Separation method of triacetyl ganciclovir isomer

Abstract

The invention discloses a separation method of a triacetyl ganciclovir isomer. The separation method includes: (1) adding a crystallization solvent into a triacetyl ganciclovir isomer crude product, raising the temperature till reflux, performing heat preservation, then conducting cooling to material precipitation, carrying out filtering, washing and drying, thus obtaining an N7 / N9 triacetyl ganciclovir isomer mixture; (2) adding a separation solvent A into the N7 / N9 triacetyl ganciclovir isomer mixture, raising the temperature till the dissolved solution is clear, lowering the temperature to precipitate solids, carrying out filtering and separation to obtain a filtrate and a filter cake, subjecting the filter cake to washing and drying to obtain an N7 triacetyl ganciclovir isomer; and (3) combining the filtrate obtained in step (2) with a washing solution, conducting pressure reduction concentration till dry, then adding a separation solvent B, raising the temperature to a reflux state and performing heat preservation, conducting cooling to precipitate solids, carrying out filtration, washing and drying the filter cake so to obtain an N9 triacetyl ganciclovir isomer. The separation method provided in the invention has the advantages of simple operation and high separation efficiency, and the obtained N9 isomer has high purity.

Description

(1) Technical field [0001] The invention relates to a separation method of N9 triacetyl ganciclovir (also known as triacetyl ganciclovir), an important intermediate of antiviral drug ganciclovir. (2) Background technology [0002] Ganciclovir (Ganciclovir, GCV) is the second listed acycloside antiviral drug after Acyclovir, it is active against all herpes viruses, and it is resistant to Epstein-Barr virus (EBV), giant Cytovirus (CMV) is much more active than acyclovir. Its mechanism of action is similar to that of acyclovir. It enters virus-infected cells to generate ganciclovir triphosphate, which inhibits viral DNA polymerase and prevents the replication process of viral DNA, because ganciclovir triphosphate can inhibit the polymerization of viral DNA. The enzyme's inhibitory effect is much stronger than that of mammalian cell DNA polymerase, so it has high selectivity to viruses and relatively low toxicity to mammals. [0003] The chemical name of ganciclovir is 9-(1,3-...

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Problems solved by technology

There are also reports on the preparation of ganciclovir by cyclization, but the raw materials for ganciclovir synthesis by cyclization are not easy to obtain, the process conditions are complicated, and the yield is low, thus losing industrial significance

[0006] In the published documents, there are not many routes that are really used for industrial production, and the main problems are as follows: 1. Although the routes adopted in some documents are relatively short, there is no effective way to separate the intermediates, and the components are more complicated. As a result, the finished product needs to be refined many times to meet the requirements of relevant standards, resulting in low yield and high cost; 2. The auxiliary materials used in some documents are not easy to obtain and difficult to recycle, which has a great impact on the environment and is not conducive to industrial production; 3. Some documents use column chromatography to separate isomers and impurities, which is inefficient and not suitable for industrial production

However, through experiments, such a separation of N7 / N9 triacetyl ganciclovir mixture will produce a larger monoacetyl alkylguanine impurity in the N9 triacetyl ganciclovir product, and it is difficult to remove. In the subsequent preparation of ganciclovir An unknown impurity (an impurity not listed in the Pharmacopoeia) alkyl guanine (content>0.1%) will be produced during Ganciclovir, and it is difficult to remove in Ganciclovir

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