Synthesis of 2-alkyl amino acids
AssigneeGenzyme Corporation
InventorsMukund S. Chorghade, Mukund K. Gurjar, Debendra K. Mohapatra
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Abstract
Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. A method of preparing a 2-alkyl amino acid involves a Michael-type addition of a nucleophile to a dialkyl 2-methylidenylpropan-1,3-dioate and the conversion of a ester moiety into an amino moiety. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In this method, an aryl nitrile or imidate is condensed with cysteine, a 2-alkyl cysteine, or a cysteine ester.
Claims17
A method of preparing a compound represented by Structural Formula (I):
- or a salt thereof
- wherein:
- R1 is —H or a substituted or unsubstituted alkyl group;
- R2 is a substituted or unsubstituted alkyl group;
- and
- R3 is —H, —SH, —OH, —NH2, —CO2H, —CONH2, —NHC(NH)NH2, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloaliphatic group, or a substituted or unsubstituted aromatic group, wherein R3 optionally comprises a protecting group;
- comprising the steps of:
- a.) reacting a nucleophile of the formula A—R3 or A—(R3)2 with a compound represented by Structural Formula (II):
- wherein:
- A is —H, —Li,
- —MgCl, —MgBr, or —MgI, provided that A and R3 are not each —H;
- R4 is —H or a substituted or unsubstituted alkyl group;
- and
- R1 and R3 are as defined above;
- thereby forming a compound represented by Structural Formula (III):
- b.) reacting the compound represented by Structural Formula (III) with one or more bases, R2X, and a phase transfer catalyst, wherein X is a leaving group;
- and
- R1, R2, R3, and R4 are as defined above;
- thereby forming a compound represented by Structural Formula (IV):
- c.) converting the compound represented by Structural Formual (IV) into a compound represented by Structural Formula (V):
- d.) optionally cleaving the protecting group of R3, thereby forming the compound represented by Structural Formula (I).
Dependencies are inferred from the claim text.