Process of making optically pure melphalan
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.
1. 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.
2. The process of claim 1 , wherein the step of purifying removes (4-(bis-(2-hydroxyethyl)amino)phenyl)-2-(2-hydroxyethylamino)-propanoic acid, an alkyl ester thereof, or a combination of both.
3. The process of claim 1 , wherein step (a) is performed in water or an aqueous organic solvent mixture.
4. The process of claim 1 , wherein said aqueous organic solvent mixture is a mixture of water and one or more water miscible solvents selected from the group consisting of alcohols having not more than six carbons, acetonitrile, acetone, dioxan, or tetrahydrofuran, and a combination thereof.
5. The process of claim 3 , wherein said aqueous organic solvent mixture is a mixture of water and one or more water miscible solvents selected from the group consisting of alcohols having not more than six carbons, acetonitrile, acetone, dioxan, or tetrahydrofuran, and a combination thereof.
6. The process of claim 1 wherein the purifying step produces at least 95% chemically and optically pure 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine.
7. The process of claim 1 , wherein step (a) occurs at room temperature.
8. The process of claim 1 , wherein step (a) occurs at a temperature in the range of about 0° C. to about 50° C.
9. The process of claim 1 , wherein step (a) occurs at a temperature in the range of about 20° C. to 50° C.
10. The process of claim 1 , wherein step (a) occurs at a temperature in the range of about 20° C. to 40° C.
11. A process of making optically pure melphalan, comprising the steps of:
(a) esterifying 4-(bis(2-hydroxyethyl)amino)-L-phenylalanine manufactured from the process in accordance with claim 1 with one or more alkyl alcohols to form an alkyl ester thereof;
(b) chlorinating the 4-(bis(2-hydroxyethyl)amino)-L-phenylalanine alkyl ester to yield 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester;
(c) hydrolyzing the 4-(bis(2-chloroethyl)amino)-L-phenylalanine alkyl ester 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);
(d) purifying the crude melphalan by dissolving the same in an aqueous acid solution and precipitating a melphalan base from the melphalan and aqueous acid solution.
12. The process of claim 11 , wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, citric acid, methane sulfonic acid, toluene sulfonic acid, or acetic acid, and combinations thereof.
13. The process of claim 11 , wherein the alkyl ester is selected from the group consisting of methyl, ethyl, or n-propyl ester, or a combination thereof.
14. A process of making optically pure melphalan, comprising the steps:
(a) chlorinating 4-(bis(2-hydroxyethyl)amino)-L-phenylalanine manufactured from the process in accordance with claim 1 and adjusting the pH to a pH in the range of from about 2 to about 4 to form crude 4-(bis(2-chloroethyl)amino)-L-phenylalanine (melphalan);
(b) purifying the crude 4-(bis(2-chloroethyl)amino)-L-phenylalanine by dissolving the crude melphalan in an aqueous acid solution and precipitating out melphalan base.
15. The process of claim 14 , wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, citric acid, methane sulfonic acid, toluene sulfonic acid, or acetic acid, and combinations thereof.
16. 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.
17. The process of claim 16 , wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, citric acid, methane sulfonic acid, toluene sulfonic acid, or acetic acid, and combinations thereof.
18. The process of claim 16 , wherein the alkyl ester is selected from the group consisting of methyl, ethyl, or n-propyl ester, or a combination thereof.
19. 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.
20. The process of claim 1 , further comprising the steps of:
(a) introducing 4-nitro-L-phenylanine; and
(b) hydrogenating the 4-nitro-L-phenylanine in a medium having methanol and sodium hydroxide to prepare 4-amino-L-phenylalanine of the formula,
wherein R1 is H or a lower straight or branched chain alkyl of 1 to 6 carbons, prior to the step of reacting with ethylene oxide.
21. The process of claim 20 , wherein said medium further has a palladium on a carbon catalyst and hydrogen gas.
22. The process of claim 20 , wherein the hydrogenating step is done under pressures in the range of from about 20 psi to about 100 psi.
23. The process of claim 1 , wherein the 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine obtained in step (a) is precipitated by the additional of isopropanol prior to step (b).
24. The process of claim 1 , wherein said predetermined amount of ethylene oxide is about 84 g for every 76 g of the 4-amino-L-pheylalanine.
25. 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.