The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.

The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.

A method for esterification of one or more carboxylic acid groups in a compound containing one or more carboxylic acid groups wherein the esterification reagent is a diazo-compound of formula:

##STR00001##

wherein the R.sub.1 and R.sub.2 groups of the diazo compound are selected such that the corresponding organic compound of formula:

##STR00002##

exhibits a —C—H pKa value between 18 and 29 as measured in DMSO. Specific reagents and methods for esterification are provided. The esterification reagents provided exhibit high selectivity for esterification of carboxylic acid groups over reaction with amine, alcohol or thiol groups in the compound containing one or more carboxylic acid groups. The method can be used to selectively esterify carboxylic acid groups in peptides or proteins.

A method for esterification of one or more carboxylic acid groups in a compound containing one or more carboxylic acid groups wherein the esterification reagent is a diazo-compound of formula:

##STR00001##

wherein the R.sub.1 and R.sub.2 groups of the diazo compound are selected such that the corresponding organic compound of formula:

##STR00002##

exhibits a —C—H pKa value between 18 and 29 as measured in DMSO. Specific reagents and methods for esterification are provided. The esterification reagents provided exhibit high selectivity for esterification of carboxylic acid groups over reaction with amine, alcohol or thiol groups in the compound containing one or more carboxylic acid groups. The method can be used to selectively esterify carboxylic acid groups in peptides or proteins.

A method for producing an amide includes: subjecting carboxylic acids to dehydration condensation or causing a reaction between a carboxylic acid and a haloformic acid ester; and subsequently causing a reaction with a first base and a reaction with an amine to obtain an amide, wherein the reaction with a first base and/or the reaction with an amine is performed by adding an acid thereto.

A method for producing an amide includes: subjecting carboxylic acids to dehydration condensation or causing a reaction between a carboxylic acid and a haloformic acid ester; and subsequently causing a reaction with a first base and a reaction with an amine to obtain an amide, wherein the reaction with a first base and/or the reaction with an amine is performed by adding an acid thereto.

The present disclosure is directed synthetic methods for the preparation of 4-valyloxybutyric acid. The synthetic methods described herein employ a diverse array of protecting group strategies and reaction conditions. Additionally, the present disclosure is directed to compounds useful as synthetic intermediates in the preparation of 4-valyloxybutyric acid.

The present disclosure is directed synthetic methods for the preparation of 4-valyloxybutyric acid. The synthetic methods described herein employ a diverse array of protecting group strategies and reaction conditions. Additionally, the present disclosure is directed to compounds useful as synthetic intermediates in the preparation of 4-valyloxybutyric acid.

This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.