbon monoxide, halides, phosphines, naphthols, l, l'-bi-2-naphthol (BINOL), 2,2'-bis(diphenylphosphino)- Ι, Γ-binaphthyl (BINAP), a,a,a,a-tetraaryl-l,3-dioxolane-4,5-dimethanols (TADDOL), 2,3-0-isopropylidene-2,3-dihydroxy-l,4-bis(diphenylphosphino)butane (DIOP), bis(oxazoline) ligands (BOX) and DuPhos (a phosphine ligand), cymene and mixtures thereof.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula V is hydrogenated to the compound of Formula IV at a temperature of about 20°C to about 45°C, for example, at about 20°C to about 25°C.
The compound of Formula V is hydrogenating to the compound of Formula IV for about 1 hour to about 10 hours, for example, for about 2 hours to about 5 hours.
The compound of Formula IV may be isolated by methods including
concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula IV is reacted with phenylboronic acid to obtain the compound of Formula III in the presence of a coupling agent and a base in a solvent.
The coupling agent is selected from the group consisting of
tetrakistriphenylphospine palladium(O), tris(dibenzylideneacetone)dipalladium and bis(dibenzylideneacetone)palladium (0).
The base is selected from the group consisting of an organic and an inorganic base.
Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethylamine. Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula IV is reacted with phenylboronic acid at a temperature of about 20°C to about 100°C, for example, at about 20°C to about 85°C.
The compound of Formula IV is reacted with phenylboronic acid for about 1 hour to about 10 hours, for example, for about 2 hours to about 5 hours.
The compound of Formula III may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula III is deprotected to obtain the compound of Formula II in the presence of a deprotecting agent in a solvent.
The deprotecting agent is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, sulfuric acid, p-toluene sulfonic acid, and methane sulfonic acid
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula III is deprotected to the compound of Formula II at a temperature of about 20°C to about 75°C, for example, at about 30°C to about 70°C.
The compound of Formula III is deprotected to the compound of Formula II for about 0.5 hours to about 4 hours, for example, for about 1 hour to about 2 hours. The compound of Formula II may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The compound of Formula II is reacted with succinic anhydride to obtain sacubitril of Formula I in the presence of a base in a solvent.
The base is selected from the group consisting of an organic and an inorganic base. Examples of an organic base include ethylamine, propyl amine, isopropyl amine, and triethylamine. Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbon include toluene or benzene.
Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2-dichloroethane. Examples of polar aprotic solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N-methylpyrrolidone.
The compound of Formula II is reacted with succinic anhydride at a temperature of about 5°C to about 30°C, for example, at about 5°C to about 20°C.
The compound of Formula II is reacted with succinic anhydride for about 1 hour to about 10 hours, for example, for about 1 hour to about 5 hours.
Sacubitril of compound of Formula I may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
Sacubitril of Formula I may be further converted to its salt or to a solid form of sacubitril and an angiotensin receptor antagonist, for example, valsartan, irbesartan, telmisartan, in their salt form or their hydrates, by the analogous methods provided in PCT Publication No. WO 2007/056546 and U.S. Patent No. 7,468,390, which are incorporated herein by reference, or process as described herein.
Examples of salts include monovalent salt or bivalent salt. The monovalent salt includes lithium, sodium, potassium, rubidium, cesium, or NPv4+ (wherein R is hydrogen or Ci-6 alkyl). The bivalent salt includes barium, magnesium, calcium, zinc, and strontium salt. The salt of sacubitril of compound of Formula I also includes benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine salt.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Preparation of methyl N-(tert-butoxycarbonyl)-0-[(trifluoromethyl) sulfonyl]-D-tyrosinate (Formula VIII)
Toluene (400 mL) was added to methyl N-(tert-butoxycarbonyl)-D-tyrosinate (a compound of Formula IX) (100.0 g) at 20°C to 25°C. The mixture was cooled to 0°C to 5°C and triethyl amine (71.3 mL) was added. Trifluoromethyl sulfonyl anhydride (68.6 mL) was drop wise added to the reaction mixture at 0°C to 5°C and then the reaction mixture was stirred at 5°C to 15°C for 1.5 hours. Water (200 mL) was added to the reaction mixture at 20°C to 25°C and the reaction mixture was stirred at 20°C to 25°C for 15 minutes. The layers obtained were separated and toluene (400 mL) was recovered from the organic layer under 150 mm to 9 mm of Hg pressure at 40°C to 45 °C for 1.0 hour to obtain the title compound.
Yield: 140.0 g
Example 2: Preparation of 4-{(2/?)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropyl} phenyl trifluoromethanesulfonate (Formula VII)
2-Propanol (600 mL) was added to a compound of Formula VIII (120.0 g; example
1) at 20°C to 25°C. A solution of potassium hydrogen phosphate ((144.0 g) in water (150 mL)) was added to the mixture and the reaction mixture was cooled to 5°C to 10°C. A solution of sodium borohydride ((24.9 g) in water (90 mL)) was added to the reaction mixture at 10°C to 15°C and the reaction mixture was stirred at 20°C to 25°C for 2 hours. The layers obtained were separated and 2-propanol (600 mL) was recovered from the reaction mixture under 150 mm to 9 mm of Hg pressure at 40°C to 45°C. Ethyl acetate (360 mL) was added to the reaction mixture followed by the addition of water (240 mL). The reaction mixture was cooled to 10°C to 15°C and the pH was adjusted to 5.0 to 5.5 by adding IN hydrochloric acid (15 mL) at 10°C to 15°C. The reaction mixture was stirred for 15 minutes and the layers obtained were separated. The ethyl acetate (360 mL) obtained was recovered from the reaction mixture under 190 mm to 9 mm of Hg pressure at 40°C to 45°C for 40 minutes to obtain the title compound.
Yield: HO.O g
Example 3: Preparation of 4-{(2/?)-2-[(tert-butoxycarbonyl)amino]-3- oxopropyl}phenyl trifluoromethanesulfonate (Formula VI)
Dichloromethane (840 mL) was added to a compound of Formula VII (105.0 g; example 2) at 20°C to 25°C. De-ionized water (262.5 mL) was added and the reaction mixture was cooled to -10°C to -5°C. Sodium bromide (13.5 g), sodium bicarbonate (44.1 g) and TEMPO (2.99 g) were added to the reaction mixture at -10°C to -5°C. A solution of 7% sodium hypochlorite (475 mL) was added to the reaction mixture at -10°C to -5°C and stirred for 1 hour. A solution of 20% sodium thiosulfate (100 mL) was added to the reaction mixture at -10°C to 0°C and stirred for 40 minutes at 0°C to 10°C. The layers obtained were separated and dichloromethane layer was washed with sodium chloride solution (20%, 500 mL). Dichloromethane layer (900 mL) was collected and was used as such in the next step.
Mass: 397.4 [M + H]+; MS/MS: 398.2, 358.2, 356.3, 344.3, 326.3, 300.1, 156.2, 142.2.
Example 4: Preparation of ethyl (2 ,4/?)-4-[(tert-butoxycarbonyl)amino]-2-methyl-5- (4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)pent-2-enoate (Formula V)
Ethyl 2-(triphenylphosphoranyl) propionate (120.6 g) was added to
dichloromethane solution (900 mL) of a compound of Formula VI (example 3) at 20°C to 25°C and stirred for 16 hours. Dichloromethane (900 mL) was recovered under 400 mm to 10 mm of Hg pressure at 40°C to 45°C. The solid obtained was purified using silica gel column using ethyl acetate: hexane solvent system as 5:95 (10 L) to obtain the title compound.
Yield: 72.0 g
*H NMR (400 MHz, CDCb), δ (in ppm): 7.20 (d, 2H), 7.13 (d, 2H), 6.43 (d, 1H), 4.58 (bs, 1NH), 4.19 (m, 3H), 2.88 (s, 1H), 2.74 (s, 1H), 1.97 (s, 1H), 1.87 (s, 1H), 1.60 (s, 2H), 1.20 (s, 3H), 1.28 (s 9H).
Mass: 481.4 [M + H]+; MS/MS: 482.4, 426.3, 382.2, 365.2, 336.2, 155.1, 127.0.
Example 5: Preparation of ethyl (2/?,45)-4-[(tert-butoxycarbonyl)amino]-2-methyl-5- (4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)pentanoate (Formula IV)
Methanol (210 mL) was added to the compound of Formula V (30.0 g; example 4) at 20°C to 25°C. Palladium/carbon (10% wet, 1.5 g) was added to the reaction mixture. The reaction mixture obtained was kept in Parr apparatus under hydrogen pressure (3.5- 4.0 Kg) at 20°C to 25°C and stirred for 4 hours. The reaction mixture obtained was filtered through celite. The methanol (210 mL) was recovered from the reaction mixture under 190 mm to 9 mm of Hg pressure at 40°C to 45°C to obtain the solid material (29.0 g). The solid material (29.0 g) was purified using silicagel column using ethyl acetate: hexane solvent system as 5: 95 (4 L) to obtain the title compound.
Yield: 24.5 g
Ή NMR (400 MHz, CDCb), δ (in ppm): 7.19 (d, J = 7.1 Hz, 2H), 7.11 (d, J = 7.1 Hz, 2H), 4.29 (m, 1H), 4.06 (m, 1H), 3.79 (m, 1H), 2.71 (m, 2H), 2.66 (m, 1H), 1.96 (m, 1H), 1.38 (s, 9H), 1.28 (t, 3H), 1.13 (d, 3H).
Mass: 483.4 [M + H]+; MS/MS: 484.4, 428.4, 385.2, 367.2, 336.3, 293.2, 236.2.
Example 6: Preparation of ethyl (2/?,45)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoate (Formula III)
Toluene (240 mL) was added to the compound of Formula IV (24.0 g; example 5) at 20°C to 25°C. Phenylboronic acid (12.1 g), potassium carbonate (13.7 g) and tetrakistriphenylphospine palladium(O) (1.72 g) were added sequentially to the mixture at 20°C to 25°C. The reaction mixture was degassed by purging with nitrogen gas for 10 minutes. The reaction mixture was heated to 80°C to 85°C and stirred for 2 hours. The reaction mixture was cooled to 20°C to 25 °C and filtered through celite. Toluene layer was washed with aqueous sodium hydroxide solution (5%, 100 mL), IN hydrochloric acid (100 mL) and de-ionized water (100 inL) sequentially. Toluene (290 mL) was recovered from the reaction mixture under 150 mm to 9 mm of Hg pressure at 40°C to 45°C to obtain the solid material (27.0 g). The solid material (27.0 g) was purified using silica gel column using ethyl acetate: hexane solvent system as 5: 95 (3 L) to obtain the title compound.
Yield: 18.0 g
Example 7: Preparation of ethyl (2/?,45)-4-amino-5-(biphenyl-4-yl)-2- methylpentanoate (Formula II)
A solution of hydrochloric acid in ethanol (10%, 32 mL) was added to the compound of Formula III (16.0 g; example 6) at 20°C to 25°C. The reaction mixture was heated to 65°C to 70°C and stirred for 1 hour. The reaction mixture was further cooled to 20°C to 25°C. Ethanol (80 mL) was recovered from the reaction mixture under 150 mm to 9 mm of Hg at 40°C to 45°C. The solid material (20 g) obtained was dissolved in toluene (64 mL) and water (48 mL) and the reaction mixture was cooled to 5°C to 10°C. The pH was adjusted to 9 by adding aqueous sodium hydroxide solution (10%, 15 mL) at 5°C to 10°C and the reaction mixture was stirred for 15 minutes. The layers obtained were separated at 20°C to 25°C. The toluene layer (48 mL) was collected and used as such in the next step.
Example 8: Preparation of sacubitril (Formula I)
Succinic anhydride (5.0 g) and diisopropyl ethyl amine (4.0 mL) were added to toluene (32 mL) at 5°C to 10°C. A solution of the compound of Formula II in toluene (64.0 mL; example 7) was added to the reaction mixture at 5°C to 10°C. The reaction mixture was stirred at 5°C to 10°C for 1 hour. Water (30 mL) was added to the reaction mixture and the pH of the solution was adjusted to 2.0 by adding IN hydrochloric acid (15 mL) at 5°C to 10°C. The reaction mixture was stirred at 5°C to 10°C for 10 minutes. The layers obtained were separated and the toluene (90 mL) was recovered from the organic layer under 400 mm to 9 mm of Hg pressure for 40 minutes to obtain the title compound.
Yield: 20.0 g
Example 9: Preparation of sodium salt of sacubitril (Formula I)
Sacubitril (130.0 g) was added to methanol (520 mL) and the reaction mixture was cooled to 5°C to 10°C. A solution of sodium hydroxide (12.26 g in 30 mL of water) was added to the reaction mixture at 5°C to 10°C and the reaction mixture was stirred for 2 hours. Methanol and water (530 mL) were recovered from the reaction mixture under reduced 200 mm to 10 mm of Hg pressure at 40°C to 45°C. Acetone (390 mL) was added to the reaction mixture at 40°C to 45 °C and the mixture was stirred for 15 minutes.
Acetone (390 mL) was recovered from the reaction mixture under reduced 300 mm to 10 mm of Hg pressure at 40°C to 45°C. Cyclohexane (390 mL) was added to the reaction mixture and stirred for 30 minutes at 20°C to 25°C. The reaction mixture was filtered and washed with cyclohexane (130 mL) to obtain the solid material (135 g) and dried under vacuum at 650 mm to 680 mm of Hg at 40°C to 45°C for 20 hours to obtain the title compound.
Yield: 116.0 g

Claims

We Claim:
1. A process for the preparation of a compound of Formula III,
Figure imgf000056_0001
Formula III
wherein the process comprises reacting a compound of Formula IV with phenylboronic acid.
Figure imgf000056_0002
Formula IV
2. The process according to claim 1, wherein the compound of Formula III is further converted into sacubitril of Formula I or a salt thereof.
Figure imgf000056_0003
Formula I A process for the preparation of a compound of Formula IV,
Figure imgf000057_0001
Formula IV
wherein the process comprises hydrogenating a compound of Formula V.
Formula V
4. The process according to claim 3, wherein the compound of Formula IV is further converted into sacubitril of Formula I or a salt thereof.
Figure imgf000057_0003
Formula I
A process for the preparation of a compound of Formula V,
Figure imgf000058_0001
Formula V
wherein the process comprises reacting a compound of Formula VI
Figure imgf000058_0002
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate.
6. The process according to claim 5, wherein the compound of Formula V is further converted into sacubitril of Formula I or a salt thereof.
Figure imgf000058_0003
Formula I
A process for the preparation of a compound of Formula VI,
Figure imgf000059_0001
Formula VI
wherein the process comprises oxidizing a compound of Formula VII.
Figure imgf000059_0002
Formula VII
8. The process according to claim 7, wherein the compound of Formula VI is further converted into sacubitril of Formula I or a salt thereof.
Figure imgf000059_0003
Formula I
A process for the preparation of a compound of Formula IV,
Figure imgf000060_0001
Formula IV
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000060_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000060_0003
Formula VIII
b) reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000060_0004
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000061_0001
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V, and
Figure imgf000061_0002
Formula V e) hydrogenating the compound of Formula V to obtain the compound of Formula IV. 10. The process according to claim 9, wherein the compound of Formula IV is further converted into sacubitril of Formula I or a salt thereof.
Figure imgf000061_0003
Formula I A process for the preparation of sacubitril of Formula I or a salt thereof,
Figure imgf000062_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000062_0002
Formula IX
with trifluoromethyl sulfonyl containing reagent to obtain a compound of Formula VIII,
Figure imgf000062_0003
Formula VIII
reducing the compound of Formula VIII to obtain a compound of Formula VII,
Figure imgf000063_0001
Formula VII
c) oxidizing the compound of Formula VII to obtain a compound of Formula VI,
Figure imgf000063_0002
Formula VI
d) reacting the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate to obtain a compound of Formula V,
Figure imgf000063_0003
Formula V
e) hydrogenating the compound of Formula V to obtain a compound of Formula IV,
Figure imgf000063_0004
Formula IV
f) reacting the compound of Formula IV with phenylboronic acid to obtain a compound of Formula III,
Figure imgf000064_0001
Formula III g) deprotecting the compound of Formula III to obtain a compound of Formula II, and
Figure imgf000064_0002
Formula II
h) reacting the compound of Formula II with succinic anhydride to obtain sacubitril of Formula I or a salt thereof.
12. A compound of Formula IV,
Figure imgf000065_0001
Formula IV 13. A compound of Formula V,
Figure imgf000065_0002
Formula V 14. A compound of Fonnula VI,
Figure imgf000065_0003
Formula VI
15. compound of Formula IV for the preparation of sacubitril or a salt thereof.
Figure imgf000066_0001
Formula IV
16. compound of Formula V for the preparation of Sacubitril or a salt thereof.
Figure imgf000066_0002
Formula V
17. Use of a compound of Formula VI for the preparation of Sacubitril or a salt thereof.
Figure imgf000066_0003
Formula VI
18. The process according to claim 1, wherein the compound of Formula IV is reacted with phenylboronic acid in the presence of a coupling agent and a base in a solvent.
19. The process according to claim 18, wherein the coupling agent is selected from the group consisting of tetrakistriphenylphospine palladium(O),
tris(dibenzylideneacetone)dipalladium and bis(dibenzylideneacetone)palladium (0).
20. The process according to claim 18, wherein the base is selected from the group consisting of an organic and an inorganic base.
21. The process according to claim 18, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
22. The process according to claim 3, wherein the compound of Formula V is hydrogenated in the presence of a hydrogenating agent in a solvent.
23. The process according to claim 22, wherein the hydrogenating agent is selected from the group consisting of metal/ carbon and an organometallic complex optionally in the presence of a chiral ligand.
24. The process according to claim 22, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
25. The process according to claim 23, wherein the transition metal is selected from the group consisting of palladium, manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, and iridium.
26. The process according to claim 23, wherein the chiral ligand is selected from the group consisting of carbon monoxide, halides, phosphines, naphthols, l, l'-bi-2-naphthol (BINOL), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP), a,a,a,a-tetraaryl-l,3- dioxolane-4,5-dimethanols (TADDOL), 2,3-0-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane (DIOP), bis(oxazoline) ligands (BOX) and DuPhos (a phosphine ligand), cymene and mixtures thereof.
27. The process according to claim 3, wherein the compound of Formula V is prepared by reacting a compound of Formula VI
Figure imgf000067_0001
Formula VI
with ethyl 2-(triphenylphosphoranyl) propionate.
28. The process according to claim 27, wherein the reaction of the compound of the Formula VI with ethyl 2-(triphenylphosphoranyl) propionate is carried out in a solvent. 29. The process according to claim 28, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
30. The process according to claim 27, wherein the compound of Formula VI is prepared by oxidizing a compound of Formula VII.
Figure imgf000068_0001
Formula VII
31. The process according to claim 30, wherein the oxidation is carried out in the presence of an oxidizing agent and a base in a solvent.
32. The process according to claim 31, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess- martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO) , and chromium oxide/pyridine.
33. The process according to claim 31, wherein the base is selected from the group consisting of an organic and an inorganic base.
34. The process according to claim 31, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
35. The process according to claim 30, wherein the compound of Formula VII is prepared by reducing a compound of Formula VIII.
Figure imgf000069_0001
Formula VIII
36. The process according to claim 35, wherein the reduction is carried out in the presence of a buffer and a reducing agent in a solvent.
37. The process according to claim 36, wherein the buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
38. The process according to claim 36, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
39. The process according to claim 36, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
40. The process according to claim 5, wherein the reaction of the compound of Formula VI with ethyl 2-(triphenyl)phosphoranyl)propionate is carried out in a solvent. 41. The process according to claim 40, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
42. The process according to claim 5, wherein the compound of Formula VI is prepared by oxidizing a compound of Formula VII.
Figure imgf000069_0002
Formula VII
43. The process according to claim 42, wherein the oxidation of the compound of Formula VII is carried out in the presence of an oxidizing agent and a base in a solvent. 44. The process according to claim 43, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess- martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO), and chromium oxide/pyridine.
45. The process according to claim 43, wherein the base is selected from the group consisting of an organic and an inorganic base.
46. The process according to claim 43, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
47. The process according to claim 42, wherein the compound of Formula VII is prepared by reducing a compound of Formula VIII.
Figure imgf000070_0001
Formula VIII
48. The process according to claim 47, wherein the reduction of the compound of Formula VIII is carried out in the presence of a buffer and a reducing agent in a solvent. 49. The process according to claim 48, wherein the buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
50. The process according to claim 48, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
51. The process according to claim 48, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
52. The process according to claim 47, wherein the compound of Formula VIII is prepared by reacting a compound of Formula IX
Figure imgf000071_0001
Formula IX
with a trifluoromethyl sulfonyl containing reagent in the presence of a base in a solvent. 53. The process according to claim 52, wherein the trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
54. The process according to claim 52, wherein the base is selected from the group consisting of an organic and an inorganic base.
55. The process according to claim 52, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
56. The process according to claim 7, wherein the compound of Formula VII is oxidized in the presence of an oxidizing agent and a base in a solvent.
57. The process according to claim 56, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess- martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO), and chromium oxide/pyridine.
58. The process according to claim 56, wherein the base is selected from the group consisting of an organic and an inorganic base.
59. The process according to claim 56, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
60. The process according to claim 7, wherein the compound of Formula VII is prepared by reducing a compound of Formula VIII.
Figure imgf000072_0001
Formula VIII
61. The process according to claim 60, wherein the reduction of the compound of Formula VIII is carried out in the presence of a buffer and a reducing agent in a solvent. 62. The process according to claim 61, wherein the buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
63. The process according to claim 61, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
64. The process according to claim 61, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
65. The process according to claim 60, wherein the compound of Formula VIII is prepared by reacting a compound of Formula IX
Figure imgf000072_0002
Formula IX
with a trifluoromethyl sulfonyl containing reagent in the presence of a base in a solvent. 66. The process according to claim 65, wherein the trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
67. The process according to claim 65, wherein the base is selected from the group consisting of an organic and an inorganic base.
68. The process according to claim 65, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
69. The process according to claim 9, wherein the reaction of the compound of Formula IX with a trifluoromethyl sulfonyl containing reagent is carried out in the presence of a base in a solvent.
70. The process according to claim 69, wherein the trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
71. The process according to claim 69, wherein the base is selected from the group consisting of an organic and an inorganic base.
72. The process according to claim 69, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
73. The process according to claim 9, wherein the reduction of the compound of Formula VIII is carried out in the presence of a buffer and a reducing agent in a solvent. 74. The process according to claim 73, wherein the buffer is selected from the group consisting of potassium hydrogen phosphate, di- potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
75. The process according to claim 73, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
76. The process according to claim 73, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
77. The process according to claim 9, wherein the oxidation of the compound of Formula VII is carried out in the presence of an oxidizing agent and a base in a solvent. 78. The process according to claim 77, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess- martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO), and chromium oxide/pyridine.
79. The process according to claim 77, wherein the base is selected from the group consisting of an organic and an inorganic base.
80. The process according to claim 77, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
81. The process according to claim 9, wherein the reaction of the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate is carried out in a solvent. 82. The process according to claim 81, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
83. The process according to claim 9, wherein the hydrogenation of the compound of Formula V is carried out in the presence of a hydrogenating agent in a solvent.
84. The process according to claim 83, wherein the hydrogenating agent is selected from the group consisting of transition metal/ carbon, and an organometallic complex optionally in the presence of a chiral ligand.
85. The process according to claim 84, wherein the transition metal is selected from the group consisting of palladium, manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, and iridium.
86. The process according to claim 84, wherein the chiral ligand is selected from the group consisting of carbon monoxide, halides, phosphines, naphthols, l,l'-bi-2-naphthol (BINOL), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP), a,a,a,a-tetraaryl-l,3- dioxolane-4,5-dimethanols (TADDOL), 2,3-0-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane (DIOP), bis(oxazoline) ligands (BOX) and DuPhos (a phosphine ligand), cymene and mixtures thereof.
87. The process according to claim 83, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
88. The process according to claim 11, wherein the reaction of the compound of Formula IX with a trifluoromethyl sulfonyl containing reagent is carried out in the presence of a base in a solvent.
89. The process according to claim 88, wherein the trifluoromethyl sulfonyl containing reagent is selected from the group consisting of trifluoromethyl sulfonic acid, trifluoromethyl sulfonyl chloride, and trifluoromethyl sulfonyl anhydride.
90. The process according to claim 88, wherein the base is selected from the group consisting of an organic and an inorganic base.
91. The process according to claim 88, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
92. The process according to claim 11, wherein the reduction of the compound of Formula VIII is carried out in the presence of a buffer and a reducing agent in a solvent. 93. The process according to claim 92, wherein the buffer is selected from the group consisting of potassium hydrogen phosphate, di-potassium hydrogen phosphate, sodium hydrogen phosphate, and di-sodium hydrogen phosphate.
94. The process according to claim 92, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane.
95. The process according to claim 92, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
96. The process according to claim 11, wherein the oxidation of the compound of Formula VII is carried out in the presence of an oxidizing agent and a base in a solvent. 97. The process according to claim 96, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite/2,2,6,6-tetramethylpiperidinooxy (TEMPO), potassium permanganate, potassium dichromate, pyridinium chlorochromate (PCC), dess- martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (DMSO), and chromium oxide/pyridine.
98. The process according to claim 96, wherein the base is selected from the group consisting of an organic and an inorganic base.
99. The process according to claim 96, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
100. The process according to claim 11, wherein the reaction of the compound of Formula VI with ethyl 2-(triphenylphosphoranyl) propionate is carried out in a solvent. 101. The process according to claim 100, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
102. The process according to claim 11, wherein the hydrogenation of the compound of Formula V is carried out in the presence of a hydrogenating agent in a solvent.
103. The process according to claim 102, wherein the hydrogenating agent is selected from the group consisting of transition metal/ carbon, and an organometallic complex optionally in the presence of a chiral ligand.
104. The process according to claim 103, wherein the transition metal is selected from the group consisting of palladium, manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, and iridium.
105. The process according to claim 103, wherein the chiral ligand is selected from the group consisting of carbon monoxide, halides, phosphines, naphthols, l, l'-bi-2-naphthol (BINOL), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP), a,a,a,a-tetraaryl-l,3- dioxolane-4,5-dimethanols (TADDOL), 2,3-0-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane (DIOP), bis(oxazoline) ligands (BOX) and DuPhos (a phosphine ligand), cymene and mixtures thereof.
106. The process according to claim 102, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
107. The process according to claim 11, wherein the reaction of the compound of Formula IV with phenylboronic acid is carried out in the presence of a coupling agent and a base in a solvent.
108. The process according to claim 107, wherein the coupling agent is selected from the group consisting of tetrakistriphenylphospine palladium(O),
tris(dibenzylideneacetone)dipalladium and bis(dibenzylideneacetone)palladium (0). 109. The process according to claim 107, wherein the base is selected from the group consisting of an organic and an inorganic base.
110. The process according to claim 107, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
111. The process according to claim 11, wherein the deprotection of the compound of Formula III is carried out in the presence of a deprotecting agent in a solvent.
112. The process according to claim 111, wherein the deprotecting agent is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, sulfuric acid, p- toluene sulfonic acid, and methane sulfonic acid.
113. The process according to claim 111, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
114. The process according to claim 11, wherein the reaction of the compound of Formula II with succinic anhydride is carried out in the presence of a base in a solvent. 115. The process according to claim 114, wherein the base is selected from the group consisting of an organic and an inorganic base.
116. The process according to claim 114, wherein the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
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CN107602410A (en) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 Sha Ku is than crystal formation II of bent sodium salt and preparation method thereof
CN108047093A (en) * 2017-11-29 2018-05-18 南通常佑药业科技有限公司 A kind of preparation method of xenyl aminopropan aldehyde compound

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CN107602410A (en) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 Sha Ku is than crystal formation II of bent sodium salt and preparation method thereof
CN107540574A (en) * 2017-09-19 2018-01-05 成都西岭源药业有限公司 The preparation method of R biphenyl Propanolamines
CN107540574B (en) * 2017-09-19 2021-06-11 成都西岭源药业有限公司 Preparation method of R-biphenylalaninol
CN108047093A (en) * 2017-11-29 2018-05-18 南通常佑药业科技有限公司 A kind of preparation method of xenyl aminopropan aldehyde compound

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