CN107805271B - 一种制备美她司酮的方法 - Google Patents
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Abstract
本发明提供了一种新的合成美她司酮的简便方法,其以米非司酮为起始原料,酞菁亚铁为催化剂,醋酸和过氧叔丁醇作为反应试剂,在常温条件下经两步反应制得美她司酮。该制备方法操作简单,避免使用大量试剂碘,降低了生产成本。
Description
技术领域
本发明属于医药技术领域,涉及药物化合物的合成方法的改进,具体涉及一种美她司酮制备方法的改进。
背景技术
米非司酮是第一个被开发的抗孕激素,是糖皮质激素受体拮抗剂(GR),又是孕激素受体(PR)和雄激素受体(AR)的拮抗剂,可用作药物,已被临床广泛用于终止妊娠。尽管新药物不断被开发,但米非司酮到目前为止仍然是临床实践中应用最广泛的抗孕激素,已被研究作为一个潜在的乳腺癌、宫颈癌、子宫癌、卵巢癌、前列腺癌和脑膜瘤的治疗剂,并且被用于治疗内分泌失调。
早期的代谢研究表明,米非司酮在体内迅速转变为单去甲基衍生物美她司酮和一个非脱甲基丙炔醇代谢物RU42698,美她司酮进一步代谢转化的去甲基代谢物为安闽司酮(RU42844)。所有三个代谢物已被证明保留强大的抗促孕和抗糖皮质激素活性,从而都有助于米非司酮整体的生理作用。研究表明,早孕妇女口服不同剂量的米非司酮二十分钟后可测得母药,两个小时以后美她司酮的血药浓度(AUC)超过母药水平,表明美她司酮是米非司酮最主要的代谢产物,并且其溶解度和稳定性均高于米非司酮。最新研究表明,美她司酮因其相对的安全性和独特的药理作用可用于癌症转移化学预防(可能具有癌症转移化学预防的潜力)。因此合成美她司酮对于临床研究具有重大意义。
本课题组前期开发的合成美她司酮的方法(专利授权号:ZL201310510394.0),由于使用了过量碘作为试剂,不利于绿色环保合成。因此,在其基础上,本发明重新提供了一条有利于绿色合成美她司酮的新的制备工艺。
发明内容
针对现有技术存在的缺点,本发明提供了一种新的制备美她司酮的方法,其可降低生产成本,避免使用过量碘,有利于环境保护。
为实现上述目的,本发明采用如下技术方案:
一种制备美她司酮的方法,其是以米非司酮为起始原料,经两步法反应获得美她司酮;其包括以下步骤:
(1)将酞菁亚铁与米非司酮在乙腈溶液中溶解,然后依次滴加醋酸、70vol%过氧叔丁醇水溶液,再在常温下反应10-20分钟,得到棕黑色反应液;
(2)将所得反应液旋干,分别加入甲醇与10 vol %盐酸水溶液,再于室温下搅拌反应12小时;
(3)将步骤(2)得到的液体用饱和碳酸氢钠水溶液调节pH至8~9,然后加入有机溶剂萃取,并用水洗涤三次,合并的有机相用硫酸钠干燥后,再除去有机溶剂,得到棕黄色固体粗品;
(4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱对固体粗品进行硅胶柱层析分离,即得到美她司酮。
步骤(1)中酞菁亚铁与米非司酮的摩尔比例为0.01:1;所滴加醋酸、过氧叔丁醇与米非司酮的摩尔比为10:2-3:1。
步骤(2)中甲醇与10vol%盐酸水溶液的体积比为1:1。
步骤(3)中所述有机溶剂为乙酸乙酯;洗涤时,其与水的体积比为1:1。
步骤(4)梯度洗脱时,石油醚与乙酸乙酯的体积比依次为2:1、1:1。
本发明的显著优点在于:本发明以米非司酮为起始原料、酞菁亚铁为催化剂,醋酸和过氧叔丁醇作为反应试剂,在常温条件下经两步反应即可制得美她司酮,其操作简单,避免了大量试剂碘的使用,降低了生产成本,有利于实现绿色环保合成。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例1
1)在50 mL烧瓶中加入0.5 mg酞菁亚铁、22 mg米非司酮、1 mL乙腈,搅拌使其溶解,然后依次滴加29 μL醋酸、10 μL 70vol%过氧叔丁醇水溶液,然后置于常温下反应10分钟,得到棕黑色反应液;
2)步骤1)反应结束后将所得反应液旋干,加入1 mL甲醇与1 mL 10 vol %盐酸水溶液,室温下搅拌反应12小时;
3)步骤2)反应结束后加入2 mL饱和碳酸氢钠水溶液,将反应液pH调至8~9,然后加入20 mL乙酸乙酯萃取,并用水洗涤三次,每次20 mL,合并有机相,加入无水硫酸钠干燥后,经旋干除去乙酸乙酯,得到棕黄色固体粗品;
4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱(洗脱梯度依次为2:1、1:1)对固体粗品进行硅胶柱层析分离,收集石油醚-乙酸乙酯体积比为1:1时的洗脱产物,经旋干得到淡黄色固体11 mg,其收率为50%。
实施例2
1)在50 mL烧瓶中加入0.5 mg酞菁亚铁、22 mg米非司酮、1 mL乙腈,搅拌使其溶解,然后依次滴加29 μL醋酸、15 μL 70vol%过氧叔丁醇水溶液,然后置于常温下反应10分钟,得到棕黑色反应液;
2)步骤1)反应结束后将所得反应液旋干,加入1 mL甲醇与1 mL 10 vol %盐酸水溶液,室温下搅拌反应12小时;
3)步骤2)反应结束后加入2 mL饱和碳酸氢钠水溶液,将反应液pH调至8~9,然后加入20 mL乙酸乙酯萃取,并用水洗涤三次,每次20 mL,合并有机相,加入无水硫酸钠干燥后,经旋干除去乙酸乙酯,得到棕黄色固体粗品;
4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱(洗脱梯度依次为2:1、1:1)对固体粗品进行硅胶柱层析分离,收集石油醚-乙酸乙酯体积比为1:1时的洗脱产物,经旋干得到淡黄色固体9 mg,其收率为41%。
实施例3
1)在50 mL烧瓶中加入0.9 mg酞菁亚铁、43 mg米非司酮、1 mL乙腈,搅拌使其溶解,然后依次滴加57 μL醋酸、20 μL 70vol%过氧叔丁醇水溶液,然后置于常温下反应10分钟,得到棕黑色反应液;
2)步骤1)反应结束后将所得反应液旋干,加入1 mL甲醇与1 mL 10 vol %盐酸水溶液,室温下搅拌反应12小时;
3)步骤2)反应结束后加入2 mL饱和碳酸氢钠水溶液,将反应液pH调至8~9,然后加入20 mL乙酸乙酯萃取,并用水洗涤三次,每次20 mL,合并有机相,加入无水硫酸钠干燥后,经旋干除去乙酸乙酯,得到棕黄色固体粗品;
4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱(洗脱梯度依次为2:1、1:1)对固体粗品进行硅胶柱层析分离,收集石油醚-乙酸乙酯体积比为1:1时的洗脱产物,经旋干得到淡黄色固体19 mg,其收率为43%。
实施例4
1)在100 mL烧瓶中加入11 mg酞菁亚铁、1 g米非司酮、3 mL乙腈,搅拌使其溶解,然后依次滴加1 mL醋酸、0.4 mL 70vol%过氧叔丁醇水溶液,然后置于常温下反应15分钟,得到棕黑色反应液;
2)步骤1)反应结束后将所得反应液旋干,加入3 mL甲醇与3 mL 10 vol %盐酸水溶液,室温下搅拌反应12小时;
3)步骤2)反应结束后加入5 mL饱和碳酸氢钠水溶液,将反应液pH调至8~9,然后加入20 mL乙酸乙酯萃取,并用水洗涤三次,每次20 mL,合并有机相,加入无水硫酸钠干燥后,经旋干除去乙酸乙酯,得到棕黄色固体粗品;
4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱(洗脱梯度依次为2:1、1:1)对固体粗品进行硅胶柱层析分离,收集石油醚-乙酸乙酯体积比为1:1时的洗脱产物,经旋干得到淡黄色固体450 mg,其收率为45%。
实施例5
1)在100 mL烧瓶中加入55 mg酞菁亚铁、5 g米非司酮、8 mL乙腈,搅拌使其溶解,然后依次滴加5 mL醋酸、2 mL 70vol%过氧叔丁醇水溶液,然后置于常温下反应20分钟,得到棕黑色反应液;
2)步骤1)反应结束后将所得反应液旋干,加入5 mL甲醇与5 mL 10 vol %盐酸水溶液,室温下搅拌反应12小时;
3)步骤2)反应结束后加入10 mL饱和碳酸氢钠水溶液,将反应液pH调至8~9,然后加入30 mL乙酸乙酯萃取,并用水洗涤三次,每次30 mL,合并有机相,加入无水硫酸钠干燥后,经旋干除去乙酸乙酯,得到棕黄色固体粗品;
4)以石油醚-乙酸乙酯的混合溶液为洗脱体系,采用梯度洗脱(洗脱梯度依次为2:1、1:1)对固体粗品进行硅胶柱层析分离,收集石油醚-乙酸乙酯体积比为1:1时的洗脱产物,经旋干得到淡黄色固体2.1 g,其收率为42%。
将实施例1-5中所得淡黄色固体进行氢谱1H-NMR、碳谱13C-NMR及高效液相色谱HPLC测定,确定为美她司酮,其含量均大于99%。相关测定数据如下:
1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.3 Hz, 2H), 6.52 (d, J = 8.6Hz, 2H), 5.7 (s, 1H), 4.32 (d, J = 6.8 Hz, 1H), 2.79 (s, 3H), 2.78-2.72 (m,1H), 2.62-2.51 (m, 2H), 2.49-2.38 (m, 2H), 2.37-2.27 (m, 3H), 2.26-2.16 (m,2H), 2.06-1.92 (m, 2H), 1.87 (s, 3H), 1.78-1.64 (m, 2H), 1.52-1.38 (m, 1H),1.39-1.28 (m, 1H), 0.54 (s, 3H)。
13C NMR (101 MHz, CDCl3) δ 199.63, 156.98, 147.15, 146.86, 132.90,129.06, 127.63, 122.67, 112.60, 82.46, 82.35, 80.14, 49.84, 46.88, 39.70,39.17, 38.94, 38.88, 36.88, 31.13, 30.84, 27.38, 25.82, 23.34, 13.70, 3.89。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (3)
1.一种制备美她司酮的方法,其特征在于,包括以下步骤:
(1)将酞菁亚铁与米非司酮在乙腈溶液中溶解,然后依次滴加醋酸、70vol%过氧叔丁醇水溶液,再在常温下反应10-20分钟,得到棕黑色反应液;
(2)将所得反应液旋干,分别加入甲醇与10 vol %盐酸水溶液,再于室温下搅拌反应12小时;
(3)将步骤(2)得到的液体用饱和碳酸氢钠水溶液调节pH至8~9,然后加入有机溶剂萃取,并用水洗涤三次,合并的有机相用硫酸钠干燥后,再除去有机溶剂,得到棕黄色固体粗品;
(4)将固体粗品经硅胶柱层析分离,即得到美她司酮;
步骤(1)中酞菁亚铁与米非司酮的摩尔比例为0.01:1;所滴加醋酸、过氧叔丁醇与米非司酮的摩尔比为10:2-3:1;
步骤(2)中甲醇与10vol%盐酸水溶液的体积比为1:1;
步骤(4)中硅胶柱层析分离采用梯度洗脱,其洗脱体系为石油醚-乙酸乙酯的混合溶液;梯度洗脱时石油醚与乙酸乙酯的体积比依次为2:1、1:1。
2.如权利要求1所述制备美她司酮的方法,其特征在于,步骤(3)中所述有机溶剂为乙酸乙酯。
3.如权利要求1所述制备美她司酮的方法,其特征在于,步骤(3)中洗涤时,有机溶剂与水的体积比为1:1。
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