CN112472697A - 一种有机酸锂-l-脯氨酸盐的制备工艺 - Google Patents

一种有机酸锂-l-脯氨酸盐的制备工艺 Download PDF

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CN112472697A
CN112472697A CN202011424798.4A CN202011424798A CN112472697A CN 112472697 A CN112472697 A CN 112472697A CN 202011424798 A CN202011424798 A CN 202011424798A CN 112472697 A CN112472697 A CN 112472697A
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proline
lithium
solvent
salt
isobutyrate
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谭骏
陈斌辉
李崧
陈江
谢非非
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Anyu Biopharmaceutical Hangzhou Co ltd
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Priority to EP21902368.6A priority patent/EP4260856A1/en
Priority to PCT/CN2021/131789 priority patent/WO2022121661A1/zh
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Abstract

一种有机酸锂‑L‑脯氨酸盐的制备工艺，涉及有机锂盐小分子药物的合成制备领域，本发明通过采用单一溶剂法和混合溶剂法制备出异丁酸锂‑L‑脯氨酸盐，以此来达到对新有机锂盐的开发和临床应用的目的，使有机酸锂‑L‑脯氨酸盐对双相情感障碍中躁狂、抑郁的反复发作有肯定的疗效和预防作用，而且具有独特的预防自杀风险的效应，同时能够有效的缓解焦虑抑郁等情绪异常，并且可以延缓中枢神经系统退行性病变，改变了现有无机锂盐的体内分布缺陷，另外，采用药物共晶或成盐技术无需改变药物分子的公价结构，即可达到修饰药物理化性质的目的，加强中枢神经系统疾病疗效的同时，降低锂盐的临床用量，避免外周不良反应的发生。

Description

一种有机酸锂-L-脯氨酸盐的制备工艺
技术领域
本发明属于有机锂盐小分子药物的合成制备领域，具体涉及一种有机酸锂-L-脯氨酸盐的制备工艺。
背景技术
公知的，锂盐不仅对双相情感障碍中躁狂、抑郁的反复发作有肯定的疗效和预防作用，而且具有独特的预防自杀风险的效应，最近研究发现锂盐通过作用于 GSK-3、Wnt、Akt 和神经递质来发挥神经保护作用，这种保护作用对包括阿尔茨海默病在内的神经退行性疾病的防治有潜在用途。
锂盐在治疗精神类疾病时往往需要长期用药，而长期用药造成的肾脏损伤极大地限制了药物的临床应用，同时，目前临床常用的无机酸锂盐（氯化锂和碳酸锂）长期使用还会导致血液PH值的紊乱，造成代谢性酸中毒、加重肾脏负担，近年来，包括丁酸、异丁酸、丙戊酸和叶酸在内的多种小分子有机酸被发现对于中枢神经系统有重要的影响，能够有效的缓解焦虑抑郁等情绪异常，并且可以延缓中枢神经系统退行性病变，并且有机酸盐的吸收分布和代谢特点往往与无机酸盐有较大的差异，有望改变现有无机锂盐的体内分布缺陷，因此有机酸锂盐具有更好的新药开发价值和市场前景。
此外，药物共晶或成盐技术是目前新药研发中的一种较为常用的方法，用来改变药物的理化性质，从而影响药物的疗效甚至产生新的药理作用，无需改变药物分子的公价结构，即可达到修饰药物理化性质的目的，这也是目前改善药物溶解性和生物利用度的常用方法，利用共晶或成盐技术，设计开发新型的小分子有机锂盐，使其具有更好的中枢神经系统分布，加强中枢神经系统疾病疗效的同时，降低锂盐的临床用量，避免外周不良反应的发生，对于新型锂盐药物的开发和临床应用具有重要的意义，但是如何制备出合格的新盐是现在业界的一大难题。
发明内容
为了克服背景技术中的不足，本发明公开了一种有机酸锂-L-脯氨酸盐的制备工艺，本发明通过采用单一溶剂法和混合溶剂法制备出异丁酸锂-L-脯氨酸盐，以此来达到对新有机锂盐的开发和临床应用的目的。
一种有机酸锂-L-脯氨酸盐的制备工艺，包括异丁酸锂和L-脯氨酸，采用单一溶剂法和混合溶剂法进行异丁酸锂和L-脯氨酸的制备，在单一溶剂法中，将不同化学当量比例的异丁酸锂和L-脯氨酸中加入适量的良溶剂，加热回流1-5小时，趁热过滤，自然冷却析晶，送XRD和氢谱检验；在混合溶剂析晶法中，将不同化学当量比的异丁酸锂和L-脯氨酸中加入适量的良溶剂，加热回流溶解后加入适量不良溶剂析出固体，补加良溶剂重新溶解，回流1-5小时，自然冷却析晶，送XRD和氢谱检验。
所述异丁酸锂和L-脯氨酸在神经退行性疾病防治中的应用。
所述异丁酸锂可替换为丁酸锂、乳酸锂、柠檬酸锂或胆固醇锂。
所述L-脯氨酸可替换为缬氨酸、赖氨酸或人工合成氨基酸。
由于采用了上述技术方案，本发明具有如下有益效果：本发明对双相情感障碍中躁狂、抑郁的反复发作有肯定的疗效和预防作用，而且具有独特的预防自杀风险的效应，同时能够有效的缓解焦虑抑郁等情绪异常，并且可以延缓中枢神经系统退行性病变，并且有机酸盐的吸收分布和代谢特点往往与无机酸盐有较大的差异，改变了现有无机锂盐的体内分布缺陷，另外，采用药物共晶或成盐技术无需改变药物分子的公价结构，即可达到修饰药物理化性质的目的，设计开发新型的小分子有机锂盐，使其具有更好的中枢神经系统分布，加强中枢神经系统疾病疗效的同时，降低锂盐的临床用量，避免外周不良反应的发生。
附图说明
图1为本发明的异丁酸锂单一化合物氢谱；
图2为本发明的L-脯氨酸单一化合物氢谱；
图3为本发明的异丁酸锂、L-脯氨酸等化学当量物理混合物氢谱；
图4为本发明的正丁醇条件下析出固体氢谱；
图5为本发明的正丁醇条件下析出固体XRD示意图；
图6为本发明的L-脯氨酸单一化合物XRD图谱；
图7为本发明的异丁酸锂单一化合物XRD图谱；
图8为本发明的叠加的XRD图谱；
图9为本发明的乙醇、四氢呋喃混合溶剂析出固体的氢谱；
图10为本发明的乙醇、四氢呋喃混合溶剂析出固体XRD示意图；
图11为本发明的叠加图谱；
图12为本发明的异丁酸锂-L-脯氨酸复合物X-射线单晶衍射示意图。
具体实施方式
通过下面的实施例子可以详细的解释本发明，公开本发明的目的旨在保护本发明范围内的一切技术改进。
实施例1，本发明所述的一种有机酸锂-L-脯氨酸盐的制备工艺，测试异丁酸锂、L-脯氨酸在以下溶剂中的溶解性，判断异丁酸锂、L-脯氨酸的良溶剂和不良溶剂。
取1 mg溶质，加入100 μL的溶剂，观察溶解情况，若不溶超声2 min再观察溶解情况；如果还是不溶，补加100 μL的溶剂，观察溶解情况，若不溶超声2 min再观察溶解情况；补加溶剂至产物完全溶解，记录加入的溶剂总量，或者补加至1 mL后产物还未溶解，停止溶解度测试，由此判断异丁酸锂、L-脯氨酸的良溶剂和不良溶剂。
如下表所示，异丁酸锂、L-脯氨酸溶解性测试结果
Figure 900707DEST_PATH_IMAGE002
实施例2，本发明所述的一种有机酸锂-L-脯氨酸盐的制备工艺，采用单一溶剂析晶法制备异丁酸锂-L-脯氨酸盐，操作步骤如下：
将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂正丁醇，在加热回流下使其恰好溶解并记录溶剂使用量，搅拌约3h，趁热过滤，自然冷却析晶，过滤固体，真空干燥至恒重得到589.3mg白色固体，质量收率为53.06%，送XRD和氢谱检验
氢谱数据：氘代试剂为：CD3OD
结合附图1~4，得出：正丁醇条件下析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1；鉴于异丁酸锂、L-脯氨酸在正丁醇下的溶解度有较大差异，析出化合物并非单纯物理混合物，而是二者的盐，且盐中异丁酸锂、L-脯氨酸以1:1形式进行结合；
XRD图谱
结合附图5，以正丁醇作为单一溶剂析出的固体2θ特征峰值为：7.909°、8.201°、11.735°、16.525°、20.395°、23.669°、24.930°、30.232°、31.427°、33.451°；
结合附图6，L-脯氨酸单一化合物2θ特征峰值为：8.564°、12.295°、15.110°、18.001°、18.390°、19.100°、19.518°、22.682°、24.770°、30.528°、32.120°、36.517°、37.602°、39.750°；
结合附图7，异丁酸锂单一化合物2θ特征峰值为：7.169°、8.489°、14.377°、17.056°、18.945°、20.329°、21.291°、21.802°、24.123°、25.713°、26.395°、27.819°、29.003°、29.577°、29.866°、33.101°、39.219°；
结合附图8，由叠加图谱可知，正丁醇条件下析出固体与异丁酸锂、L-脯氨酸单一化合物或者两个单一化合物的叠加图谱均不相同，故可判断正丁醇条件下析出固体为不同于两种原料的盐。
实施例3，本发明所述的一种有机酸锂-L-脯氨酸盐的制备工艺，采用混合溶剂析晶法制备异丁酸锂-L-脯氨酸盐
将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂，加热回流使其恰好溶解，而后加入适量不良溶剂至恰好析出固体，补加良溶剂使其重新溶解，回流3 h，自然冷却析晶，过滤固体，真空干燥至恒重得到374.8mg白色固体，质量收率为33.75%，送XRD和氢谱检验
氢谱：氘代试剂为：CD3OD
结合附图9和附图1~3，分析可知：乙醇、四氢呋喃混合溶剂析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1；鉴于异丁酸锂、L-脯氨酸在乙醇、四氢呋喃下的溶解度均有较大差异，析出化合物并非单纯物理混合物，而是盐，且盐中异丁酸锂、L-脯氨酸以1:1形式进行结合；
XRD图谱
结合附图10，以乙醇、四氢呋喃混合溶剂析出共晶/盐的2θ特征峰值为：8.255°、11.782°、16.584°、16.811°、18.711°、18.800°、20.451°、23.715°、25.017°、25.040°、30.281°、31.490°、33.537°、35.886°；
结合附图11，由叠加图谱可知，乙醇、四氢呋喃混合溶剂条件下析出固体与异丁酸锂、L-脯氨酸单一化合物或者两个单一化合物的叠加图谱均不相同，故可判断乙醇、四氢呋喃混合溶剂条件下为不同于两种原料的盐；由乙醇、四氢呋喃混合溶剂条件下析出固体的XRD和正丁醇单一溶剂条件下析出固体的XRD图可看出，两者的2θ特征峰值在±0.2偏差范围内，且峰强特征相同，基本可判定两者为同一种盐。
实施例4，本发明所述的一种有机酸锂-L-脯氨酸盐的制备工艺，盐结构的表征
根据XRD和氢谱结果，选择正丙醇、正丁醇体系进行单晶培养，确定所形成的复合物，最终正丁醇条件下析出晶体质量符合测试要求，其单晶结构如附图12所示；
使用Mercury软件对单晶晶格内的L-脯氨酸的C-O键键长进行测量，其C-O键键长分别为1.233Å和1.2 68Å,比值为1.028，L-脯氨酸的C-O键键长基本相同，证明复合物中L-脯氨酸明显发生质子转移导致其羧酸根C-O键键长趋于相同，确认制备产物为异丁酸锂-L-脯氨酸盐。
本发明未详述部分为现有技术，尽管结合优选实施方案具体展示和介绍了本发明，具体实现该技术方案方法和途径很多，以上所述仅是本发明的优选实施方式，但所属领域的技术人员应该明白，在不脱离所附权利要求书所限定的本发明的精神和范围内，在形式上和细节上可以对本发明做出各种变化，均为本发明的保护范围。

Claims (10)

1.一种有机酸锂-L-脯氨酸盐的制备工艺，包括异丁酸锂和L-脯氨酸，异丁酸锂和L-脯氨酸在神经退行性疾病防治中的应用。
2.根据权利要求1所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的异丁酸锂和L-脯氨酸采用单一溶剂法和混合溶剂法进行异丁酸锂或L-脯氨酸的制备。
3.根据权利要求2所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的单一溶剂法中，将不同化学当量比例的异丁酸锂和L-脯氨酸中加入适量的良溶剂，加热回流1-5小时，趁热过滤，自然冷却析晶。
4.根据权利要求2所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的混合溶剂析晶法中，将不同化学当量比的异丁酸锂和L-脯氨酸中加入适量的良溶剂，加热回流溶解后加入适量不良溶剂析出固体，补加良溶剂重新溶解，回流1-5小时，自然冷却析晶。
5.根据权利要求2所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的异丁酸锂可替换为丁酸锂、乳酸锂、柠檬酸锂或胆固醇锂。
6.根据权利要求2所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的L-脯氨酸可替换为缬氨酸、赖氨酸或人工合成氨基酸。
7.根据权利要求3或4所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的良溶剂判断步骤为：取1 mg溶质，加入100 μL的溶剂，观察溶解情况，若不溶超声2 min再观察溶解情况；如果还是不溶，补加100 μL的溶剂，观察溶解情况，若不溶超声2 min再观察溶解情况；补加溶剂至产物完全溶解，记录加入的溶剂总量，或者补加至1 mL后产物还未溶解，停止溶解度测试，由此判断异丁酸锂、L-脯氨酸的良溶剂和不良溶剂。
8.根据权利要求3所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的单一溶剂法的操作步骤为：将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂正丁醇，在加热回流下使其恰好溶解并记录溶剂使用量，搅拌约3h，趁热过滤，自然冷却析晶，过滤固体，真空干燥至恒重得到589.3mg白色固体，质量收率为53.06%，所得出正丁醇条件下析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1，异丁酸锂、L-脯氨酸在正丁醇下的溶解度析出化合物为二者的盐，且盐中异丁酸锂、L-脯氨酸以1:1形式进行结合，以正丁醇作为单一溶剂析出的固体2θ特征峰值为：7.909°、8.201°、11.735°、16.525°、20.395°、23.669°、24.930°、30.232°、31.427°、33.451°；
L-脯氨酸单一化合物2θ特征峰值为：8.564°、12.295°、15.110°、18.001°、18.390°、19.100°、19.518°、22.682°、24.770°、30.528°、32.120°、36.517°、37.602°、39.750°；
异丁酸锂单一化合物2θ特征峰值为：7.169°、8.489°、14.377°、17.056°、18.945°、20.329°、21.291°、21.802°、24.123°、25.713°、26.395°、27.819°、29.003°、29.577°、29.866°、33.101°、39.219°；。
9.根据权利要求4所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的混合溶剂析晶法的操作步骤为：将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂-乙醇、四氢呋喃混合溶剂，加热回流使其恰好溶解，而后加入适量不良溶剂至恰好析出固体，补加良溶剂使其重新溶解，回流3 h，自然冷却析晶，过滤固体，真空干燥至恒重得到374.8mg白色固体，质量收率为33.75%，混合溶剂析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1，析出化合物中异丁酸锂、L-脯氨酸以1:1形式进行结合；
以乙醇、四氢呋喃混合溶剂析出共晶/盐的2θ特征峰值为：8.255°、11.782°、16.584°、16.811°、18.711°、18.800°、20.451°、23.715°、25.017°、25.040°、30.281°、31.490°、33.537°、35.886°；
乙醇、四氢呋喃混合溶剂条件下析出的固体和正丁醇单一溶剂条件下析出的固体2θ特征峰值在±0.2偏差范围内，且峰强特征相同，判定两者为同一种盐。
10.根据权利要求3或4所述的一种有机酸锂-L-脯氨酸盐的制备工艺，其特征是：所述的析晶使用Mercury软件对单晶晶格内的L-脯氨酸的C-O键键长进行测量，其C-O键键长分别为1.233Å和1.2 68Å,比值为1.028，L-脯氨酸的C-O键键长基本相同，证明复合物中L-脯氨酸明显发生质子转移导致其羧酸根C-O键键长趋于相同，确认制备产物为异丁酸锂-L-脯氨酸盐。
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