CN115160395A - 一种由植物甾醇降解物合成地屈孕酮的方法 - Google Patents
一种由植物甾醇降解物合成地屈孕酮的方法 Download PDFInfo
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- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明提供了一种新的地屈孕酮合成方法,以一种植物甾醇降解物为起始物料,经过分子内酯化反应,wittig构建侧链烯烃反应,格式试剂开环反应,硼氢化反应,氢化反应,Robinson增环反应,氧化反应和脱氢反应得到地屈孕酮。本发明的方法原料易得,收率高,反应条件简单温和,适合用于地屈孕酮的工业化生产。
Description
技术领域
本发明属于医药合成领域,特别涉及一种地屈孕酮的新合成方法。
背景技术
地屈孕酮是一种人工合成的孕激素,可用于治疗内源性孕酮不足引起的疾病,如痛经,子宫内膜异位症,继发性闭经,月经周期不规则,功能失调性子宫出血,经前期综合征,孕激素缺乏所致先兆性流产或习惯性流产,黄体不足所致不孕症,地屈孕酮无雌激素、雄激素及肾上腺皮质激素作用。地屈孕酮不产热,且对脂代谢无影响。是目前比较理想的孕激素药物。
在众多文献和专利中分为几个方面。一个方案主要是从利用光化学开环再关环对19位角甲基构型异构化的核心步骤,举例如下:
文献Recueil des Travaux Chimiques des Pays-Bas(1961),80:43-46报道了以3-羟基-孕甾 -5,7-二烯-20-酮为原料,在四氢呋喃中用高压汞灯进行甾体B开关环反应完成19位角甲基由构型异构化翻转,产物经沃氏氧化和重排得到地屈孕酮。在光照这一步,使用了大量的四氢呋喃,有大量的原料剩余,整个光照的收率仅为10.6%,严重制约了后续反应的原料来源以及整个生产过程的效率。
文献Recueil des Travaux Chimiques des Pays-Bas(1971),90:27-32报道了以黄体酮为原料通过乙二醇对双酮的保护,溴化,脱溴,高压汞灯光照再重排得到地屈孕酮的路线。这条路线中乙二醇的保护收率比较低(32%-67%The Journal of OrganicChemistry,1952,vol.17,p. 1369,1373),溴化和脱溴也存在很多的异构导致两步收率比较低(49%),在关键的光照步骤收率也仅仅为22%,这个也为工业化造成很大困难。
2014年公开的中国专利(CN 102558272 B)报道中科院理化所基于上述双缩酮的内浸上行鼓泡式双滤光系统路线,光照原料总转化率为35.4~44.6%,光化学总收率为35.8~41.6%。
2014年的公开中国专利CN103848880 A也是中科院理化所对这一路线进行了反应装置上的优化。他们使用了双波长微流技术,最高的光化学总收率为46.3%
2008公开的专利CN101318982A台州万福制药有限公司以3-乙酰氧基-孕甾-5,7-二烯 -20-酮的光化学反应,光化学收率比较低(30~35%),究其原因可能是由于分子中的羰基会发生NorrishⅠ型和/或NorrishⅡ型等反应(《现代分子光化学》吴骊珠佟振合等译),使得光照的产物杂质增加,目标产物收率偏低。
2019公开的专利CN 110198949 A意大利工业化学有限公司报道了一种全合成的方法制备地屈孕酮的方案,但是该方案中的起始原料需要多步合成,整体路线效率比较低。
基于以上调研的结果我们希望开发一条效率跟高原料来源更容易的路线来实现地屈孕酮的工业生产。
发明内容
本发明提供一种地屈孕酮的新合成方法,可以高效合成地屈孕酮,有力解决了上述路线中的不足。
本发明提供了一种新的地屈孕酮合成方法,以一种植物甾醇降解物为起始物料,经过分子内酯化反应,wittig构建侧链烯烃反应,格式试剂开环反应,硼氢化反应,氢化反应、Robinson增环反应,氧化反应和脱氢反应得到地屈孕酮。本发明的方法原料易得,收率高,反应条件简单温和,适合用于地屈孕酮的工业化生产。
本发明的地屈孕酮合成路线如下:
步骤a中,DG-8在醋酸酐醋酸钠酸催化下进行羰基保护得到缩酮DG-7。
步骤b中,DG-8经wittig反应得到DG-6,所述wittig试剂为三苯基膦叶立德或者磷酯叶立德。
步骤c中,DG-6经格式试剂对内酯加成开环反应得到DG-5。所述格式试剂为乙基溴化镁或者乙基氯化镁。
步骤d中,DG-5经硼氢化,缩合得到烯酮DG-4,所述硼试剂为硼烷或者9-BBN或者二环己基硼烷。
步骤e中,DG-4经氢化反应得到DG-3,所述催化剂为Raney-Ni或者钯/碳催化剂。
步骤f中,DG-3经Robinson增环反应得到DG-2,所用到的受体为甲基乙烯基酮。
步骤h中,DG-1经脱氢反应得到产品地屈孕酮DG,所述脱氢试剂为二氯二氰苯醌(DDQ) 或者四氯苯醌。
综上,本发明以一种植物甾醇降解物为起始物料,经过分子内酯化反应,wittig构建侧链烯烃反应,格式试剂开环反应,硼氢化反应,氢化反应、Robinson增环反应,氧化反应和脱氢反应得到地屈孕酮。本发明的方法原料易得,收率高,反应条件简单温和,适合用于地屈孕酮的工业化生产。
作为整个路线的核心和关键步骤,起始原料的易得决定了整条生产工艺的效率,采用本发明的方法,大大提高了整条路线转化率及选择性,且产品纯度高,整体是一条非常高效简洁的路线,非常适合工业化生产。
具体实施方式
为了使本领域技术人员可以更好地理解本发明,以下通过具体实施例对本发明技术方案进行进一步说明。需要理解的是,下属实施例只为更好地说明本发明而给出,并不是对本发明内容的限制。
化合物DG-7的合成
实施例1:
反应瓶中加入500g DG-8、258g醋酸钠和2000ml醋酸酐,回流搅拌反应6小时完毕,减压浓缩除去多余的醋酸酐,将至室温,体系用乙酸乙酯稀释,有机相水洗,饱和碳酸氢钠水溶液洗,盐水洗,无水硫酸钠干燥,过滤,滤液浓缩得到444.6g DG-7,收率96.2%。
化合物DG-6的合成
实施例2:
反应瓶中加入340g DG-7、甲苯(1000mL)搅拌溶解,80℃搅拌条件下滴加乙烯叶立德 (538g)的甲苯溶液(500mL),滴加完80℃继续反应2完毕,减压浓缩除去甲苯,加入甲叔醚(500mL),过滤,滤液浓缩,粗产物用甲叔醚重结晶得到331.7g DG-6,收率92.5%。
化合物DG-5的合成
实施例3:
反应瓶中加入310g DG-6、四氢呋喃(800mL)搅拌溶解,0℃搅拌条件下滴加乙基溴化镁四氢呋喃溶液(1.3L,1M in THF),滴加完毕,在0℃继续反应4小时完毕,反应用饱和氯化铵水溶液淬灭,加入乙酸乙酯稀释,有机相用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得到粗产物,经丙酮重结晶得到311.6g DG-5,收率89%。
化合物DG-4的合成
实施例4:
反应瓶中加入200g DG-5、四氢呋喃(800mL)搅拌溶解,25℃搅拌条件下滴加硼烷的四氢呋喃溶液(992mL,1M in THF),滴加完在继续反应2小时完毕,反应中加入117 mL的30%过氧化氢水溶液和190 mL NaOH水溶液(5M in H2O)反应先25℃搅拌2小时,再升高温度到80℃继续反应6小时后结束,反应冷却至室温,加入乙酸乙酯稀释,有机相用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得到粗产物,经85%乙醇水溶液重结晶得到163.2gDG-4,收率81.6%。
化合物DG-3的合成
实施例5:
反应瓶中加入150g DG-4、甲醇(500mL)搅拌溶解,加入10g Raney-Ni在25℃常压氢化反应5小时,过滤,滤液浓缩得到粗产物,经丙酮:水溶液=4:1混合溶剂重结晶得到144.5g DG-3,收率95.6%。
化合物DG-2的合成
实施例6:
反应瓶中加入120g DG-4、甲醇(500mL)搅拌溶解,加入109mL KOH水溶液(5M inH2O),反应加热到65℃,滴加64g甲基乙烯基酮,加毕,在此温度下继续反应8小时,冷至室温,将反应体系倒入100g醋酸和200g冰混合物中,大量固体析出,过滤,滤饼用水洗,烘干,粗产品乙醇重结晶得到112.0g DG-2,收率78%。
化合物DG-1的合成
实施例7:
反应瓶中加入108g DG-2,THF(200mL)搅拌溶解,加入174g戴斯-马丁试剂,在25℃下反应16小时,反应体系加入饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取,有机相用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液浓缩得粗产物,丙酮重结晶得到99.4g DG-1,收率92.6%。地屈孕酮的合成
实施例8:
向反应瓶中加入40g DG-1、35g四氯苯醌,醋酸20mL甲苯200mL溶液,反应回流1 小时,冷却,过滤,滤液乙酸乙酯稀释。有机相水洗,饱和碳酸氢钠,饱和食盐水洗,无水硫酸钠干燥,浓缩,粗品用丙酮和正己烷重结晶得到地屈孕酮33.9g,收率85.3%。
ESI-HRMS理论值:C21H28O2[M+H]+313.2089,实测值313.2092。
1H-NMR(δ,ppm,CDCl3):6.20-6.14(m,2H);5.68(s,1H);2.60-2.52(m,2H);2.60-2.52(m, 2H);2.48-2.40(m,2H);2.31-2.17(m,2H);2.13(s,3H);2.03-1.95(m,2H);1.88-1.80(m,2H); 1.79-1.62(m,3H);1.40-1.18(m,6H);0.71(s,3H)。
Claims (8)
2.根据权利1要求所述的制备方法,其特征在于:步骤a中,DG-8在醋酸酐-醋酸钠酸催化下进行羰基保护得到缩酮DG-7
3.根据权利1要求所述的制备方法,其特征在于:步骤b中,DG-8经wittig反应得到DG-6,所述wittig试剂为三苯基膦叶立德或者磷酯叶立德。
4.根据权利1要求所述的制备方法,其特征在于:步骤c中,DG-6经格式试剂对内酯加成开环反应得到DG-5。所述格式试剂为乙基溴化镁或者乙基氯化镁。
5.根据权利1要求所述的制备方法,其特征在于:步骤d中,DG-5经硼氢化,缩合得到烯酮DG-4,所述硼试剂为硼烷或者9-BBN或者二环己基硼烷。
6.根据权利1要求所述的制备方法,其特征在于:步骤e中,DG-4经氢化反应得到DG-3,所述催化剂为Raney-Ni或者钯/碳催化剂
7.根据权利1要求所述的制备方法,其特征在于:步骤f中,DG-3经Robinson增环反应得到DG-2,所用到的受体为甲基乙烯基酮。
8.根据权利1要求所述的制备方法,其特征在于:步骤h中,DG-1经脱氢反应得到产品地屈孕酮DG,所述脱氢试剂为二氯二氰苯醌(DDQ)或者四氯苯醌。
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