【摘要】：孕激素屈螺酮(Drospirenone,6β,7β:15β,16β-二亞甲基-3-氧代-17α-孕甾-4-烯-21,17-羧內(nèi)酯)是一種高效、低毒、無副作用的新一代甾體類避孕藥,是目前唯一一種與天然孕酮藥理特性相近的孕激素,為甾體類17α-螺內(nèi)酯的衍生物。本文針對屈螺酮的合成工藝路線,純化過程,檢測系統(tǒng)等方面進(jìn)行了探究。首先在原有的工藝路線基礎(chǔ)上設(shè)計(jì)出新的合成路線;然后進(jìn)行屈螺酮的合成實(shí)驗(yàn)研究;最后設(shè)計(jì)簡便的層析檢測系統(tǒng),對產(chǎn)品進(jìn)行檢測和表征。(1)工藝路線研究中,確定了鉻酸酐氧化工藝路線的可行性。針對鉻酸酐氧化工藝路線進(jìn)行了優(yōu)化,重新設(shè)計(jì)了屈螺酮的合成工藝路線,使得所設(shè)計(jì)的合成路線,安全、環(huán)保且經(jīng)濟(jì)性良好。(2)合成屈螺酮的研究實(shí)驗(yàn),在環(huán)氧物的合成過程中,確定了反應(yīng)時(shí)間為3h,新鮮的叔丁醇鉀的反應(yīng)效果最為優(yōu)異。在酯化物的合成過程中,確定了反應(yīng)溫度設(shè)定在80℃,反應(yīng)時(shí)間為5h后,乙醇鈉的效果優(yōu)于乙醇鉀的效果。在消除物的合成過程中,確定了反應(yīng)時(shí)間為24h的,溫度為120℃時(shí),最適宜的pH值范圍8～8.5。在屈螺酮(粗品)的合成過程中,確定了第一步反應(yīng)時(shí)間為6h;第二步反應(yīng)時(shí)間為2h。(3)屈螺酮粗品純化實(shí)驗(yàn),設(shè)計(jì)層析在線監(jiān)控一體機(jī),可以快速簡便地對層析純化過程進(jìn)行實(shí)時(shí)監(jiān)控。選擇硅膠作為本實(shí)驗(yàn)的吸附劑;確定了環(huán)己烷與EA的混合溶液作為洗脫劑,并確定環(huán)己烷與EA的比值為1時(shí),分離效果最好。對屈螺酮粗品中含有的雜質(zhì)進(jìn)行了分析,確定了雜質(zhì)的種類以及產(chǎn)生的原因。對得到的產(chǎn)品進(jìn)行全分析,分析結(jié)果表明屈螺酮產(chǎn)品符合USP36質(zhì)量要求標(biāo)準(zhǔn)。通過IR分析以及元素分析表明屈螺酮中各元素含量與理論值吻合,說明產(chǎn)品在層析過程中未發(fā)生變質(zhì)。(4)純化工藝比較,通過對比吡啶-鹽酸成鹽法純化工藝、亞硫酸鈉-水溶液還原法純化工藝與研究的新工藝---硅膠層析純化法工藝三種工藝所得產(chǎn)品的外觀、收率以及總純度、單雜等多方面進(jìn)行比較,結(jié)果表明硅膠層析純化法所得的產(chǎn)品外觀最好、純化收率達(dá)到90.76%及總純度達(dá)到99.84%和最大單雜為0.08%,說明本文設(shè)計(jì)的純化工藝與其它工藝相比具有極大的優(yōu)勢。對層析過程進(jìn)行數(shù)學(xué)模擬,通過GR模型擬合層析結(jié)果,并分析各參數(shù)對層析結(jié)果的影響,可為工業(yè)放大提供依據(jù)。通過對屈螺酮合成工藝以及純化工藝的研究,所得的結(jié)果為工業(yè)化生產(chǎn)提供數(shù)據(jù)與理論基礎(chǔ),且在本公司進(jìn)行大批量投產(chǎn)使用,提高了企業(yè)的生產(chǎn)效率,降低了企業(yè)的生產(chǎn)成本。
[Abstract]:The progesterone (Drospirenone,6 尾, 7 尾: 15 尾, 16 尾 -dimethylene-3-oxo-17 偽 -pregna-4ene-21- 1-1-carboxylactone) is a new generation of steroid contraceptive with low toxicity and no side effects. Progesterone is the only progesterone similar to the pharmacological properties of natural progesterone and is a derivative of steroid 17 偽-spironolactone. In this paper, the synthesis process, purification process and detection system of draconone were studied. Firstly, a new synthetic route was designed based on the original technological route, and then the experimental study on the synthesis of dracurone was carried out. Finally, a simple chromatographic detection system was designed to detect and characterize the product. (1) the feasibility of chromic anhydride oxidation process was determined in the study of the process route. In this paper, the oxidation process of chromic anhydride is optimized, and the synthetic route of duspirone is redesigned to make the synthesized route safe, environmentally friendly and economical. (2) the experimental study on the synthesis of duspirone is carried out. In the process of synthesis of epoxide, the reaction time was determined to be 3 h, and the reaction effect of fresh potassium tert-butanol was the best. In the process of esterification, the effect of sodium alcohol was better than that of potassium alcohol when the reaction temperature was set at 80 鈩，

本文編號：2423999