CN110950797A - 一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法 - Google Patents
一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法 Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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Abstract
本发明公开了一种2‑三氟甲基‑3‑氟‑4‑吡啶甲酸及其衍生物的制备方法,其特征在于,在多取代吡啶环2‑位,通过自由基的机理引入三氟甲基的方法,提供了一种适合大规模应用的2‑三氟甲基‑3‑氟‑4‑吡啶甲酸及其衍生物的制备方法。本发明中对于3‑氟‑4‑吡啶羧酸烷基酯的2‑位直接进行三氟甲基化反应的方法为首次报道,而且该工艺简便、原料易得、转化率高,反应后处理操作简单。同时,该方法在吡啶的2‑位引入三氟甲基的选择性很高,只需要简单重结晶就可以得到单一的三氟甲基取代在2‑位的产品。
Description
技术领域
本发明属于医药化工领域,具体涉及一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法。
背景技术
在药物化学领域中,三氟甲基是一类重要的化学基团,因其具有高脂溶性、良好的代谢稳定性、高电负性和生物利用度使得它在生物活性分子中有着广泛的应用(Tomashenko,O.A.;Grushin,V.V.Chem.Rev.2011,111,4475-4521)。早在1928年,Lehmann等人就发表了其对一些简单三氟甲基有机化合物生物活性的观测结果,在该文献中,研究者们发现不同取代的三氟甲基苯可以对中枢神经系统造成影响(Lehmann,F.,Arch.Exptl.Path.Pharmakol.,130,250(1928);C.A.,22,2993(1928))。
据统计,含有三氟甲基基团的上市药物有将近80余种。肿瘤和感染性疾病仍然是热门领域,心脑血管疾病、神经系统疾病、精神障碍以及内分泌和代谢疾病的药物也占据相当的比例,消化系统疾病、泌尿生殖系统疾病、肌肉骨骼和结缔组织疾病、眼病疾病和皮肤病等在三氟甲基药物中属于次要领域。
合成的2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物结构,在药物分子中同样也有非常广泛的应用。
例如:研究表明,化合物A是两面神激酶(Janus kinase,JAK)抑制剂,对于治疗类风湿性关节炎、血液系统疾病以及肿瘤和其它皮肤免疫性疾病方面有很好的治疗效果(US2014/256941A1,US2011/224190A1)。另外,最近文献报道化合物B是有效的P2X7受体拮抗剂。P2X7受体及其介导的信号通路在中枢系统疾病中发挥着关键的调控作用。这类受体已经成为中暑系统疾病潜在的药物靶点。而研究表明,化合物B在极低的ED50下也能表现出很好的作用。极有可能在治疗诸如阿尔茨海默症、帕金森症、抑郁症及失眠等中枢神经系统疾病中表现出很好的效果(J.Med.Chem.2018,61,207-223)。
而现有的2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法主要是采用了三氟甲基自由基的方法在芳环或芳杂环中引入三氟甲基结构是近年来发展出来的一种高效的引入三氟甲基的方法。
但在实际应用方面,对于吡啶邻位的化学环境不同的情况其产物存在两个反应点位的位置选择性问题,而且得到的一组异构体往往由于物理性质接近而很难分离,这导致其一直未能在多取代吡啶结构反应中有比较大规模的应用。值得注意的是,为解决上述问题,在中国专利CN108239021A中提供了一种以邻溴吡啶为原料,通过梅本试剂氟代-S-(三氟甲基)-二苯并噻吩盐的作用来引入三氟甲基的方法,如下对比反应式:
该方法通过在吡啶上先引入卤素原子,再经过官能团转化的方式将卤素原子转换为三氟甲基,成功解决了三氟甲基位置异构的问题。但是对于吡啶邻位取代的三氟甲基结构,该方法需要先引入卤素原子,操作更加复杂,而且在引入卤素原子的过程中同样面临位置选择性的问题。此外,该方法所用到的梅本试剂价格昂贵,并且会有大量的副产物产生,原子经济性不足。
发明内容
为了克服现有的制备方法在实际大规模应用上存在的问题,本发明的目的在于在多取代吡啶环2位,通过自由基的机理直接引入三氟甲基的方法,提供了一种适合大规模应用的2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法。
为了实现本发明的目的,所采用的技术方案是:
一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其中,所述2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物如式(I)所示:
所述方法的具体步骤如下反应式1所示:
在本发明的一个优选实施例中,所述方法包括如下步骤:
步骤1:式(II)所示原料与醇ROH在酸性条件下,-20℃至90℃反应生成式(III)所示的酯,其中R为C1-C6烷基或苄基;
步骤2:式(III)所示结构,在三氟甲基亚磺酸钠和过氧叔丁醇的作用下,-20℃至90℃反应生成式(I)所示的中间体;
步骤:3:式(IV)所示化合物在碱性条件下水解,0℃至100℃反应分别生成式(IV)所示化合物。
在本发明的一个优选实施例中,所述步骤1所涉及到酯化反应试剂为烷基醇,所提供的酸性条件来源为硫酸、盐酸、二氯亚砜或草酰氯中的任意一种或多种,所用溶剂为C1-C6烷基醇或苄醇中的任意一种或多种。
在本发明的一个优选实施例中,所述步骤2所涉及到三氟甲基化试剂为三氟甲基亚磺酸钠,反应氧化剂为过氧叔丁醇,试剂的溶剂包括醚类、卤代烷烃类中的任意一种或多种与水的混合物。
在本发明的一个优选实施例中,所述步骤3的水解方法为碱性水解,所用碱为无机碱;所用溶剂包括醚类或醇类溶剂中的任意一种或多种与水的混合物。
在本发明的一个优选实施例中,所述无机碱优选为氢氧化钠、氢氧化锂或氢氧化钾中的任意一种或多种。
在本发明的一个优选实施例中,所述烷基醇包括C1-C6烷基醇或苄醇中的任意一种或多种。
在本发明的一个优选实施例中,所述方法的具体步骤如反应式2所示,具体包括如下步骤:
步骤一:式(II)所示原料与甲醇在硫酸催化的条件下,70℃反应生成式(V)所示的甲酯;
步骤二:式(V)所示结构,在三氟甲基亚磺酸钠和过氧叔丁醇的作用下,在二氯甲烷和水的混合溶剂中,在室温下反应得到式(VI)所示的产品;
步骤三:式(VI)所示化合物在氢氧化锂碱性条件下水解,室温下反应分别生成式(IV)所示化合物。
在本发明的一个优选实施例中,所述步骤三的在三氟甲基亚磺酸钠和过氧叔丁醇的作用下,在二氯甲烷和水的混合溶剂中,具体加入量是:水与二氯甲烷比例为10:1-1:10,三氟甲基磺酸钠的当量为1.0-5.0当量,过氧叔丁醇为1.0-10.0当量。
在本发明的一个优选实施例中,所述步骤三的氢氧化锂碱性条件下水解具体加入量是:氢氧化锂使用量为1.0-5.0当量。
本发明的有益效果在于:
本发明中对于3-氟-4-吡啶羧酸烷基酯的2-位直接进行三氟甲基化反应的方法为首次报道,而且该工艺简便、原料易得、转化率高,反应后处理操作简单。同时,反应在吡啶的2-位引入三氟甲基的选择性很高,只需要简单重结晶就可以得到单一的三氟甲基取代在2-位的产品。
具体实施方式
本发明的主要原理在于:
本发明的方法原料成本低廉、易得、后处理简便,适合实验室小量制备也适合较大规模的工业化生产。另外,在反应过程中发现,三氟甲基引入吡啶2位的选择性很高,而且6-位三氟甲基取代的副产品很容易采用重结晶的办法除去从而实现纯化的目的。
以下结合具体实施例,进一步阐明本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。比例和百分比基于重量,除非特别说明。
实施例1
1.制备2-三氟甲基-3-氟-4-吡啶羧酸甲酯(VI),如反应式4。
5L三口反应瓶中,加入1.25L二氯甲烷,500mL水以及式(V)所示化合物3-氟-4-吡啶甲酸甲酯(250g,1.0eq)搅拌均匀后,加入250mL过氧叔丁醇以及360g三氟甲基亚磺酸钠(5.0eq)。混合物室温下搅拌12小时监测反应完全。
室温下小心抽去二氯甲烷溶剂,残余物小心加入到碎冰中,搅拌均匀,加乙醚萃取2次。合并的有机相冰水洗涤三次后,有机相干燥低温浓缩,得到的产品(VI)直接投入到下一步反应中。
实施例2
1.制备3-三氟甲基-4-吡啶羧酸甲酯(V),如反应式3。
在100L反应釜中,加入甲醇20L,化合物3-氟吡啶-4-甲酸(2.0kg,14.18mol,1.0eq),搅拌均匀溶解后加入浓硫酸。混合物升温到70℃搅拌过夜检测反应完全。
混合物将至室温后浓缩除去溶剂,浓缩液降温至0℃用饱和碳酸氢钠溶液调节至pH=9。乙酸乙酯萃取后,合并有机相干燥,过滤浓缩得到产物为黄色油状物(2.06kg,94%收率):H NMR(400MHz,CDCl3):δ8.62(d,J=Hz,1H),8.54(d,J=4.8Hz,1H),7.77(t,J=4.8Hz,1H),3.98(s,3H);MS-ESI:理论值(M):155.0;实际值:178.1(M+Na+)。
2.制备2-三氟甲基-3-氟-4-吡啶羧酸甲酯(VI),如反应式4。
100L反应釜中,加入25L二氯甲烷,10L水以及式(V)所示化合物3-氟-4-吡啶甲酸甲酯(5.0kg,1.0eq)搅拌均匀后,加入5.0L过氧叔丁醇以及18kg三氟甲基亚磺酸钠(5.0eq)。混合物室温下搅拌12小时监测反应完全。
零下20摄氏度到25摄氏度下小心抽去二氯甲烷溶剂,残余物小心加入到碎冰中,搅拌均匀,加乙醚萃取2次。合并的有机相冰水洗涤三次后,有机相干燥低温浓缩,得到的产品(VI)直接投入到下一步反应中。
3.制备2-三氟甲基-3-氟-4-吡啶甲酸(IV),如反应式5。
100L反应釜中,中间体2-三氟甲基-3-氟-4-吡啶羧酸甲酯(5kg,1.0eq)溶于MeOH/THF/H2O(1:1:1,5v/v)的混合溶剂中,加入一水合氢氧化锂(1.35kg,1.2eq)。
混合物室温下搅拌12小时,检测反应完全。反应液低温浓缩除去大部分MeOH和THF,反应液调节pH到弱酸性,产品析出。
过滤收集固体,烘干后用乙醇结晶,即得到产品(4.22kg,90%yield):H NMR(400MHz,CDCl3):δ14.4(brs,1H),8.68(d,J=4.4Hz,1H),8.18(t,J=4.8Hz,1H);MS-ESI:理论值(M):209.0;实际值:232.0(M+Na+)。
实施例3
1.制备2-三氟甲基-3-氟-4-吡啶羧酸甲酯(VI),如反应式4。
500L反应釜中,加入120L二氯甲烷,50L水以及式(V)所示化合物3-氟-4-吡啶甲酸甲酯(25.0kg,1.0eq)搅拌均匀后,加入25.0L过氧叔丁醇以及72kg三氟甲基亚磺酸钠(4.0eq)。混合物室温下搅拌24小时监测反应完全。
零摄氏度下小心抽去二氯甲烷溶剂,残余物小心加入到碎冰中,搅拌均匀,加乙醚萃取2次。合并的有机相冰水洗涤三次后,有机相干燥低温浓缩,得到的产品(VI)直接投入到下一步反应中。
2.制备2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物(IV),如反应式5。
500L反应釜中,中间体2-三氟甲基-3-氟-4-吡啶羧酸甲酯(20kg,1.0eq)溶于MeOH/THF/H2O(1:1:1,5v/v)的混合溶剂中,加入一水合氢氧化锂(8.10kg,1.8eq)。
混合物室温下搅拌24小时,检测反应完全。反应液低温浓缩除去大部分MeOH和THF,反应液调节pH到弱酸性,产品析出。
过滤收集固体,烘干后用乙醇结晶,即得到产品(21.0kg,89%yield):H NMR(400MHz,CDCl3):δ14.4(brs,1H),8.68(d,J=4.4Hz,1H),8.18(t,J=4.8Hz,1H);MS-ESI:理论值(M):209.0;实际值:232.0(M+Na+)。
Claims (8)
2.如权利要求1所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述方法包括如下步骤:
步骤1:式(II)所示原料与醇ROH在酸性条件下,-20℃至90℃反应生成式(III)所示的酯,其中R为C1-C6烷基或苄基;
步骤2:式(III)所示结构,在三氟甲基亚磺酸钠和过氧叔丁醇的作用下,-20℃至90℃反应生成式(I)所示的中间体;
步骤3:式(IV)所示化合物在碱性条件下水解,0℃至100℃反应分别生成式(IV)所示化合物。
3.如权利要求2所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述步骤1所涉及到酯化反应试剂为C1-C6烷基醇或苄醇,所提供的酸性条件来源为硫酸、盐酸、二氯亚砜或草酰氯中的任意一种或多种,所用溶剂为C1-C6烷基醇或苄醇中的任意一种或多种。
4.如权利要求2所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述步骤2所涉及到三氟甲基化试剂为三氟甲基亚磺酸钠,反应氧化剂为过氧叔丁醇,涉及的溶剂包括醚类、氯代烷烃类或醇类中的任意一种或多种与水的混合物。
5.如权利要求2所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述步骤3的水解方法为碱性水解,所用碱为无机碱;所用溶剂包括醚类或醇类溶剂中的任意一种或多种与水的混合物。
6.如权利要求5所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述无机碱为氢氧化钠、氢氧化锂或氢氧化钾中的任意一种或多种。
7.如权利要求2所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述步骤2的在三氟甲基亚磺酸钠和过氧叔丁醇的作用下,在有机溶剂与水的混合溶剂中,具体加入量是:水与有机溶剂的比例为10:1-1:10,三氟甲基磺酸钠的当量为1.0-5.0当量,过氧叔丁醇为1.0-10.0当量。
8.如权利要求2所述的一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法,其特征在于,所述步骤3的碱性条件下水解具体加入量是1.0-5.0当量。
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