Technique for synthesizing antineoplastic melphalan

Abstract

Synthesis of antineoplastic Melphalan is carried out by esterification reacting, amino-protection reacting, hydrogenation reducing, hydroxyethylation reacting, chlorination reacting, de-protection reacting, taking chlorinating agent, absolute alcohol protecting carboxyl and pyrocarbonic di-tert-butyl protecting amino, hydrolyzing by hydrochloric acid to obtain final product. It's cheap, efficient and non-toxic, has gentle reactive condition and can be used for industrial production. It's cheap, convenient, efficient and non-toxic and can be used for industrial production.

Description

technical field [0001] The invention relates to a synthesis process of an antineoplastic drug melphalan (Melphalan), belonging to the field of drug synthesis. Background technique [0002] Melphalan (Melphalan) is the left-handed form of melphalan, its chemical name is 4-[bis(2-chloroethyl)-amino]-L-phenylalanine (4-bis(2-chloroethyl) )amino-L-phenylalanine), its structural formula is: [0003] [0004] Melphalan is a cycle non-specific antineoplastic drug. Because of its specific structure, it can enter into tumor cells and take effect, leading to the death of tumor cells, thereby playing an antitumor effect. Initially, melphalan was only used to treat multiple myeloma, but subsequent clinical studies have shown that melphalan has a broader anti-tumor spectrum. At present, melphalan can treat breast cancer, ovarian cancer, chronic lymphocytic and myeloid leukemia, malignant lymphoma and multiple myeloma through systemic administration. Tumors and soft tissue sarcomas,...

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Problems solved by technology

The disadvantages of this synthetic method mainly contain the following aspects: (1) the reaction of using phthalic anhydride to protect the amino group needs to be completed in two steps, resulting in a very low yield (about 65%); (2) using the more toxic Benzene is used as a reaction solvent, which is more harmful to the human body during the operation; (3) using acetone petroleum ether mixed solvent to carry out recrystallization, the solvent consumption is relatively large, and it is difficult to recycle, resulting in an increase in reaction costs, which is not conducive to industrial production

[0007] In the synthesis method described in US3032585, after splitting the important intermediate 4-nitro-N-phthaloyl-DL-phenylalanine of melphalan, the effective group nitrogen of melphalan is synthesized mustard, and finally obtain the melphalan product; and the synthesis method described in GB1377336 is to obtain the L-isomer through resolution from the racemic melphalan, and these two synthesis methods are all based on the synthesis method described in US3032584 Although the improvement carried out can obtain qualified optically active melphalan products, the operation process is more cumbersome and the yield is lower

[0008] In the synthesis method described in JP62192357, L-4-nitrophenylalanine is used as a starting material, and phthalimide derivatives are used to replace phthalic anhydride to protect amino groups. The operation process is still very cumbersome, which is not conducive to industrial production

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