The present technology relates to processes, mixtures and intermediates useful for making picolinamide fungicides. The picolinamide compounds are prepared by processes that include coupling together a 4-methoxy-3-acyloxypicolinic acid with key 2-amino-L-alaninate esters derived from substituted 2-phenylethanols.

The present technology relates to processes, mixtures and intermediates useful for making picolinamide fungicides. The picolinamide compounds are prepared by processes that include coupling together a 4-methoxy-3-acyloxypicolinic acid with key 2-amino-L-alaninate esters derived from substituted 2-phenylethanols.

The present technology relates to processes, mixtures and intermediates useful for making picolinamide fungicides. The picolinamide compounds are prepared by processes that include coupling together a 4-methoxy-3-acyloxypicolinic acid with key 2-amino-L-alaninate esters derived from substituted 2-phenylethanols.

The invention relates to a process for the preparation of Melphalan (4-[bis(2-5 chloroethyl)amino]-L-phenylalanine of formula (I) said process comprising the reaction of a 4-amino-L-phenylalanine protected at the carboxy and amino aminoacidic groups with an agent able to convert the aromatic amino group into a group of formula: —N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2, wherein n is 1 or 2 followed by conversion of the .fwdarw.N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2 group into a —N(CH.sub.2CH.sub.2Cl).sub.2 group. The invention also provides novel intermediates useful for the preparation of Melphalan.

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The invention relates to a process for the preparation of Melphalan (4-[bis(2-5 chloroethyl)amino]-L-phenylalanine of formula (I) said process comprising the reaction of a 4-amino-L-phenylalanine protected at the carboxy and amino aminoacidic groups with an agent able to convert the aromatic amino group into a group of formula: —N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2, wherein n is 1 or 2 followed by conversion of the .fwdarw.N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2 group into a —N(CH.sub.2CH.sub.2Cl).sub.2 group. The invention also provides novel intermediates useful for the preparation of Melphalan.

##STR00001##

The invention relates to a process for the preparation of Melphalan (4-[bis(2-5 chloroethyl)amino]-L-phenylalanine of formula (I) said process comprising the reaction of a 4-amino-L-phenylalanine protected at the carboxy and amino aminoacidic groups with an agent able to convert the aromatic amino group into a group of formula: —N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2, wherein n is 1 or 2 followed by conversion of the .fwdarw.N(CH.sub.2CH.sub.2OS(O).sub.nO—).sub.2 group into a —N(CH.sub.2CH.sub.2Cl).sub.2 group. The invention also provides novel intermediates useful for the preparation of Melphalan.

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Certain disclosed embodiments concern a crosslinker having a Formula I

(Polymerizing Group 1).sub.s-(Amino Acid).sub.u-(Polymerizing Group 2).sub.y   Formula I,

where polymerizing group 1 and polymerizing group 2 independently are selected from an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile or a (hydroxyalkyl) acrylate; s and y are from 1 to 10, with s and y each typically being 1; the amino acid is any naturally occurring amino acid, any non-naturally occurring amino acid, and any and all combinations thereof; and u is 2 to 100. Crosslinkers may include a naturally occurring amino acid or acids that are selected to provide amino-acid defining functional groups that are zwitterionic at a pH of from 2.5 to 10. Disclosed crosslinkers can also include “internal spacers”, “external spacers,” or both. Crosslinkers according to the present invention are used to make zwitterionic hydrogels that address fouling and bacteria adhesion issues associated with previously known hydrogels. Accordingly, such products are particularly suitable for biomedical applications, such as contact lenses, drug delivery vehicles, tissue engineering platforms, tissue regeneration platforms, catheters, implants and sensors.

Certain disclosed embodiments concern a crosslinker having a Formula I

(Polymerizing Group 1).sub.s-(Amino Acid).sub.u-(Polymerizing Group 2).sub.y   Formula I,

where polymerizing group 1 and polymerizing group 2 independently are selected from an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile or a (hydroxyalkyl) acrylate; s and y are from 1 to 10, with s and y each typically being 1; the amino acid is any naturally occurring amino acid, any non-naturally occurring amino acid, and any and all combinations thereof; and u is 2 to 100. Crosslinkers may include a naturally occurring amino acid or acids that are selected to provide amino-acid defining functional groups that are zwitterionic at a pH of from 2.5 to 10. Disclosed crosslinkers can also include “internal spacers”, “external spacers,” or both. Crosslinkers according to the present invention are used to make zwitterionic hydrogels that address fouling and bacteria adhesion issues associated with previously known hydrogels. Accordingly, such products are particularly suitable for biomedical applications, such as contact lenses, drug delivery vehicles, tissue engineering platforms, tissue regeneration platforms, catheters, implants and sensors.

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.