CN106432198B - 一种制备伏立康唑拆分中间体的方法 - Google Patents
一种制备伏立康唑拆分中间体的方法 Download PDFInfo
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Abstract
本发明提供了一种新的伏立康唑左旋樟脑磺酸盐的制备方法,该方法包括将伏立康唑外消旋体和左旋樟脑磺酸溶解在水和丙酮组成混合溶剂中,降温析晶,过滤烘干得到伏立康唑左旋樟脑磺酸盐。本发明通过调整拆分溶剂,有效降低了生产成本。
Description
技术领域
本发明涉及一种制备伏立康唑中间体的方法。
背景技术
伏立康唑(voriconazole,VRC,UK109496)是美国辉瑞公司在氟康唑基础上合成的一种新型抗真菌药,主要用于进行性、有致命危险的免疫损害患者。由于伏立康唑抗真菌谱广、抗菌效力强,安全性好,且国内市场对抗真菌药物的需求增长迅速,因此市场前景巨大。
伏立康唑,其化学名为:(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇,结构式如式Ⅰ所示:
伏立康唑外消旋体作为一种重要的中间体,化学名为:(2R,3S/2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇,结构式如式Ⅱ所示:
从伏立康唑的结构可以看出其有两个手性中心,可能存在四种异构体,对于异构体的分离一般有两种方法,第一种是在反应过程中手性诱导,这种方法一般需要采用手性催化剂,成本比较高,不利于大规模的工业生产,第二种是采用手性拆分剂进行拆分,手性拆分剂的回收比较简便,一般可以反复使用,这种方法在工业生产中经常采用。
在经过一系列的预处理后,我们可以得到伏立康唑的外消旋体,即(2R,3S)构型和(2S,3R)构型的混合物。伏立康唑的外消旋体需要一步拆分得到伏立康唑,即(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)-2-丁醇。
专利EP2444398A2中公开了伏立康唑外消旋体的拆分方法,使用的拆分剂是左旋樟脑磺酸,拆分溶剂是甲醇和丙酮的混合溶剂,合成路线如下:
上述拆分溶剂存在以下两个问题:
1.甲醇和丙酮这两种溶剂沸点比较接近,且挥发性都比较强,很难进行分离,因此,拆分物的溶剂回收是一个很大的问题,增加了生产成本,同时也不符合环保生产的要求。
2.在拆分过程中,拆分溶剂的使用量非常大,产能较低,严重影响的了拆分物的大规模生产。
为了解决这两个问题,我们对伏立康唑的拆分方法进行了改进,开发了一种新型的拆分方法。
发明内容
本发明提供了一种伏立康唑左旋樟脑磺酸盐的制备方法,包括如下步骤:将伏立康唑外消旋体和左旋樟脑磺酸溶解在水和丙酮组成混合溶剂中,降温析晶,过滤烘干得到伏立康唑左旋樟脑磺酸盐。
上述制备方法中,其中丙酮和水的体积比为100:1-1:100,优选为15:1-5:1。所述混合溶剂的使用量相对于伏立康唑外消旋体为10-30mL/g,优选为10-15mL/g。析晶温度为0-40℃,优选为15-30℃。
本发明得到的伏立康唑左旋樟脑磺酸盐可以根据现有技术的方法,加碱游离即得到伏立康唑。
本发明有意义的技术效果是通过调整拆分溶剂,降低生产成本,提高产能,极具工业生产价值。
具体实施方式
实施例1:
伏立康唑外消旋体(9g),左旋樟脑磺酸(6g),丙酮(150mL),水(30mL),升温至50℃,溶液澄清,自然降温至0℃,在0℃搅拌2小时,过滤,HPLC检测,ee%=99.3%,产率30.1%。
实施例2:
伏立康唑外消旋体(9g),左旋樟脑磺酸(6g),丙酮(150mL),水(15mL),升温至50℃,溶液澄清,自然降温至25℃,在25℃搅拌2小时,过滤,HPLC检测,ee%=99.7%,产率36.6%。
实施例3:
伏立康唑外消旋体(15g),左旋樟脑磺酸(10g),丙酮(150mL),水(15mL),升温至50℃,溶液澄清,自然降温至20℃,在20℃搅拌2小时,过滤,HPLC检测,ee%=99.7%,产率40.4%。
实施例4:
伏立康唑外消旋体(15g),左旋樟脑磺酸(10g),丙酮(150mL),水(10mL),升温至50℃,溶液澄清,自然降温至25℃,在25℃搅拌2小时,过滤,HPLC检测,ee%=99.8%,产率37.5%。
对比实施例:
伏立康唑外消旋体(15.1g)溶于丙酮(288mL)中,加入左旋樟脑磺酸(8.51g)的甲醇(96mL)溶液,升温至50℃,溶液澄清,缓慢降温至20℃,并在20℃搅拌18小时,过滤,HPLC检测,ee%=99.8%,产率35%。
Claims (2)
1.一种伏立康唑左旋樟脑磺酸盐的制备方法,包括如下步骤:将伏立康唑外消旋体和左旋樟脑磺酸溶解在水和丙酮组成混合溶剂中,降温析晶,过滤烘干得到伏立康唑左旋樟脑磺酸盐,其中丙酮和水的体积比为15:1-10:1,所述混合溶剂的使用量相对于伏立康唑外消旋体为10-15mL/g,析晶温度为15-30℃。
2.一种伏立康唑的合成方法,包括以下步骤:
a)将伏立康唑外消旋体和左旋樟脑磺酸溶解在水和丙酮组成混合溶剂中,降温析晶,过滤烘干得到伏立康唑左旋樟脑磺酸盐,其中丙酮和水的体积比为15:1-10:1,所述混合溶剂的使用量相对于伏立康唑外消旋体为10-15mL/g,析晶温度为15-30℃,
b)将步骤a)所述的方法制备得到的伏立康唑左旋樟脑磺酸盐,加碱游离得到伏立康唑。
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CN201610811521.4A CN106432198B (zh) | 2016-09-08 | 2016-09-08 | 一种制备伏立康唑拆分中间体的方法 |
EP16915563.7A EP3511326B1 (en) | 2016-09-08 | 2016-11-10 | Method for preparing voriconazole l-camphorsulphonate and voriconazole |
ES16915563T ES2911289T3 (es) | 2016-09-08 | 2016-11-10 | Procedimiento para preparar L canforsulfonato de voriconazol y voriconazol |
PCT/CN2016/105312 WO2018045629A1 (zh) | 2016-09-08 | 2016-11-10 | 一种制备伏立康唑左旋樟脑磺酸盐以及伏立康唑的方法 |
US16/330,692 US11919884B2 (en) | 2016-09-08 | 2016-11-10 | Method for preparing voriconazole L-camphorsulphonate and voriconazole |
EP22154723.5A EP4019509A1 (en) | 2016-09-08 | 2016-11-10 | Method for preparing voriconazole l-camphorsulphonate |
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CN113354625B (zh) * | 2021-06-16 | 2023-09-26 | 安徽普利药业有限公司 | 伏立康唑的合成工艺 |
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- 2016-11-10 US US16/330,692 patent/US11919884B2/en active Active
- 2016-11-10 ES ES16915563T patent/ES2911289T3/es active Active
- 2016-11-10 EP EP16915563.7A patent/EP3511326B1/en active Active
- 2016-11-10 WO PCT/CN2016/105312 patent/WO2018045629A1/zh unknown
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EP3511326A4 (en) | 2019-08-07 |
ES2911289T3 (es) | 2022-05-18 |
EP3511326B1 (en) | 2022-03-09 |
EP3511326A1 (en) | 2019-07-17 |
US11919884B2 (en) | 2024-03-05 |
US20210276980A1 (en) | 2021-09-09 |
CN106432198A (zh) | 2017-02-22 |
WO2018045629A1 (zh) | 2018-03-15 |
EP4019509A1 (en) | 2022-06-29 |
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