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US 8,575,385 B2Granted
Process of making optically pure melphalan
AssigneeNavinta LLC
InventorsChristopher N. Jobdevairakkam, Hero Velladurai
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Abstract
This invention provides a process of making optically pure melphalan of the formula by hydroxyethylation, in a regioselective manner, of the aromatic amino group rather than the glycinic amino group.
Claims25
A process of making 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, comprising the steps of;
- (a) reacting a predetermined amount of ethylene oxide, with 4-amino-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, to obtain 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons;
- and
- (b) purifying the 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine obtained in step (a) with an aqueous organic solvent mixture.
3 more elements
A process of making optically pure Melphalan, comprising the steps:
- (a) chlorinating 4-(bis(2-hydroxyethyl)amino)-L-phenylalanine alkyl ester to produce crude 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester;
- (b) reacting said crude 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester with an aqueous solution to form an acid salt of 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester;
- (c) hydrolyzing said 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester acid salt and adjusting the pH to a pH in the range of from about 2 to about 4 to yield crude 4-(bis(2-chloroethyl)amino)-L-phenylalanine (melphalan);
- and
- (d) purifying crude melphalan by dissolving the same in an aqueous acid solution and precipitating the melphalan base.
2 more elements
A process of making 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, comprising the steps of;
- (a) hydroxyethylation, in a regioselective manner of the aromatic amino group of 4-amino-L-phenylalanine of the formula
- where R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, to obtain 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine;
- and
- (b) purifying the 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine obtained in step (a) with an aqueous organic solvent.
2 more elements
A process of making 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, comprising the steps of;
- (a) dissolving 4-amino-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, in water;
- (b) reacting a predetermined amount of ethylene oxide with said 4-amino-L-phenylalanine dissolved in water obtained in step (a) to obtain 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine of the formula
- wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons;
- and
- (c) purifying the 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine obtained in step (b) with an aqueous organic solvent mixture.
4 more elements
Dependencies are inferred from the claim text.