Process for the purification of melphalan

Abstract

A method for the purification and preparation of melphalan that allows to obtain melphalan with purity higher than 99.5% is described.

Claims

1. A process for the purification of melphalan comprising: (a) treating a compound of formula IV ##STR00009## wherein R is hydrogen or a linear or branched C.sub.1-C.sub.6 alkyl group and R.sub.1 is hydrogen or an amine protective group; or a hydrochloric salt or a dimeric form thereof, in HCl 37% under reflux; and (b) isolating the compound obtained from step (a) in the presence of water, methyl-tert-butyl ether and diethylamine at pH=2.

2. A process according to claim 1 further comprising washing the compound obtained from step (b) with a linear or branched C.sub.1-C.sub.4 alcohol.

3. A process for the preparation of melphalan comprising: (a) alkylating a compound of formula II ##STR00010## wherein R.sup.2 is a linear or branched C.sub.1-C.sub.6 alkyl group and PG is an amine protective group; in the presence of an aprotic polar solvent, a base and an alkylating agent, to give a compound of formula III ##STR00011## (b) chlorinating the resultant compound of formula III in the presence of a chlorinating agent in a suitable solvent to give a compound of formula IV-1 ##STR00012## (c) isolating and purifying of the melphalan comprising: (i) treating a compound of formula IV-1 in HCl 37% under reflux; (ii) isolating the compound obtained from step (i) in the presence of water, methyl-tert-butyl ether and diethylamine at pH=2; (iii) washing of the compound obtained from step (ii) with a linear or branched C.sub.1-C.sub.4 alcohol; and (d) optionally treating the compound obtained from step (iii) with a mineral acid.

4. A process according to claim 3 wherein in step (a) the aprotic polar solvent is selected from the group consisting of acetonitrile and dichloromethane and the base is selected from the group consisting of Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 and CaO.

5. A process according to claim 3 wherein in step (b) the chlorinating agent is POCl.sub.3 or SOCl.sub.2.

6. A process according to claim 1 wherein in step (a) HCl 37% is used in a ratio HCl 37%/melphalan of about 4:1.

7. A process according to claim 1 wherein in step (b) the ratio water/melphalan is of about 10:1.

8. A process according to claim 1 wherein in step (b) the ratio methyl-tert-butyl ether/water is of about 2:1.

9. A process according to claim 3 wherein in step (d) the mineral acid is an ethanol solution of gaseous HCl in acetone.

10. A process comprising: (a) alkylating the amine group on the aromatic ring of N-BOC-L-phenylalanine ethyl ester in the presence of acetonitrile, Na.sub.2CO.sub.3 and iodoethanol to give 4-(bis-(2 hydroxyethyl)-amino-N-BOC-L-phenylalanine ethyl ester; (b) chlorinating the compound obtained from step (a) in the presence of POCl.sub.3 and isopropylacetate; (c) isolating and purifying of the melphalan comprising: (i) treating the compound obtained from step (b) in HCl 37% under reflux; (ii) isolating the compound obtained from step (i) in the presence of water, methyl-tert-butyl ether and diethylamine at pH=2; and (iii) washing of the compound obtained from step (ii) with ethanol; and (d) converting the compound obtained from step (iii) into melphalan hydrochloride by treatment with an ethanol solution of gaseous HCl in acetone.

11. The process of claim 1, wherein the Melphalan and melphalan hydrochloride have an HPLC purity >99.5%.

12. The process of claim 11, wherein the impurity G level for the Melphalan or melphalan hydrochloride is NMT 0.5%.

Description

EXAMPLE 1

Preparation of 4-(bis-(2-hydroxyethyl)-amino-N-BOC-L-phenylalanine ethyl ester

(1) Into a suitable reactor A, 2.0 kg of N-BOC-L-phenylalanine ethyl ester and acetonitrile were loaded. The suspension was let under stirring until complete dissolution, maintaining the temperature at 23 C. and 1.5 kg of sodium carbonate were then added. Subsequently, 3.2 L of 2-iodoethanol were added dropwise, the solution was heated up to 85 C. and these conditions were maintained for 2 hours. At the end of the reaction the mixture was quickly cooled down to 20 C.

(2) In another suitable reactor B, 35L of water and 4 kg of Celite were loaded and the mixture was left under stirring for at least 5 minutes. The compound obtained into reactor A was transferred into reactor B and the suspension was kept under stirring for an hour. The suspension was filtered and washed with 12 L of water.

(3) The wet Celite obtained into the reactor B and 140 L of ethyl acetate were loaded into a reactor C and the mixture was kept under stirring for 30 minutes then filtered by collecting the filtrate into a reactor D and letting the phases separate. The organic phase was distilled at reduced pressure. The residue was purified by chromatography using methylene chloride/ethyl acetate about 2:1.

(4) About 1.8 kg of 4-(bis-(2-hydroxyethyl)-amino-N-BOC-L-phenilalanine ethyl ester were then obtained.

EXAMPLE 2

Preparation of Melphalan hydrochloride

(5) 4-(bis-(2-hydroxyethyl)-amino-N-BOC-L-phenilalanine ethyl ester contained into the rich fractions was dissolved in 16 L of isopropyl acetate and dropped into 4.6 L of phosphoryl chloride, maintaining the temperature at 40 C., in an inert atmosphere. The solution was heated at 50 C. and the solution was kept under stirring for 2 hours and 30 minutes in an inert atmosphere.

(6) At the end of the reaction the solution was then transferred into a separated funnel letting the phases separate for 30 minutes.

(7) The phase containing the chlorinated product was dropped into 8.8 L of 37% HCl and let under stirring at 130 C. under reflux for at least 12 hours. The solution was subsequently cooled down to 50 C.

(8) At the end of the reaction the solution was cooled down to 20 C. under stirring and subsequently concentrated at a reduced pressure.

(9) To the concentrated residue were added 9 L of water, 18 L of methyl-tert-butyl ether and 2.6 L of diethylamine. The mixture was kept under stirring up to stable pH=2 and these conditions were maintained for 10 minutes, the mixture was subsequently filtered and washed with 10 L of methyl-t-butyl ether.

(10) The resultant product was transferred into a suitable reactor and 18 L of ethanol at 99.9% were subsequently loaded. The suspension was left under stirring for at least 10 minutes, then filtered. The product was dried under vacuum for 8-12 hours obtaining melphalan.

(11) Into a suitable reactor were loaded 0.7 Kg of melphalan, obtained as previously described, and 22 L of acetone, the solution was cooled down and kept under stirring for 30 minutes. The stoichiometric amount of gaseous HCl absorbed in ethanol was subsequently added according to the titration. The suspension was kept under stirring under cooling for a few hours. The suspension was filtered and the solid washed with acetone and methyl-tert-butyl ether.

(12) The solid was dried under vacuum for one night.

(13) About 0.7 kg of melphalan hydrochloride were obtained.