CN116332927A - 一种脲类化合物的柠檬酸盐产品及制备方法 - Google Patents
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Abstract
本发明具体涉及一种脲类化合物的盐及其制备方法。该方法采用有机溶剂与水混合结晶溶剂体系,游离碱与酸进行配对形成离子对,进行结晶,然后在一定的温度范围内进行保温打浆结晶,得到该新型晶型,该产品水中溶解度高,制备方法简单,产率高,性质稳定,易于储藏和运输和后期使用。本发明提供的制备方法工艺重现性好,操作简单,适合工业化生产。
Description
技术领域:
本发明具体涉及一种脲类化合物的柠檬酸盐及其制备方法。
背景技术:
FGFR(fibroblast growth factor receptor)酪氨酸激酶家族包括FGFR1、FGFR2、FGFR3和FGFR4。在生理状态下,FGFR4信号通路被严格控制,而FGFR4信号失调导致癌症的发生发展、增殖、存活及转移。通过阻断胞外配体分子与受体的结合或胞内激酶信号的传递,抑制FGFR4所介导的增殖信号,是治疗此类肿瘤的有效手段,其方法包括小分子激酶抑制剂、单克隆抗体、配体捕获蛋白和shRNA等。
其中,化合物I是一种抑制FGFR4受体的小分子。
化合物I为一种具有脲类结构的“裸露碱”,为了解决该裸露碱的水溶性问题,拟定将化合物I制备成为“盐类”化合物,这样有利于增加化合物I的水溶性,具有提高化合物I在生物体中的生物利用度。
另一方面,“盐类”化合物往往是具有更加良好固态特征性质产品(例如:性质稳定的盐类化合物,性质稳定的晶型特征),对化合物I的后期使用,会带来较大的获益,例如:固体制剂产品生产中需要原料药性质稳定,原料药和制剂产品需要在较长的货架期内保持产品的质量稳定。
本发明的目的在于克服现有技术的不足,解决抑制FGFR4受体的小分子化合物I的溶解性等技术难题,研究化合物I可供开发的“盐类”化合物。
发明内容:
本发明的目的在于克服现有技术的不足,解决抑制FGFR4受体的小分子化合物I的溶解性和稳定性技术难题,首先需要研究并确定化合物I可供开发的“盐类”化合物,然后基于“盐类”化合物,进行固态性质特征的研究,确定最终用于药品开发的“盐类”化合物I的具有稳定固态性质的产品,保证后期药物开发对原料药性质的稳定要求,并确保药品顺利上市。
本发明提供一种如式XX所示化合物:
其中,n=1,2,3,4;
YM代表结晶溶剂,其中M选自:
H2O,甲醇,乙醇,异丙醇,丙酮;
Y=0,0.5,1,2,3,4。
本发明所述式XX化合物的制备方法,其特征在于它包括步骤:
(a)将式I化合物“裸露碱”分散于溶剂中;
(b)一定温度下搅拌分散,加入定量柠檬酸,溶解后,过滤不溶物;
(c)滤液在一定温度析出晶体,过滤晶体;
(d)在一定的温度下干燥。
本发明所述的化合物的制备方法,其特征在于步骤(a)中分散溶剂选自,水,醚类,C1~C8醇类,C3~C8酮类,C1~C8酯类,C5~C8烷烃类,C1~C8卤代烷烃类,芳香烷烃类中的一种或多种;所述的溶剂B优先选自:叔丁基甲基醚,乙醚,四氢呋喃,二氧六环,二氯甲烷,三氯甲烷,四氯化碳,乙腈,二氯乙烷,正己烷,正戊烷,正庚烷,乙醇,甲醇,叔丁醇,正丁醇,异丙醇,丙酮,丁酮,乙酸乙酯,甲苯,苯,二甲苯中的一种或多种。
本发明所述的式XX的制备方法,其特征在于步骤(b)中溶解温度为-10℃~100℃,优选温度为-5℃~70℃。
本发明所述的式XX的制备方法,其特征在于步骤(c)中滤液析出晶体的温度控制为-10~60℃。
本发明所述的式XX的制备方法,其特征在于步骤(d)中干燥的温度为0~80℃,干燥方式为鼓风干燥和减压干燥。
本发明所述的式XX的制备方法,其特征在于它包括步骤:
(a)将式I化合物“裸露碱”分散于水和丙酮的混合溶剂中;
(b)25℃~60℃条件下,加入定量柠檬酸搅拌溶解,过滤不溶物;
(c)滤液在0~30℃条件下析出晶体,过滤晶体;
(d)在40~60℃的温度下鼓风干燥得到式XX。
附图说明:
图1为实施例中式XX制备方案。
图2为XX的核磁共振氢谱。
具体实施方式:
下面用实施例来进一步说明本发明,但本发明并不受其限制。
实施例1:化合物I的制备方案如下:
化合物N1-甲基-N2-叔丁氧羰基乙二胺(10.0g,57.4mmol)溶于四氢呋喃(100ml)中,然后加入三乙胺(8.4ml,60mmol),将其冷却至0℃,然后滴加溴乙酸乙酯(6.31ml,57.4mmol),滴加完毕后继续反应。经薄层层析监测反应完全,浓缩,加入水用二氯甲烷萃取两次,有机相分别用饱和氯化铵水溶液、水和饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩,柱层析得到目标产物(13.4g)。将产物溶于二氯甲烷(20ml)中,加入三氟乙酸(10ml),室温反应8小时后,减压浓缩得到化合物1A的粗品三氟乙酸盐(20.5g)。
将化合物1B(4.73g,20mmol)(按照公开专利文献WO2015059668制备并鉴定)和化合物1A的三氟乙酸盐(5.43g,18.8mmol)溶于1,2-二氯乙烷(50ml)中,然后加入三乙胺(8.36ml,60mmol)搅拌0.5小时后,分批加入三乙酰氧基硼氢化钠(8.48g,40mmol),继续搅拌反应。经薄层层析监测反应完全,加入饱和氯化铵水溶液淬灭,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩得到化合物1C(4.5g),1H NMR(400MHz,CDCl3)δ7.09(s,1H),5.19(s,1H),4.95(s,1H),4.70(s,2H),3.41–3.37(m,8H),3.22–3.18(m,4H),2.70–2.67(m,2H),2.59–2.56(m,2H),2.23(s,3H),1.91–1.85(m,2H);ESI-MS m/z:335.2[M+H]+。
将化合物1C(1.0g,3.0mmol)溶于二氯甲烷(10ml)中,然后加入DIPEA(744μl,4.5mmol),冷却至0℃,滴入氯甲酸对硝基苯酯(907mg,4.5mmol)的二氯甲烷(5ml)溶液,恢复至室温反应,反应完全后,加入饱和氯化铵水溶液,二氯甲烷萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析得到化合物1D(989mg),按照以上方案大量制备1D备用。1D化合物的核磁共振数据:1H NMR(400MHz,CDCl3)δ8.28–8.26(d,J=8Hz,2H),7.39–7.37(d,J=8Hz,2H),5.19(s,1H),4.88(s,2H),3.95–3.92(m,2H),3.38(s,6H),3.30–3.27(m,2H),3.22(s,2H),2.85–2.81(m,2H),2.64–2.61(m,2H),2.36(s,3H),2.08–2.01(m,2H)。
在1L圆底烧瓶中,加入原料1E化合物50g(388.9mmol)溶于500mlDMF中,冰浴冷却至0℃,缓慢分批加入87.5g(388.9mmol)原料N-碘代丁二酰亚胺,反应液透明澄清,10min后恢复室温,搅拌反应过夜。TLC监控反应进程,反应完全后,将反应液在搅拌下缓慢倒入5L冰水中,析出大量土黄色固体,过滤,水洗涤,干燥,得到土黄色固体产物1F投入下一步反应,ESI-MS m/z:255.4[M+H]+。
单口圆底烧瓶中,加入1F化合物90.7g(357.1mmol)溶于500mlNMP中,加入Zn(CN)2共21.4g(182.1mmol),再快速加入41g(35.7mmol)Pd(PPh3)4,135℃反应5h。反应完全,得到褐色油状液体,将反应液在搅拌下缓慢倒入3L冰水中,析出大量黄褐色固体,过滤,水洗涤,干燥,得到化合物1G,ESI-MS m/z:154.2[M+H]+。
在1L的圆底三口烧瓶中,加入24g(156.3mmol)原料1G溶于400ml无水THF中,在0℃和N2保护下,加入117ml(234.4mmol)LiHMDS(浓度2mol/L),0℃搅拌反应2h,加入40.9g(187.5mmol)Boc2O升温至室温,反应过夜。反应完全后,加入20ml水淬灭反应,旋蒸除去THF,加入水,用乙酸乙酯萃取,再用水洗涤,MgSO4干燥,过滤,旋干,硅胶柱层析得到产物1H,ESI-MS m/z:254.2[M+H]+。
单口圆底烧瓶中,加入原料1H化合物10g(39.5mmol),溶于30mlDMSO中,依次加入DIPEA共计11.2g(86.9mmol)、炔丙胺10.9g(197.5mmol),70℃反应过夜。反应完全后,将反应液冷却,有大量白色固体析出,过滤,水洗,干燥得到产物1J,1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.39(s,1H),4.12–4.10(m,2H),2.36–2.35(m,1H),1.55(s,9H)。
反应容器中,加入1J化合物5g(18.4mmol),溶于30ml二氯甲烷中,加入三氟乙酸30ml,40℃反应,0.5h后,旋干,用饱和NaHCO3溶液调pH=8,用乙酸乙酯萃取,水洗涤,MgSO4干燥,过滤,旋干得到白色产物1K,1H NMR(400MHz,CD3OD)δ7.93(s,1H),5.85(s,1H),3.99(s,2H),3.31–3.30(m,1H)。
将1D(5.8g,11.6mmol)和1K(2.5g,14.5mmol)用无水THF溶解,充入氮气保护。然后置于-25℃的冷阱中搅拌,取LiHMDS(30ml,1mol/L in THF,30mmol)在该温度下缓慢滴加到反应液中,该温度搅拌反应两小时,然后自然恢复至室温过夜。薄层层析板监测反应,反应完全后加入饱和NH4Cl溶液淬灭,乙酸乙酯萃取,干燥,浓缩,柱层析纯化得到化合物1N。1HNMR(400MHz,CDCl3)δ13.83(s,1H),8.26(s,1H),7.69(s,1H),7.49(s,1H),5.14–5.12(m,1H),4.87(s,2H),4.15–4.13(m,2H),4.07–4.04(m,2H),3.51(s,6H),3.32–3.30(m,2H),3.26(s,2H),2.86–2.83(m,2H),2.69–2.67(m,2H),2.41(s,3H),2.39–2.37(m,1H),2.01–1.99(m,2H)。
将化合物1N(4g)溶于THF中,然后缓慢加入3N的HCl溶液。室温搅拌反应两小时,薄层层析板监测反应。反应完全后用饱和NaHCO3溶液调节pH至碱性,此时析出大量白色固体,过滤,干燥后,收集固体即为化合物I。1H NMR(400MHz,CDCl3)δ13.68(s,1H),10.23(s,1H),8.22(s,1H),7.68(s,1H),7.63(s,1H),5.29–5.26(m,1H),5.09(s,2H),4.15–4.13(m,2H),4.11–4.08(m,2H),3.37–3.35(m,2H),3.21(s,2H),2.95–2.92(m,2H),2.68–2.65(m,2H),2.38–2.36(m,4H),2.06–2.03(m,2H);13C NMR(100MHz,CDCl3)δ193.6,167.6,156.0,154.9,152.68,152.61,150.9,143.9,140.2,128.5,128.2,116.3,93.5,90.6,78.1,73.1,59.2,51.8,47.2,45.1,44.0,43.8,32.5,28.4,20.9;ESI-MS m/z:487.4[M+H]+。
实施例2:XX的制备与表征:
按照图1的方案制备得到化合物XX,其核磁共振氢谱(400MHz,氘代溶剂:氘代二甲亚砜)如图2。
水中溶解度比较:将以上化合物XX与裸露碱I,分别配置成系列浓度的水溶液,并充分搅拌,以澄清无不溶物为充分溶解,有关溶解度结果总结如下:
裸露碱I的水中溶解度:A;化合物XX水中溶解度:C。
其中A<0.5mg/mL,0.5mg/mL<B<5mg/mL,5mg/mL<C<10mg/mL。
虽然已通过上述具体实施方式和实施例详细说明了本发明的多个方面和不同实施方案,但本领域技术人员基于上述教导,将很容易预见到本发明所述方法、反应条件可具有适当的变化和调整,以适应具体的需要和实际情况,并且这些变化和调整均认为在本发明的范围内,即权利要求所限定的范围内。
Claims (8)
2.一种如权利要求1所述式XX化合物的制备方法,其特征在于它包括步骤:
(a)将式I化合物“裸露碱”分散于溶剂中;
(b)一定温度下搅拌分散,加入定量柠檬酸,溶解后,过滤不溶物;
(c)滤液在一定温度析出晶体,过滤晶体;
(d)在一定的温度下干燥。
3.如权利要求2所述的化合物的制备方法,其特征在于步骤(a)中分散溶剂选自,水,醚类,C1~C8醇类,C3~C8酮类,C1~C8酯类,C5~C8烷烃类,C1~C8卤代烷烃类,芳香烷烃类中的一种或多种;所述的溶剂B优先选自:叔丁基甲基醚,乙醚,四氢呋喃,二氧六环,二氯甲烷,三氯甲烷,四氯化碳,乙腈,二氯乙烷,正己烷,正戊烷,正庚烷,乙醇,甲醇,叔丁醇,正丁醇,异丙醇,丙酮,丁酮,乙酸乙酯,甲苯,苯,二甲苯中的一种或多种。
4.如权利要求2所述的式XX的制备方法,其特征在于步骤(b)中溶解温度为-10℃~100℃,优选温度为-5℃~70℃。
5.如权利要求2所述的式XX的制备方法,其特征在于步骤(c)中滤液析出晶体的温度控制为-10~60℃。
6.如权利要求2所述的式XX的制备方法,其特征在于步骤(d)中干燥的温度为0~80℃,干燥方式为鼓风干燥和减压干燥。
7.一种如权利要求2~6所述的式XX的制备方法,其特征在于它包括步骤:
(a)将式I化合物“裸露碱”分散于水和丙酮的混合溶剂中;
(b)25℃~60℃条件下,加入定量柠檬酸搅拌溶解,过滤不溶物;
(c)滤液在0~30℃条件下析出晶体,过滤晶体;
(d)在40~60℃的温度下鼓风干燥得到式XX。
8.如权利要求1所述的化合物IIX及其组合物在治疗癌症中的应用,治疗的各种癌症包括:肝癌,肺癌,食管癌,胃癌,肾细胞癌,肉瘤,胆管癌,结肠癌,前列腺癌,卵巢癌,乳腺癌。
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