CN113816943A - 屈昔多巴关键中间体的拆分方法 - Google Patents
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Abstract
本发明涉及屈昔多巴苏式关键中间体（合成路线一、二、三中的关键中间体I、关键中间体II、关键中间体III）的拆分方法，其特征在于采用非生物碱、商业化易得、价格便宜的S‑二苯基脯氨醇为拆分剂，采用10倍‑20倍溶剂，0.6‑1.0摩尔当量的拆分剂，回流反应，于25‑45℃析晶，拆分得到关键中间体I，II，III/S‑二苯基脯氨醇复盐，然后在酸性条件下将复盐游离，得到L‑苏式‑关键中间体I，II，III。本发明的拆分方法，拆分收率高、拆分得到的目标产物手性纯度高、拆分剂商业易得、适合工业化生产。
Description
技术领域
本发明属于原料药制备技术领域，特别涉及屈昔多巴关键中间体的新拆分方法。
背景技术
屈昔多巴（化学名：L-苏式-3-（3,4-二羟基苯基）丝氨酸）是一种合成氨基酸，其化学结构式如下：
屈昔多巴可使脑内异常降低的去甲肾上腺素浓度恢复至正常水平，因而可改善去甲肾上腺素缺乏引起的各种症状，如直立性低血压所致的头晕，乏力，帕金森病患者的步态僵直等，目前屈昔多巴主要用于治疗原发性自主神经衰弱（帕金森病，多系统萎缩症和纯自主神经衰弱），多巴胺β羟基化酶缺乏症，非糖尿病性自主神经病变等患者有症状的神经源性体位性低血压（NOH）。
关于屈昔多巴的合成路线和制备方法目前有较多报道，归纳总结，采用较多的主要为以下3条路线：
路线一: 参考文献US4480109，该路线为原研公司日本住友制药发表化合物专利的合成路线。该专利路线以胡椒醛为起始原料，首先与甘氨酸缩合并用水重结晶得到苏式-3-（3,4-亚甲二氧苯基）丝氨酸，该中间体与氯甲酸苄酯反应进行氨基保护得到如下所示的关键中间体I，经拆分得到所需的L-苏式-产物，再经过脱亚甲基和氨基保护得到目标产物屈昔多巴，具体合成路线如下：
路线二：参考文献合成化学，2012,18,124-127，该路线采用3,4-二苄氧苯甲醛替代胡椒醛为起始原料，然后与甘氨酸缩合，后处理得到苏式-3-（3,4-二苄氧基-苯基）丝氨酸，该中间体再与氯甲酸苄酯反应进行氨基保护得到如下中所示的关键中间体II，经拆分得到所需的L-苏式-产物，再脱去保护基得到目标产物屈昔多巴，具体合成路线如下：
路线三：参考文献WO2013142093，该路线是对原研合成路线的改进，该路线仍然以胡椒醛为起始原料，先与甘氨酸缩合后处理得到苏式-3-（3,4-亚甲二氧苯基）丝氨酸，然后通过与N-甲氧羰基邻苯二甲酰亚胺进行氨基保护，经拆分得到所需的L-苏式-产物，再脱去保护基得到目标产物屈昔多巴，具体合成路线如下：
如上所述，目前采用的主要路线为路线一、路线二、路线三，这三条路线中最关键的步骤为苏式-关键中间体的拆分（即关键中间体I、关键中间体II、关键中间体III），拆分质量不仅影响终产品屈昔多巴的质量，拆分收率也对终产品屈昔多巴成本影响重大。
然而纵观现有的文献报道，屈昔多巴苏式-关键中间体的拆分主要采用大多为生物碱类，如奎尼丁、奎宁、马钱子碱、辛可尼丁、辛可宁、麻黄碱、去甲麻黄碱以及去氢松香胺等，以上的生物碱中使用最多的为麻黄碱和去甲麻黄碱，但麻黄碱和去甲麻黄碱均属于管制药品，商业上购买和使用都受到限制，且价格较为昂贵，限制了工业上大规模使用；也有极少非生物碱的拆分剂报道，但其拆分收率和拆分后L-苏式产物的手性纯度远未达到原料药的质量要求标准。
发明内容
本发明的目的在于针对现有屈昔多巴苏式-关键中间体（关键中间体I，关键中间体II，关键中间体III）拆分技术中的缺陷，提供一种拆分效果好、商业化易购买、成本低、适合工业应用的屈昔多巴苏式-关键中间体的拆分剂及其拆分工艺。
在前期对屈昔多巴苏式-关键中间体拆分剂的筛选过程中，我们发现一种新的适用于屈昔多巴苏式-中间体的非生物碱拆分剂，该拆分剂商业化易购买，价格便宜，且其应用于屈昔多巴苏式-中间体拆分效果明显优于现有技术（见实施例1-12），拆分收率为40-45%，拆分后L-型目标产物收率纯度达到98-99.7%，无需再进行精制就可达到原料药手性纯度要求。
本发明提供一种屈昔多巴苏式-关键中间体（关键中间体I，关键中间体II，关键中间体III）的拆分方法，其反应如下：
上述反应中，拆分原料为目前报道采用最多的3条合成路线中的苏式-关键中间体（关键中间体I，关键中间体II，关键中间体III）。
上述反应中，拆分剂为S-二苯基脯氨醇，其摩尔用量为关键中间体I或关键中间体II或关键中间体III的0.6-1倍，优选0.6-0.7倍。
上述反应中，拆分使用溶剂选自质子性溶剂包括乙醇、甲醇、异丙醇、正丁醇，正戊醇、四氢呋喃中的一种或多种按任意比例的混合；非质子性溶剂包括乙酸乙酯、甲苯、二氯甲烷、氯仿中的一种或多种按任意比例的混合；极性溶剂包括DMF。其中质子性溶剂优选异丙醇或正丁醇，非质子性溶剂优选乙酸乙酯。
上述反应中，溶剂用量（体积）与所要拆分原料的重量（g）的比选自10:1-20:1,优选10:1。
上述反应中，反应温度为回流，析晶温度由所选溶剂的不同，范围为25-45℃，
优选30-45℃。
本发明的优势：本发明旨在提供一种屈昔多巴苏式-关键中间体（关键中间体I，关键中间体II，关键中间体III）的拆分方法，克服现有技术中普遍采用生物碱为拆分剂，商业购买不易、成本高、不易工业化放大的缺陷，与现有技术相比，采用本发明技术拆分剂及拆分工艺有如下几点优势：
1.相比于现有技术中普遍采用的管制品生物碱为拆分剂，本发明采用的拆分剂S-二苯基脯氨醇为商业产品，易购买、价格较低、成本较生物碱大大降低，更适用于工业化生产；
2.相比于现有技术的拆分剂，本发明采用的拆分剂S-二苯基脯氨醇拆分效果更好，拆分收率为40-45%，一次拆分后L-苏式-产物（L-苏式-关键中间体I、L-苏式-关键中间体II、L-苏式-关键中间体III）的手性纯度为98-99.5%，不用再进行手性纯度精制，即可满足原料药手性纯度要求。
说明书附图
图1：实施例1拆分所得L-苏式-关键中间体I手性纯度HPLC图谱；
图2：实施例2拆分所得L-苏式-关键中间体II手性纯度HPLC图谱；
图3：实施例3拆分所得L-苏式-关键中间体III手性纯度HPLC图谱。
具体实施方式
为了使本发明所解决的技术问题，技术方案及有益效果更清楚明白，以下将结合实施例对本发明进行进一步详细说明，但并非是对本发明的限制。凡依据本发明公开内容作的任何本邻域的等同替换，均属于本发明的保护范围。
实施例1
将路线一中的关键中间体I 3g（0.0088mol）置于三口瓶之中，加入异丙醇30ml，然后加入S-二苯基脯氨醇1.34g（0.0053mol），加热回流反应30min-1h，冷却反应液至35±2℃，析晶3h，抽滤，滤液用异丙醇洗涤，得到关键中间体I-S-二苯基脯氨醇复盐2.4g，收率43%。
将复盐溶于乙酸乙酯20ml之中，冷却至10-15℃，滴加入稀盐酸调节溶液pH=2-3，搅拌30min，分层，水层用EA萃取至无产品，合并有机层，用饱和食盐水洗涤，干燥浓缩至干，残留物加入甲醇20ml溶解，冷却至10-15℃，滴加入50ml纯化水，搅拌析晶1.5-2h，抽滤，于45℃真空干燥过夜，得到L-苏式-关键中间体I 1.2g，收率40%，手性纯度：98.54%（HPLC检测图谱见附图1）。
实施例2
将路线二中的关键中间体II 3g（0.0059mol）置于三口瓶之中，加入异丙醇30ml，然后加入S-二苯基脯氨醇0.89g（0.00354mol），加热回流反应30min-1h，冷却反应液至30±2℃，析晶3h，抽滤，滤液用异丙醇洗涤，得到关键中间体II-S-二苯基脯氨醇复盐2.07g，收率46%。
将复盐溶于乙酸乙酯20ml之中，冷却至10-15℃，滴加入稀盐酸调节溶液pH=2-3，搅拌30min，分层，水层用EA萃取至无产品，合并有机层，用饱和食盐水洗涤，干燥浓缩至干，残留物加入甲醇20ml溶解，冷却至10-15℃，滴加入50ml纯化水，搅拌析晶1.5-2h，抽滤，于45℃真空干燥过夜，得到L-苏式关键中间体II 1.32g，收率44%，手性纯度：99.35%（HPLC检测图谱见附图2）。
实施例3
将路线三中的关键中间体III 3g（0.0084mol）置于三口瓶之中，加入异丙醇30ml，然后加入S-二苯基脯氨醇1.28g（0.005mol），加热回流反应30min-1h，冷却反应液至45±2℃，析晶3h，抽滤，滤液用异丙醇洗涤，得到关键中间体III-S-二苯基脯氨醇复盐2.19g，收率46%。
将复盐溶于乙酸乙酯20ml之中，冷却至10-15℃，滴加入稀盐酸调节溶液pH=2-3，搅拌30min，分层，水层用EA萃取至无产品，合并有机层，用饱和食盐水洗涤，干燥浓缩至干，残留物加入甲醇20ml溶解，冷却至10-15℃，滴加入50ml纯化水，搅拌析晶1.5-2h，抽滤，于45℃真空干燥过夜，得到L-苏式关键中间体III 1.35g，收率45%，手性纯度：99.68%（HPLC检测图谱见附图3）。
实施例4-12
按照实施例1-3所述方法，变换拆分溶剂，溶剂用量，拆分剂用量及析晶温度，所得的L-目标产物收率及手性纯度概括入下表：
注：1、表格中的拆分剂用量指：拆分剂比拆分原料的摩尔倍数；
2、表格中的溶剂量指：采用的溶剂体积（ml）与所要拆分原料的重量（g）的比值。
Claims (7)
1.屈昔多巴苏式关键中间体III的拆分方法，其特征在于在有机溶剂中，采用S-二苯基脯氨醇为拆分剂，回流反应，冷却析晶，得到关键中间体III复盐，然后在酸性条件下游离得到L-苏式-关键中间体III, 其反应式如下：
2.如权利要求1所述的拆分方法，其特征在于拆分使用的有机溶剂选自乙醇、甲醇、异丙醇、正丁醇，正戊醇、四氢呋喃、乙酸乙酯、甲苯、二氯甲烷、氯仿、DMF中的一种或多种按任意比例的混合。
3.如权利要求2所述的拆分溶剂，其特征在于优选异丙醇、正丁醇、乙酸乙酯中的一种或多种按任意比例的混合。
4.如权利要求2所述的拆分溶剂，其特征在于溶剂用量为每1g关键中间体III所用溶剂体积为10-20ml。
5.如权利要求1所述的拆分方法，其特征在于拆分剂摩尔用量为关键中间体III摩尔量的0.6-1.0倍。
6.如权利要求1所述的拆分方法，其特征在于拆分剂摩尔用量优选为关键中间体III摩尔量的0.6-0.7倍。
7.如权利要求1所述的拆分方法，其特征在于析晶温度为25-45℃。
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| EP0084928B1 (en) * | 1982-01-14 | 1985-09-11 | Sumitomo Chemical Company, Limited | Process for producing threo-3-(3,4-dihydroxyphenyl)serine |
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