3223-07-2

Usage

Safety Profile

Deadly poison by intravenousroute. Human systemic effects by ingestion: nausea andvomiting. Questionable carcinogen with experimentalcarcinogenic data. When heated to decomposition it emitsvery toxic fumes of Cl-, NOx, and HCl.

InChI:InChI=1/C13H18Cl2N2O2.ClH/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19;/h1-4,12H,5-9,16H2,(H,18,19);1H/t12-;/m0./s1

Upstream product

• 17451-67-1 N-phthalimido-4-nitro-L-phenylalanine ethyl ester 
• 116366-27-9 (S)-N-[(tert-butyloxy)carbonyl]-[4-nitrophenyl]alanine tert-butyl ester 
• 189744-28-3 N-(tert-butyloxycarbonyl)-4-(bis(2-chloroethyl)amino)-L-phenylalanine ethyl ester 
• 792864-20-1 N-phthalimido-4-(bis-2-chloroethyl)amino-L-phenylalanine ethyl ester 
• 74743-23-0 N-phthalimido-4-amino-L-phenylalanine ethyl ester 
• 148-82-3 L-PAM 

Relevant academic research and scientific papers

Proteoglycans as target for an innovative therapeutic approach in chondrosarcoma: Preclinical proof of concept

To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo 99mTc-NTP 15-5 scintigraphic imaging of PGs, 1H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma.

A PROCESS FOR THE SYNTHESIS OF MELPHALAN

The invention relates to a process for the preparation of Melphalan (4-[bis(2-5 chloroethyl)amino]-L-phenylalanine of formula (I) said process comprising the reaction of a 4-amino-L-phenylalanine protected at the carboxy and amino aminoacidic groups with an agent able to convert the aromatic amino group into a group of formula: -N(CH2CH2OS(O)nO-)2, wherein n is 1 or 2 followed by conversion of the –-N(CH2CH2OS(O)nO-)2 group into a -N(CH2CH2Cl)2 group. The invention also provides novel intermediates useful for the preparation of Melphalan.

Synthesis method of melphalan

The invention discloses a synthesis method of melphalan. The synthesis method comprises the following steps: (a), carrying out a reduction reaction: taking a compound which has a structure shown as aformula I as a raw material, and carrying out reduction reaction on the compound, a catalyst and hydrogen to obtain a reduction product shown in formula I, wherein in the formula I, X represents one of oxygen or nitrogen; R1 represents one of hydrogen, saturated alkyl group or unsaturated alkyl group; R2 and R3 respectively represent one of the hydrogen, alkyl carbonyl, amino carbonyl or alkoxycarbonyl; carrying out alkylation reaction on an alkylating reagent and the obtained reduction product in the presence of an acid binding agent to obtain an alkylated product; carrying out hydrolysis reaction on the alkylated product in acid or alkali; after concentrating, adjusting a pH value, extracting, washing and carrying out salification in dried alcohol or ester solvents of hydrochloric acid;then refining with acetonitrile to obtain melphalan hydrochloride. The synthesis method of the melphalan, disclosed by the invention, has the advantages of high yield in each step, simple operation, mild reaction conditions, no high-toxic or high-corrosion reagent, high purity of the obtained product and suitability for industrialized production.

Process for the Synthesis of Melphalan and the Hydrochloride Salt

The present invention relates to an improved process for the preparation of Melphalan, more specifically the invention relates to an efficient process for the preparation of substantially pure Melphalan hydrochloride (I).

An Improved Process for the Synthesis of Melphalan and the Hydrochloride Salt

The present invention relates to an improved process for the preparation of Melphalan, more specifically the invention relates to an efficient process for the preparation of substantially pure Melphalan hydrochloride (I).

PROCESS FOR THE PURIFICATION OF MELPHALAN

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

PROCESS FOR THE PREPARATION OF MELPHALAN HYDROCHLORIDE

The present invention provides a simple and efficient method for synthesis of 4-[bis (2-chloroethyl)-amino]-L-phenylalanine hydrochloride. The process involves the treatment of 4-[bis(2-chloroethyl)-amino]-L-phenylalanine free base with hydrochloric acid in water followed by isolation of 4-[bis(2-chloroethyl)-amino]-phenylalanine hydrochloride of desired purity.

Pharmaceutical formulations

The present invention relates to a new two-component pharmaceutical formulation of melphalan in which the two components comprise (a) freeze-dried mephalan hydrochloride and (b) a solvent-diluent comprising a citrate, propylene glycol and ethanol. Substantially pure melphalan, substantially pure melphalan hydrochloride and methods for preparing them are also described.