TJ1508的合成及晶型研究

目的研发一种新型唑烷酮类抗生素((3R,3a S)-7-(6-((S)3-甲基-2-唑烷酮-5-基)吡啶-3-基)-1-氧-1,3,3a,4-四氢苯并b]唑3,4-d]1,4]嗪-3-基)甲基)磷酸单酯(TJ1508)的合成工艺,并研究其晶型。方法以磷酸二苄酯中间体为原料,通过酸催化脱苄基得到TJ1508,在不同的溶剂体系中析晶得到不同晶型,采用粉末X射线衍射分析(PXRD)和差示扫描量热分析(DSC)对其进行表征,并对其进行加速稳定性试验和溶剂残留检测。结果目标化合物的收率最高为89%,得到3种不同的晶型A、B和C,稳定性、溶剂残留和钯残留均优于化合物专利无定型产品。结论设计了一种TJ1508的简易合成路线,得到3种稳定的晶型,其中晶型C最为稳定。

Synthesis and polymorphic study of TJ1508

Objective To study the synthetic technology of a novel oxazolidinone antibiotic ((3R,3aS)-7-(6-((S)3-methyl-2-oxazolidino-5-yl) pyridin-3-yl)-1-oxo-1,3,3a,4-tetrahydrobenzob]oxazolo3,4-d] 1,4]oxazin-3-yl)methyl)phpsphate (TJ1508), and study its crystal form. Methods TJ1508 was synthesized from dibenzyl phosphate intermediate by acid-catalyzed de-protection. Crystal forms were obtained from different solvent systems and characterized by powder X-ray diffraction (PXRD) and differential scanning calorimeter (DSC). Accelerated stability test and residual solvent analysis were also performed. Results The best yield was 89%, and crystal form A, B and C were obtained from different solvent systems. According to stability test, residual solvent and palladium residue analysis, three crystal forms were superior to amorphous one described in product patent. Conclusion A facile synthetic route for synthesis of TJ1508 is developed. Three stable crystal forms are obtained, and crystal form C is the most stable polymorph.