CN116462643A - 一种氘或氚标记的多西他赛的合成方法 - Google Patents
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Abstract
本发明公开了一种氘或氚标记的多西他赛的制备方法,包括以下步骤:(1)在有机碱的作用下,氘或氚代叔丁醇和对硝基苯基氯甲酸酯进行酯化反应,得到氘或氚代(4‑硝基苯基)碳酸叔丁酯;(2)步骤(1)得到的氘或氚代(4‑硝基苯基)碳酸叔丁酯与化合物IM‑1进行酰胺化反应,反应完成后经过后处理得到所述的多西他赛;该合成方法中间体合成方便,化学性质稳定,并且氘代试剂的利用率和产物收率高。
Description
技术领域
本发明属于氘代或氚代药物的制备领域,具体涉及一种氘或氚标记的多西他赛的合成方法。
背景技术
多西他赛为紫杉烷类抗癌药,通过促进微管双聚体装配成微管,同时通过防止去多聚化过程而使微管稳定,阻滞细胞于G2和M期,从而抑制癌细胞的有丝分裂和增殖。多西他赛的药理作用比紫杉醇强,在细胞内浓度比紫杉醇高3倍,并在细胞内滞留时间长,其对微管亲和力是紫杉醇的2倍;作为微管稳定剂和装配促进剂,活性比紫杉醇大2倍;作为微管解聚抑制剂,活性比紫杉醇大2倍。在体外抗瘤活性试验中,已证实多西他赛的抗瘤活性是紫杉醇的1.3~12倍。临床研究表明,对于蒽环类耐药乳腺癌,多西他赛较紫杉醇有更高的有效率。多西他赛是目前为止蒽环类耐药乳腺癌的二线治疗中最有效的药物;在非小细胞肺癌单药治疗和联合化疗中,多西他赛是最有效的药物之一。
多西他赛和其他传统的紫杉类治疗药物可能不会分布到体内所需的区域。在这方面,这些传统的分子可能会相对均匀地分布在患者的全身,从而对正常组织和癌变组织都发挥作用。然而,如果多西他赛和其他传统的紫杉基可以这样修饰,使其在肿瘤组织中积累,同时仍然保持其强大的抗癌作用,那将是可取的。为支持研究多西他赛的代谢情况,本发明将对多西他赛(如式1)中的叔丁基进行氘代标记
以往的研究参照合成二碳酸二叔丁酯的方法(如式2)以D10-叔丁醇为原料,以二氧化碳为另一反应物和溶剂,在二氧化碳超临界状态下反应生成产品氘代二碳酸二叔丁酯,最后合成D9-多西他赛。该方法操作复杂且不利于少量的实验室操作;还有参照该反应路线用光气或者三光气反应合成氘代二碳酸二叔丁酯,反应具有危险性,且在实验室操作中可靠性较差。而且用合成的氘代二碳酸二叔丁酯进行下一步反应,氘代试剂的利用率差(有一半氘代标记物无法参与反应)。
另外还有报导(如式3)用双(1-苯并[d]三咪唑)碳酸酯和D10-叔丁醇为原料,先合成D9-叔丁基苯并三唑基碳酸酯,然后再合成D9-多西他赛。该方法合成的D9-叔丁基苯并三唑基碳酸酯稳定性差,不利于分离提纯,而且对反应无法进行有效监控。
发明内容
本发明提供了一种氘或氚标记的多西他赛的合成方法,该合成方法中间体合成方便,化学性质稳定,并且氘或氚代试剂的利用率和产物收率高。
本发明的技术方案如下:
一种氘或氚标记多西他赛的制备方法,其特征在于,包括以下步骤:
(1)在有机碱的作用下,氘或氚代叔丁醇和对硝基苯基氯甲酸酯进行酯化反应,得到氘或氚代(4-硝基苯基)碳酸叔丁酯;
(2)步骤(1)得到的氘或氚代(4-硝基苯基)碳酸叔丁酯与化合物IM-1进行酰胺化反应,反应完成后经过后处理得到所述的氘或氚标记的多西他赛;
所述的氘或氚代-多西他赛为D9-多西他赛或T9-多西他赛;
合成D9-多西他赛的反应式如下:
本发明的方法能够较高收率的合成氘代中间体氘或氚代(4-硝基苯基)碳酸叔丁酯,该中间体合成方便且化学性质稳定,元素氘的利用率也比较高,以氘或氚代-(4-硝基苯基)碳酸叔丁酯能够高效地合成D9-多西他赛。
步骤(1)中,有机碱的种类、溶剂的种类和反应温度会对反应收率产生较大的影响。
步骤(1)中所述有机碱对反应的影响较大,作为优选,步骤(1)中,所述的有机碱为吡啶。
作为优选,步骤(1)中,所述的酯化反应在卤代烃类溶剂中进行,所述的卤代烃类溶剂为二氯甲烷或三氯甲烷。
作为优选,步骤(1)中,将所述的对硝基苯基氯甲酸酯溶解在所述的卤代烃类溶剂中,然后滴加到所述的氘或氚代叔丁醇和有机碱的混合物中进行反应。
作为优选,步骤(1)中,反应温度为-20~0℃,反应时间为10~30h。
作为优选,步骤(2)中,所述酰胺化反应在DMAP的作用下进行。
作为优选,步骤(2)中,所述酰胺化反应在醚类溶剂和水的混合溶剂中进行;
所述醚类溶剂为THF或者二氧六环。
作为优选,步骤(2)中,所述酰胺化反应的温度为10~30℃,反应时间为10~20小时。
作为优选,步骤(2)中,反应结束后后处理过程如下:
向反应液中依次加水和饱和氯化铵水溶液,然后用乙酸乙酯萃取,干燥,浓缩,柱层析得到所述的氘或氚代多西他赛。
同现有技术相比,本发明的有益效果体现在:
(1)采用本发明的合成方法,得到的中间体氘或氚代(4-硝基苯基)碳酸叔丁酯性质稳定,便于合成,操作时易于实施;
(2)采用本发明的合成方法,氘代试剂利用率高,得到的产物的收率和纯度更高。
具体实施方式
实施例1
D9-(4-硝基苯基)碳酸叔丁酯的合成:于25mL单口瓶中,D10-叔丁醇(1g,11.8mmol,1eq)与吡啶(1.148mL,14.2mmol,1.2eq)混合,氮气球保护,CaCl2冰盐浴下(-15℃)搅拌滴加对硝基苯基氯甲酸酯(2.394g,11.88mmol,1eq)的DCM(13mL)溶液,加完后常温水浴下搅拌反应22h。反应完毕,直接浓缩反应液(35℃以下),柱层析(Hex:EA=50:1~20:1)得白色固体D9-(4-硝基苯基)碳酸叔丁酯:2.238g,收率:75.8%。
D9-多西他赛的合成:向IM-1(5.739g,8.1mmol,0.9eq)中加入THF(75mL),搅拌下再加入H2O(12mL)、DMAP(2.2g,18mmol,2eq),最后加入D9-(4-硝基苯基)碳酸叔丁酯(2.238g,9.01mmol,1eq),常温下搅拌反应14h。反应完毕,搅拌下加水50mL,饱和氯化铵35mL,EA萃取(100mL*4),无水MgSO4干燥,浓缩(35℃以下),柱层析(Hex:EA=5:1~1:2),得白色固体D9-多西他赛:1.996g,收率:30.2%。纯度:99.45%,同位素丰度:98Atom%D
反应式如下:
对比例1
于25mL单口瓶中,D10-叔丁醇(1g,11.8mmol,1eq)与三乙胺(1.44g,14.2mmol,1.2eq)混合,氮气球保护,CaCl2冰盐浴下(-15℃)搅拌滴加对硝基苯基氯甲酸酯(2.394g,11.88mmol,1eq)的DCM(13mL)溶液,加完后常温水浴下搅拌反应22h,取样检测基本无D9-(4-硝基苯基)碳酸叔丁酯生成。
实施例2
D9-(4-硝基苯基)碳酸叔丁酯的合成:于25mL单口瓶中,D10-叔丁醇(1g,11.8mmol,1eq)置于25mL圆底瓶中,加入吡啶(4.8mL)作为溶剂。室温下加入对硝基苯基氯甲酸酯(2.394g,11.8mmol,1eq),在氮气条件下搅拌4小时。加入MTBE(5mL),过滤悬浮液以去除固体。用MTBE(5mL)洗涤固体。有机相用水(5ml)洗涤,水相再用MTBE(5mL)萃取。分别用1N盐酸(5mL*3)、NaHCO3(10%,5mL*2)、NaCO3(5mL)、NaHCO3(5mL*2)、水(5mL)和盐水(5mL)洗涤。有机层用Na2SO4干燥。除去溶剂,将残渣溶解在乙醇(8mL)中。缓慢加入水(10mL)到沉淀固体中。悬浮液被放在冰箱里冷却一夜。悬浮液被过滤,收集固体,并用乙醇(8mL)/水(10mL)溶液洗涤。将洗涤后的固体置于室温真空中两天,得到白色固体D9-(4-硝基苯基)碳酸叔丁酯:34mg,收率:1.16%。
D9-多西他赛的合成:向IM-1(88mg,0.12mmol,0.9eq)中加入THF(1mL),搅拌下再加入H2O(0.5mL)、DMAP(31mg,0.27mmol,2eq),最后加入D9-(4-硝基苯基)碳酸叔丁酯(34mg,0.13mmol,1eq),常温下搅拌反应10h。反应完毕,搅拌下加水3mL,饱和氯化铵1mL,EA萃取(10mL*4),无水MgSO4干燥,浓缩(35℃以下),柱层析(Hex:EA=5:1~1:2),得白色固体D9-多西他赛:31mg,收率:30%。纯度:95.50%,同位素丰度:98Atom%D。
Claims (9)
1.一种氘或氚标记的多西他赛的制备方法,其特征在于,包括以下步骤:
(1)在有机碱的作用下,氘或氚代叔丁醇和对硝基苯基氯甲酸酯进行酯化反应,得到氘或氚代-(4-硝基苯基)碳酸叔丁酯;
(2)步骤(1)得到的氘或氚代-(4-硝基苯基)碳酸叔丁酯与化合物IM-1进行酰胺化反应,反应完成后经过后处理得到所述的氘或氚标记的多西他赛;
所述的氘或氚代-多西他赛为D9-多西他赛或T9-多西他赛;
合成D9-多西他赛的反应式如下:
2.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(1)中,所述的有机碱为吡啶。
3.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(1)中,所述的酯化反应在卤代烃类溶剂中进行,所述的卤代烃类溶剂为二氯甲烷或三氯甲烷。
4.根据权利要求3所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(1)中,将所述的对硝基苯基氯甲酸酯溶解在所述的卤代烃类溶剂中,然后滴加到所述的氘或氚代叔丁醇和有机碱的混合物中进行反应。
5.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(1)中,反应温度为-20~0℃,反应时间为10~30h。
6.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(2)中,所述酰胺化反应在DMAP的作用下进行。
7.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(2)中,所述酰胺化反应在醚类溶剂和水的混合溶剂中进行;
所述醚类溶剂为THF或者二氧六环。
8.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(2)中,所述酰胺化反应的温度为10~30℃,反应时间为10~20小时。
9.根据权利要求1所述的氘或氚标记的多西他赛的制备方法,其特征在于,步骤(2)中,反应结束后后处理过程如下:
向反应液中依次加水和饱和氯化铵水溶液,然后用乙酸乙酯萃取,干燥,浓缩,柱层析得到所述的氘或氚代多西他赛。
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