WO2011035569A1 - Process for manufacture of n-acylbphenyl alanine - Google Patents

Process for manufacture of n-acylbphenyl alanine Download PDF

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Publication number
WO2011035569A1
WO2011035569A1 PCT/CN2010/071243 CN2010071243W WO2011035569A1 WO 2011035569 A1 WO2011035569 A1 WO 2011035569A1 CN 2010071243 W CN2010071243 W CN 2010071243W WO 2011035569 A1 WO2011035569 A1 WO 2011035569A1
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Prior art keywords
formula
compound
salt
acid
preparing
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PCT/CN2010/071243
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English (en)
French (fr)
Inventor
Guoliang Zhu
Desong Shi
Junhui Wei
Fengfeng Tao
Original Assignee
Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/CN2009/074125 external-priority patent/WO2010034236A1/en
Priority to JP2012530106A priority Critical patent/JP5894531B2/ja
Priority to AU2010297892A priority patent/AU2010297892B2/en
Priority to ES10818263.5T priority patent/ES2627060T3/es
Priority to RU2012116208/04A priority patent/RU2534619C2/ru
Priority to CA2772681A priority patent/CA2772681C/en
Priority to MX2012003488A priority patent/MX2012003488A/es
Priority to US13/497,544 priority patent/US20130172572A1/en
Priority to IN1968DEN2012 priority patent/IN2012DN01968A/en
Priority to KR1020167036201A priority patent/KR101821090B1/ko
Application filed by Zhejiang Jiuzhou Pharmaceutical Co., Ltd., Novartis Ag filed Critical Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
Priority to BR112012006406A priority patent/BR112012006406A2/pt
Priority to EP10818263.5A priority patent/EP2480523B1/en
Priority to CN201080042243.1A priority patent/CN102639486B/zh
Publication of WO2011035569A1 publication Critical patent/WO2011035569A1/en
Priority to US14/163,526 priority patent/US9242927B2/en
Priority to US14/990,832 priority patent/US20160115118A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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
    • C07C233/51—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 an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • 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
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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 of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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 of a carbon skeleton containing six-membered aromatic rings

Definitions

  • the invention relates to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors.
  • NEP neutral endopeptidase
  • the present invention relates to a method to prepare N-acyl derivatives of biphenyl alanine.
  • N-acyl derivatives of biphenyl alanine are key intermediates in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors, such as those described in U.S. Patent No. 4,722,810, U.S. Patent No. 5,223,516, U.S. Patent No. 4,610,816, U.S. Patent No.
  • NEP neutral endopeptidase
  • biphenyl alanine derivatives typically use expensive starting materials such as non-natural D-tyrosine. Moreover, said methods require the use of trifluoromethanesulfonic anhydride, which is also expensive, to activate the phenolic hydroxyl in order to carry out the aryl coupling reaction leading to the desired biphenyl structure.
  • trifluoromethanesulfonic anhydride which is also expensive, to activate the phenolic hydroxyl in order to carry out the aryl coupling reaction leading to the desired biphenyl structure.
  • This invention provides a method for preparing a N-acylbiphenyl alanine of formula (3), as defined herein.
  • the new process, according to the present invention, for producing compounds according to formula (3) is summarized in Scheme 2.
  • a compound of formula (1) is obtained.
  • Said compound of formula (1) is next converted into a compound of formula (2), as defined herein, which in turn is hydrogenated, for example with hydrogen and palladium on charcoal, to provide the compound of formula (3).
  • a compound of formula (3) can be converted into a neutral endopeptidase (NEP) inhibitors, for example, as described in the Journal of Medicinal Chemistry, 1995, Vol. 38, No. 10, 1691, and the patent documents cited hereinbefore, the disclosure for each of which is incorporated by reference
  • NEP neutral endopeptidase
  • Step a
  • the present invention relates to a method for preparing a compound of formula (1-a), or salt thereof, preferably wherein the compound of formula (1-a) is of the formula (1),
  • Rl is Ci_ 7 alkyl, preferably methyl, or C 6 _ioaryl, preferably phenyl,
  • Rl is as defined for the compound of formula (1-a),
  • R2 is Ci_ 7 alkyl, preferably methyl or propyl, most preferably methyl or ethyl,
  • solvents generally known in the art, for example, in the presence of a solvent, (named solvent I), selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, heptane, acetic acid, propionic acid, isobutyric acid, n-butyric acid, acetic anhydride or propionic anhydride.
  • solvent I selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, heptane, acetic acid, propionic acid, isobutyric acid, n-butyric acid, acetic anhydride or propionic anhydride.
  • anhydride (B) is acetic anhydride or propionic anhydride.
  • under alkaline conditions means that the step requires a base.
  • said base is selected from triethylamine, pyridine, N-methylpyrrole, N-methylmorpholine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium propionate, or potassium propionate.
  • step a is carried out at a reaction temperature of from 80 deg C to reflux, preferably, with a reaction time of 0.5 to 48 hours.
  • the molar ratio of said biphenyl formaldehyde : said N-acylglycine (A) : said anhydride (B) : said base is 1.0 : (0.7 to 5.0) : (1.0 to 6.0) : (0.05 to 2.00); the amount of said solvent I is 0 to 20 times the weight of feed amount of said biphenyl formaldehyde.
  • Step b
  • the present invention relates to a method for preparing a compound of formula (2-a), or salt thereof,
  • Rl is Ci_ 7 alkyl, preferably methyl, or C 6 -ioaryl, preferably phi
  • the reactions described above can be carried out in solvents generally known in the art, for example, in the presence of a solvent, (named solvent II), selected from water, ethanol, methanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, ethyl propionate, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, or N-methylpyrrole.
  • a solvent selected from water, ethanol, methanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, ethyl propionate, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, or N-methylpyrrole.
  • step b is carried out at a reaction temperature of from room temperature to reflux.
  • step c is carried out at a reaction temperature of from room temperature to reflux.
  • the present invention relates to a method for preparing a compound of formula (3), or salt thereof, preferably wherein the compound of formula (3) is of the formula (3-a),
  • Rl is Ci_ 7 alkyl, preferably methyl, or C 6 -ioaryl, preferably phenyl, comprising
  • Rl is Ci_ 7 alkyl, preferably methyl, or C 6 -ioaryl, preferably phenyl,
  • Hydrogenation conditions are well-known in the art and thus refer to the use of hydrogen and a transition metal catalyst, for example, as described in Section B.3.3 in WO2009/090251, which is incorporated herein by reference.
  • the transition metal catalyst is palladium, preferably palladium on charcoal, preferably containing 1% to 20% palladium by weight.
  • the hydrogenation takes place with hydrogen in the presence of a transition metal catalyst comprising an organometallic complex and a chiral ligand, for example as described in Section C.2 in WO2009/090251, which is incorporated herein by reference.
  • solvent III selected from ethanol, methanol, ethyl acetate, N, N-dimethyl formamide, N-methylpyrrole and tetrahydrofuran.
  • the weight of feed amount of said solvent III is 5 to 50 times of the amount of the compound of formula (1) [named product 1] in step a.
  • the amount of palladium on charcoal is 0.1% to 20%> of the compound of formula (2) [named product 2] in step b by weight.
  • step c glacial acetic acid is also added in order to maintain acidic conditions.
  • the reaction temperature is of from 20 deg C to 150 deg C.
  • the pressure of hydrogen is 0.2 MPa to 10.0 MPa.
  • the present invention relates to a method for preparing a compound of formula (3), as defined herein, or salt thereof, comprising
  • step a) step a), as described above;
  • step c) as described above.
  • the present invention relates to a method for preparing a compound of formula (3), as defined herein, or salt thereof, comprising
  • Embodiment [1] A method for preparing N-acylbiphenyl alanine which is characterized by the following steps:
  • Rl is a straight-chain or branched-chain alkyl or aryl and R2 is a methyl or ethyl.
  • Embodiment [2] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step a, the molar ratio of said biphenyl formaldehyde: said N-acylglycine: said anhydride: said base is 1.0: (0.7 to 5.0): (1.0 to 6.0): (0.05 to 2.00), and the amount of said solvent I is 0 to 20 times the weight of feed amount of said biphenyl formaldehyde.
  • Embodiment [3] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step a, said solvent I is selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, heptane, acetic acid, propionic acid, isobutyric acid, n-butyric acid, acetic anhydride, or propionic anhydride; said anhydride is acetic anhydride or propionic anhydride; said base is selected from triethylamine, pyridine, N-methylpyrrole, N-methylmorpholine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium propionate, or potassium propionate.
  • said solvent I is selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitro
  • Embodiment [4] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that step a is carried out at a reaction temperature from 80 deg C to reflux with a reaction time of 0.5 to 48 hours.
  • Embodiment [5] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step b, said solvent II is selected from water, ethanol, methanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, ethyl propionate, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, or N-methylpyrrole.
  • said solvent II is selected from water, ethanol, methanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, ethyl propionate, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide,
  • Embodiment [6] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step b, the weight of feed amount of said solvent II is 2 to 50 times the amount of product 1 in step a; the feed amount of said water is 0.5 to 20 times the amount of product 1 in step a.
  • Embodiment [7] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that step b is carried out at a reaction temperature from room temperature to reflux.
  • Embodiment [8] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step c, the said solvent III is selected from ethanol, methanol, ethyl acetate, N, N-dimethyl formamide, N-methylpyrrole, or tetrahydrofuran; and said palladium charcoal contains 1% to 20% palladium by weight.
  • Embodiment [9] A method for preparing N-acylbiphenyl alanine according to embodiment [1], characterized in that for step c, wherein the weight of feed amount of said solvent III is 5 to 50 times the amount of product 1 in step a, the amount of said palladium charcoal is 0.1% to 20% of the product 2 in step b by weight.
  • Embodiment [10] A method for preparing N-acylbiphenyl alanine according embodiment [1], characterized in that glacial acetic acid is also added in order to adjust pH and maintain acidic conditions while step c is carried out, and the range of reaction temperature is from 20 deg C to 150 deg C, and said pressure of hydrogen is 0.2 MPa to 10.0 MPa.
  • Alkyl being a radical or part of a radical is a straight or branched (one or, if desired and possible, more times) carbon chain, and is especially Ci-Cy-alkyl, such as Ci-C 4 -alkyl, in particular branched Ci-C 4 -alkyl, such as isopropyl.
  • the term "lower” or "C 1 -C7-" defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Ci-Cy-alkyl for example, is n-pentyl, n-hexyl or n-heptyl or preferably Ci-C 4 -alkyl, especially as methyl, ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Very preferred is methyl or ethyl.
  • Aryl as a radical or part of a radical, for example is a mono- or bicyclic aryl with 6 to 22 carbon atoms, such as phenyl, indenyl, indanyl or naphthyl, in particular phenyl.
  • reaction mixture refers to the temperature at which the reaction mixture boils, preferably a temperature up to 180 °C, preferably up to 140 °C.
  • room temperature or “ambient temperature” means a temperature of from 20 to 35 °C, such as of from 20 to 25 °C.
  • any reference to "compounds", “starting materials” and “intermediates” hereinbefore and hereinafter, is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate, metabolic precursor such as ester or amide, or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
  • Different crystal forms may be obtainable and then are also included.
  • Salts can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form.
  • salts may be formed preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane- 1 ,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphtha- lene-disulfonic acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
  • carboxylic, phosphonic, sulfonic or sulfamic acids for example
  • salts may be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts
  • ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
  • salts include the hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric, lactic acid, fumaric acid, succinic acid, oxalic acid, malic acid, malonic acid, tartaric acid, tolyltartaric acid, benzoyltartaric acid, orotic acid, nicotinic acid, methane-sulfonic acid or 4-methylbenzenesulfonic acid salts of compounds of formula (1), (1-a), (2), (2-a), (3), (3-a) and the like formed from reaction with the above reagents.
  • Methods to prepare acid addition salts are described in the literature, for example, in the relevant chapters of "CRC Handbook of Optical Resolutions via Diasteromeric Salt

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
PCT/CN2010/071243 2008-09-24 2010-03-23 Process for manufacture of n-acylbphenyl alanine WO2011035569A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
CN201080042243.1A CN102639486B (zh) 2009-09-23 2010-03-23 生产n-酰基联苯基丙氨酸的方法
US13/497,544 US20130172572A1 (en) 2008-09-24 2010-03-23 Process for Manufacture of N-acylbiphenyl alanine
ES10818263.5T ES2627060T3 (es) 2008-09-24 2010-03-23 Proceso para la elaboración de N-acil-bifenil-alanina
RU2012116208/04A RU2534619C2 (ru) 2009-09-23 2010-03-23 Способ получения n-ацилбифенилаланина
CA2772681A CA2772681C (en) 2009-09-23 2010-03-23 Process for manufacture of n-acylbphenyl alanine
MX2012003488A MX2012003488A (es) 2008-09-24 2010-03-23 Proceso para la elaboracion de n-acil-bifenil-alanina.
IN1968DEN2012 IN2012DN01968A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2009-09-23 2010-03-23
JP2012530106A JP5894531B2 (ja) 2009-09-23 2010-03-23 Ｎ−アシルビフェニルアラニンを製造するための方法
KR1020167036201A KR101821090B1 (ko) 2009-09-23 2010-03-23 Ｎ-아실비페닐 알라닌의 제조 방법
AU2010297892A AU2010297892B2 (en) 2009-09-23 2010-03-23 Process for manufacture of N-acylbphenyl alanine
BR112012006406A BR112012006406A2 (pt) 2009-09-23 2010-03-23 "processo para a fabrição de n-acilbifenil alanina"
EP10818263.5A EP2480523B1 (en) 2009-09-23 2010-03-23 Process for manufacture of n-acylbphenyl alanine
US14/163,526 US9242927B2 (en) 2008-09-24 2014-01-24 Process for the manufacture of N-acylbiphenyl alanine
US14/990,832 US20160115118A1 (en) 2009-09-23 2016-01-08 Process for the manufacture of n-acylbiphenyl alanine

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CNPCT/CN2009/074125 2009-09-23
PCT/CN2009/074125 WO2010034236A1 (en) 2008-09-24 2009-09-23 Process for the manufacture of n-acylbiphenyl alanine

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US13/497,544 A-371-Of-International US20130172572A1 (en) 2008-09-24 2010-03-23 Process for Manufacture of N-acylbiphenyl alanine
US13497544 A-371-Of-International 2012-03-22
US14/163,526 Continuation US9242927B2 (en) 2008-09-24 2014-01-24 Process for the manufacture of N-acylbiphenyl alanine

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
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