Process for the synthesis of Melphalan

1. A process for the synthesis of Melphalan (I):

said process comprising

reacting a 4-amino-L-phenylalanine protected at the carboxy and amino groups with an agent able to convert the aromatic amino group into a group of formula: —N(CH 2 CH 2 OS(O) n O − ) 2 , wherein n is 1 or 2 followed by conversion of the —N(CH 2 CH 2 OS(O) n O − ) 2 group into a —N(CH 2 CH 2 Cl) 2 group.

2. A process according to claim 1 comprising the following steps:

a) reacting a protected 4-amino-L-phenylalanine of formula (II):

wherein R 1 is a carboxy-protecting group and one of R 2 and R 3 is hydrogen and the other one is an amino protecting group or R 2 and R 3 , together with the nitrogen atom they are bound to, form an amino-protecting group with 1,3,2-dioxathiolane 2,2-dioxide of formula (IIIa):

or with 1,3,2-dioxathiolan-2-oxide of formula (IIIb):

in the presence of an inorganic base, to provide a protected 4-(bis-(2-ethylsulfate)-amino-L-phenylalanine of formula or a protected 4-(bis-(2-ethylsulfite)-amino-L-phenylalanine of formula (IV):

wherein R 1 , R 2 and R 3 are as defined above, each X is —OS(O) n O − wherein n is 1 or 2, and M + or M 2+ is a metallic cation,

b) replacing the —X groups of the compound of formula (IV) with chlorine to provide protected Melphalan of formula (V):

wherein R 1 , R 2 and R 3 are as defined above and

c) removing the protecting groups R 1 -R 3 to provide Melphalan (I).

3. A process according to claim 2 wherein, in step a), a protected 4-amino-L-phenylalanine of formula (II) is reacted with 1,3,2-dioxathiolane 2,2-dioxide (IIIa).

4. A process according to claim 2 wherein, in compound of formula (II), R 1 is straight or branched C 1 -C 6 alkyl, R 2 is hydrogen and R 3 is a group of formula R 4 —C(O), wherein R 4 is hydrogen or straight or branched C 1 -C 6 alkyl or R 2 and R 3 , together with the nitrogen atom they are bound to, represent a group of formula (VI):

5. A process according to claim 4 wherein R 1 is ethyl and R 2 and R 3 , together with a nitrogen atom they are bound to, form a group of formula (VI) as defined in claim 4 .

6. A process according to claim 2 , wherein step b) is carried out by desulfating a compound of formula (IV) as defined in claim 2 using absolute ethanol and sulfuric acid, thereby obtaining protected 4-(bis-(2-hydroxyethyl)-amino-L-phenylalanine of formula (VII):

wherein R 1 , R 2 and R 3 are as defined in claim 2 , followed by reaction of compound (VII) with POCl 3 or SOCl 2 to provide protected Melphalan of formula (V) as defined in claim 2 .

7. A process according to claim 2 , wherein step c) is carried out by treating protected Melphalan of formula (V) with an acid at pH<1 in water at a temperature ranging from 85 to 115° C. to provide an acidic aqueous solution comprising Melphalan (I) bis-hydrochloride, and then increasing the pH to crystallize Melphalan.

8. The process according to claim 7 wherein the pH is increased to a value ranging from 7.5 to 8.5, to crystallize Melphalan hydrochloride salt.