【摘要】：研究背景:唑來(lái)膦酸為第三代二膦酸鹽類(lèi)藥物,唑來(lái)膦酸可以用于惡性腫瘤引起的骨轉(zhuǎn)移、高鈣血癥、骨質(zhì)疏松癥等的治療,其治療具有給藥劑量小,給藥方便,依從性好等優(yōu)點(diǎn)�；趯�(shí)驗(yàn)室的前期工作,以咪唑?yàn)樵?生成咪唑-1-乙酸中間體,之后進(jìn)行兩步磷酸化后,生成唑來(lái)膦酸。前期中試工藝中,對(duì)咪唑乙酸(中間體)中試工藝放大到870.40g(咪唑的投藥量),對(duì)唑來(lái)膦酸的工藝放大到1kg(咪唑乙酸的投藥量),結(jié)果比較穩(wěn)定,而且純度較好。根據(jù)本實(shí)驗(yàn)的前期工作,本文對(duì)唑來(lái)膦酸的中試工藝做了進(jìn)一步研究:(1)對(duì)中間體咪唑乙酸,我們制定了咪唑投料量為2kg、5kg、8kg、10kg時(shí)的中試工藝,收率較高,純度較好。(2)對(duì)目標(biāo)產(chǎn)物唑來(lái)膦酸一水合物,我們制定了中間體咪唑乙酸投料量在2kg、5kg、8kg時(shí)的中試工藝,并對(duì)其重要參數(shù)進(jìn)行了系統(tǒng)優(yōu)化,獲得了較好的收率及純度。并參考文獻(xiàn)及我們的合成經(jīng)驗(yàn),制備了重要雜質(zhì)A和B,并鑒定了其結(jié)構(gòu),為下一步的質(zhì)量研究提供了條件。在實(shí)驗(yàn)室前期工作的基礎(chǔ)上,我們利用高效液相色譜法對(duì)唑來(lái)膦酸含量測(cè)定方法學(xué)進(jìn)行了系統(tǒng)研究,制定了其含量測(cè)定條件:苯基柱4.6*250mm 5μm(漢邦);流動(dòng)相:取2m L三乙胺加到800m L去離子水中,加磷酸調(diào)p H為3.0,加水定容至1L,取950m L加50m L甲醇為流動(dòng)相。檢測(cè)波長(zhǎng):220nm,流速:0.7m L/min,柱溫:40℃,進(jìn)樣濃度:0.1mg/m L,進(jìn)樣量:10μL。并對(duì)自制的唑來(lái)膦酸三批樣品進(jìn)行測(cè)定,含量為:99.91%、100.2%、99.78%。該結(jié)果表明,本工藝制備的唑來(lái)膦酸中試樣品含量穩(wěn)定,結(jié)果較好。此外我們尚對(duì)中間體咪唑乙酸中起始原料咪唑及雜質(zhì)B的殘留以及終產(chǎn)品唑來(lái)膦酸中起始原料咪唑及中間體咪唑乙酸的殘留進(jìn)行了初步探討。上述結(jié)果表明:(1)經(jīng)本工藝制備的中間體咪唑乙酸中未發(fā)現(xiàn)咪唑及雜質(zhì)B的殘留;(2)經(jīng)本工藝制備的終產(chǎn)物唑來(lái)膦酸中也未發(fā)現(xiàn)起始原料咪唑及中間體咪唑乙酸的殘留。該部分工作為唑來(lái)膦酸原料藥及其中間體咪唑乙酸最終質(zhì)量標(biāo)準(zhǔn)的確定奠定基礎(chǔ)。
[Abstract]:Background: zoledronic acid is a third-generation diphosphonic acid drug. Zoledronic acid can be used in the treatment of bone metastasis, hypercalcemia, osteoporosis and so on. Good compliance and other advantages. Based on the laboratory work, imidazole-1-acetic acid intermediate was synthesized from imidazole, and then phosphorylated to zoledronic acid. In the earlier pilot-scale process, imidazole acetic acid (intermediate) was amplified to 870.40 g (dosage of imidazole), and zoledronic acid was amplified to 1kg (dosage of imidazolyl acetic acid). The results were stable and the purity was good. According to the previous work of this experiment, the pilot-scale process of zoledronic acid was studied in this paper. (1) for imidazolyl acetic acid, the pilot-scale process of imidazole was developed when the dosage of imidazole was 2 kg / L, 5 kg / kg ~ (8 kg) ~ (10 kg), and the yield was high. (2) for the target product, Zoledronic acid monohydrate, a pilot-scale process of imidazolium acetic acid at the dosage of 2 kg ~ 5kg ~ (-1) was established, and its important parameters were systematically optimized, and a good yield and purity were obtained. With reference to literature and our synthetic experience, important impurities A and B were prepared, and their structures were identified, which provided conditions for further quality study. On the basis of the previous work in laboratory, we systematically studied the method of determination of zoledronic acid by high performance liquid chromatography (HPLC). The determination conditions of zoledronic acid content were determined as follows: phenyl column 4.6*250mm 5 渭 m (Hanbang); Mobile phase: 2m L triethylamine was added to 800 mL deionized water, pH was adjusted by phosphoric acid 3.0, water volume was fixed to 1L, and 950ml + 50ml methanol was used as mobile phase. The detection wavelength was 220 nm, the flow rate was 0.7 mL / min, the column temperature was 40 鈩，

本文編號(hào)：2363885