Preparation process of clofarabine intermediate

Abstract

The invention discloses a preparation process of a clofarabine intermediate. The preparation process comprises the following steps of a) preparing the following raw materials including 5-8 g of D-ribose, 20-30 ml of a hydrogen chloride gas-methanol solution, 15-25 ml of pyridine, 50-70 ml of chloroform, 40-55 ml of glacial acetic acid, 5-8 ml of acetic anhydride, 20-30 ml of barium chloride, 3-5 ml of concentrated sulfuric acid, 80-100 ml of 95% ethyl alcohol, 6-10 ml of dinitrobenzotrifluoride, and 200-300 ml of ice water; and b) preparing following instruments of a low-temperature cooling circulating pump, a reduced pressure distillation kettle, a 250 ml beaker, a stirrer and a mixed reaction kettle. The D-ribose, hydrogen chloride gas-methanol solution, pyridine, chloroform, glacial acetic acid, acetic anhydride and other raw materials are all common chemical raw materials with low price, and the production cost is low; and besides, guanosine which is difficult to remove thoroughlyis not adopted as a raw material, the subsequent processing of the finished product of the clofarabine intermediate is convenient while low cost is achieved, and the potential safety hazard is small.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation process of a clorabine intermediate. Background technique [0002] Clorabine, also known as clofarabine, belongs to nucleotide analogs. On December 29, 2004, the US FDA approved it for the treatment of children with refractory or relapsed acute lymphoblastic leukemia (ALL) clofarabine Bin is the first new drug approved for the treatment of ALL in children in the past 10 years. FDA fast-track approval of the drug is based on the results of a core phase II clinical trial involving 49 children with relapsed or refractory ALL. Fourteen percent of the children received bone marrow or stem cell transplantation after clofarabine treatment. The most common side effects of clofarabine are gastrointestinal symptoms such as nausea, vomiting and diarrhea, hematological reactions such as anemia, leukopenia, thrombocytopenia, neutropenia, fever with neutr...

AI Technical Summary

Problems solved by technology

[0003] In the prior art, the clorabine intermediate generally refers to 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-ribofuranose, and its synthetic route is generally based on D- Ribose is used as raw material 16.7, and the target product is obtained through 4 steps of methylation, acylation, substitution, and hydrolysis, and the yields are 33.8% and 44.1%, respectively; or using guanosine as raw material, after acylation, substitution, and hydrolysis reactions, Although the yield is as high as 88%, the resulting product has a low melting point, and the product has not been characterized by IR, 'H NMR and MS. It cannot be proved that the guanine on the guanosine is completely removed, and the amount of material used is large, and the reaction temperature is too high. High, and intermediates can usually be produced in ordinary chemical plants, as long as they reach a certain level, they can be used in the synthesis of drugs, but their yield cannot meet the requirements of modern industrial production, and the process has a large amount of materials and pyridine termination Complicated post-processing steps such as methylation reaction, sulfuric acid neutralization, and sodium bicarbonate washing