CN106588804B - 一种作为类法尼醇x受体(fxr)的化合物的制备方法 - Google Patents
一种作为类法尼醇x受体(fxr)的化合物的制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本申请公开了一种由如下化学式1表示的化合物的制备方法，该制备方法是平行路线，相对总收率更高，且反应前后的反应物和产物的结构差别较大，极性相也较大，因此更加容易纯化，原料成本相对也更加经济。
Description
技术领域
本发明涉及化学合成领域，具体而言，涉及一种作为类法尼醇X受体(FXR)的化合物的制备方法。
背景技术
类法尼醇X受体(FXR)是一种细胞核激素受体(当指的是人类受体时也常称为NR1H4)，属孤儿核受体家族。胆汁酸和类法尼醇(farnesoid)都是FXR的配体。FXR在调节胆固醇化合物中起重要作用，其作用机理与许多基因的调控有关。从印度香胶树中发现的天然产物guggul固醇(GS)是一种FXR拮抗剂，具有很好的降脂作用。研究天然产物与FXR等细胞核受体的关系将会发现更多类似GS的降脂化合物。例如如下化学式1表示的化合物就是非常受到关注的NR1H4化合物(CAS:1268246-14-5)。
化学式1
在现有技术WO2011/020615A1中公开了一种该化合物的制备方法，该制备方法如下进行：
然而该反应路线为垂直反应路线，即逐步依次合成化合物，其总收率相对不高，并且步骤4后的终产物含有未反应完全的原料，而未反应完全的原料因与产物结构相似且极性相差不大，难以分离纯化。因此造成该工艺效率底下。因此仍然需要开发更为高效的合成工艺路线。
发明内容
针对上述现有技术的问题，根据本发明的一个方面，提供了一种新颖的由化学式1表示的NR1H4化合物的合成方法，所述方法如下反应式进行：
步骤1：化合物B的制备
将化合物A，乙烯基硼酸酯和碱1’加入无水有机溶剂1’中，氮气保护下加入催化剂1’。反应升至60-100℃反应1-20小时，反应冷却至室温并过滤。滤液再用饱和氯化钠溶液洗涤干燥过滤得到粗品。柱层析纯化得到黄色固体化合物B，
其中化合物A中的取代基X为卤素原子，优选为I，Br或Cl，进一步优选为Br；
步骤2：化合物C的制备
在反应器中加入化合物B，用乙醚溶解，加入催化剂2’。体系N2置换，-40至-10℃下，滴加重氮甲烷(CH2N2)的乙醚溶液，滴加完毕，体系自然升至室温，LCMS监控反应，反应结束后，将反应液加入EtOAc，柱层析，得无色液体化合物C。
步骤3：化合物E的制备
在反应器中依次加入化合物D、3-氯-4-溴苯酚、碱2’、N,N’-二甲基甲酰胺(DMF)，40-80℃下搅拌反应过夜，反应结束后，反应液加EtOAc稀释，用水洗涤，干燥，旋干，得固体化合物E，
其中在化合物中的取代基X1为卤素原子，优选为I、Br或Cl，进一步优选为Br。
步骤4：化合物F的制备
在反应器中加入化合物E、化合物C、Cy3P、碱3’和溶剂，体系用N2置换，再加入催化剂3’，体系用N2置换。反应液80-150℃搅拌反应过夜。TLC，LCMS监控反应至原料消失。反应结束后反应液加EtOAc稀释，用水洗涤，干燥，旋干，柱层析得浅黄色起泡固体化合物F。
优选地，步骤1中的所述有机溶剂1’选自苯、甲苯、二甲苯、二氧六环、DMF、THF中的一种或多种，优选为甲苯。反应温度优选为80℃，反应时间优选为1-5小时，更优选为1-3小时，更优选为2小时。催化剂1’选自PdCl2(Dppf)、Pd(PPh3)4、Pd(OAc)2/PCy3、Pd2dba3/xPhos，优选为PdCl2(dppf)。所述碱1’选自碳酸钾、碳酸钠、碳酸铯、磷酸钾、三乙胺(TEA)、DBU中的一种或多种，优选三乙胺。
优选地，步骤2中在-30至-20℃下滴加重氮甲烷(CH2N2)的乙醚溶液，优选为-20℃；所述催化剂2’选自Pd(PPh3)4、PdCl2(dppf)、Pd(OAc)2/PCy3、Pd2dba3/xPhos、Pd2dba3/sPhos，优选为Pd(OAc)2/PCy3。
优选地，步骤3中所述碱2’与步骤1中的碱1’可以相同或不同，优选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、钠氢、三乙胺、DBU、二异丙基乙胺，优选碳酸钾。步骤3中所述反应优选在60℃下搅拌反应过夜。
优选地，步骤4中所述溶剂为有机溶剂2’与无机溶剂的混合物，所述有机溶剂2’可以与步骤1中所述有机溶剂1’可以相同或不同，优选自苯、甲苯、二甲苯、二氧六环、四氢呋喃、DMF中的一种或多种，优选为甲苯，所述无机溶剂为水；所述有机溶剂与无机溶剂的体积比为10:1至1:1，优选为8:1至2:1，更优选为5:1。反应液优选在90-140℃搅拌反应过夜，更优选为110℃。步骤4中所述催化剂3’选自Pd(PPh3)4、PdCl2(dppf)、Pd(OAc)2/PCy3、Pd2dba3/xPhos、Pd2dba3/sPhos，优选为Pd(OAc)2/PCy3。所述碱3’与步骤1中的碱1’可以相同或不同，优选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、钠氢、磷酸钠、磷酸氢钠、磷酸钾、磷酸氢钾、三乙胺、DBU、二异丙基乙胺，优选为磷酸钾。
有益效果
根据本发明的制备方法是平行路线，相对总收率更高；并且步骤4中反应前后的反应物和产物的结构差别较大，极性相也较大，因此更加容易纯化，原料成本相对也更加经济(化合物D需求量更少)；此外，可衍生的化合物结构更加灵活。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
以下实施例仅是作为本发明的实施方案的例子列举，并不对本发明构成任何限制，本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明，以下实施例中所用的试剂和仪器均为市售可得产品和实验室常规仪器。
实施例1
步骤1：化合物B的制备
化合物A(18.2g)乙烯基硼酸频哪醇酯(13.3g)和三乙胺(TEA)(23.5mL)在无水甲苯(200mL)中，氮气保护下加入催化剂PdCl2(Dppf)(0.5g)。反应升至80℃反应2小时。反应冷却至室温并过滤。滤液再用饱和氯化钠溶液(brine)洗涤干燥过滤得到粗品。柱层析纯化得到9.2g黄色固体化合物B，收率为37％。
步骤2：化合物C的制备
重氮甲烷(CH2N2)的制备：
在1L三口瓶中加入KOH(27g，0.5mol)，水(50mL)，乙二醇单甲醚(150mL)，体系搭常压蒸馏装置，升温70℃，滴加N-甲基-N-亚硝基对甲苯磺酰胺(103g，0.5mol)的乙醚溶液(500mL)，边滴加边有浅黄色组分蒸出，接收瓶用干冰/乙醇浴冷却。得浅黄色液体约400mL(约1M)。溶液直接用于下一步反应。
在500mL三口瓶中加入化合物B(4.6g，16mmol)，用乙醚(20mL)溶解，加入醋酸钯(0.5g)。体系N2置换，-20℃下，滴加重氮甲烷的乙醚溶液(320mL，1M)，滴加完毕，体系自然升至室温，LCMS监控反应。后处理：反应液加入EtOAc(100mL)，柱层析，得无色液体4g化合物C，收率：83％。
LCMS(M+H):303.2
1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),3.88(s,3H),2.14-2.11(m,1H),1.28-1.17(m,13H),1.09-1.00(m,1H),0.45-0.33(m,1H).
步骤3：化合物E的制备
在100mL单口瓶中依次加入化合物D(0.9g，3.0mmol)(按照文献WO2011/020615A1中公开的方法获得)、3-氯-4-溴苯酚(0.62g，3.0mmol)、K2CO3(0.62g，4.5mmol)、DMF(12mL)，反应液60℃搅拌反应过夜。后处理：反应液加EtOAc(40mL)稀释，用水洗涤(30mL×3)，干燥，旋干，得固体1.3g化合物E，收率：93％。
步骤4：化合物F的制备
在100mL单口瓶中加入化合物E(1.3g，2.7mmol)、化合物C(0.82g，2.7mmol)、Cy3P(0.3g，1.08mmol)、K3PO4(2.3g，10.8mmol)、甲苯/水(20mL/4mL)，体系用N2置换3次，再加入醋酸钯(0.12g，0.54mmol)，体系用N2置换3次。反应液110℃搅拌反应过夜。TLC，LCMS监控反应至原料消失。后处理：反应液加EtOAc(40mL)稀释，用水洗涤，干燥，旋干，柱层析得浅黄色起泡固体1.1g化合物F，CP>95％，收率：70％。
LCMS(M+H)：568.1
1H NMR(400 MHz,CDCl3)δ7.96(d,J＝8.4 Hz,2H),7.42-7.38(m,2H),7.34-7.30(m,1H),7.21(d,J＝8.4 Hz,2H),7.02-6.90(m,1H),6.82(t,J＝6.6 Hz,1H),6.65(dd,J＝8.4,2.6 Hz,1H),4.76(s,2H),3.89(s,3H),2.39-2.35(m,1H),2.17-2.14(m,1H),2.13-2.00(m,1H),1.31-1.25(m,4H),1.21-1.11(m,2H).
Claims (18)
1.一种由化学式1表示的NR1H4化合物的制备方法，所述方法如下反应式进行：
步骤1：化合物B的制备
将化合物A，乙烯基硼酸酯和碱1’加入甲苯中，氮气保护下加入PdCl2(dppf)，反应升至60-100℃反应1-20小时，反应冷却至室温并过滤，滤液再用饱和氯化钠溶液洗涤干燥过滤得到粗品，柱层析纯化得到黄色固体化合物B，
其中化合物A中的取代基X为卤素原子，
所述碱1’选自碳酸钾、碳酸钠、碳酸铯、磷酸钾、三乙胺、DBU中的一种或多种；
步骤2：化合物C的制备
在反应器中加入化合物B，用乙醚溶解，加入Pd(OAc)2，体系N2置换，-40至-10℃下，滴加重氮甲烷(CH2N2)的乙醚溶液，滴加完毕，体系自然升至室温，LCMS监控反应，反应结束后，将反应液加入EtOAc，柱层析，得无色液体化合物C；
步骤3：化合物E的制备
在反应器中依次加入化合物D、3-氯-4-溴苯酚、碱2’、N,N’-二甲基甲酰胺(DMF)，40-80℃下搅拌反应过夜，反应结束后，反应液加EtOAc稀释，用水洗涤，干燥，旋干，得固体化合物E，
其中所述碱2’选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、钠氢、三乙胺、DBU或二异丙基乙胺；
步骤4：化学式1表示的化合物的制备
在反应器中加入化合物E、化合物C、Cy3P、碱3’和溶剂，体系用N2置换，再加入催化剂3’，体系用N2置换，反应液80-150℃搅拌反应过夜，TLC，LCMS监控反应至原料消失，反应结束后反应液加EtOAc稀释，用水洗涤，干燥，旋干，柱层析得浅黄色起泡固体由化学式1表示的NR1H4化合物，
其中所述溶剂为有机溶剂2’与无机溶剂的混合物，所述有机溶剂2’选自苯、甲苯、二甲苯、二氧六环、四氢呋喃、DMF中的一种或多种，所述无机溶剂为水；
所述催化剂3’选自Pd(PPh3)4、PdCl2(dppf)或醋酸钯；所述碱3’选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、钠氢、磷酸钠、磷酸钾、三乙胺、DBU或二异丙基乙胺。
2.根据权利要求1所述的制备方法，其特征在于，所述化合物A中的取代基X为I，Br或Cl。
3.根据权利要求1所述的制备方法，其特征在于，所述化合物A中的取代基X为Br。
4.根据权利要求1所述的制备方法，其特征在于，步骤1中反应温度为80℃，反应时间为1-5小时。
5.根据权利要求1所述的制备方法，其特征在于，步骤1中反应温度为80℃，反应时间为1-3小时。
6.根据权利要求1所述的制备方法，其特征在于，步骤1中所述反应时间为2小时。
7.根据权利要求1所述的制备方法，其特征在于，步骤1中所述碱1’为三乙胺。
8.根据权利要求1所述的制备方法，其特征在于，步骤2中在-30至-20℃下滴加重氮甲烷(CH2N2)的乙醚溶液。
9.根据权利要求1所述的制备方法，其特征在于，步骤2中在-20℃下滴加重氮甲烷(CH2N2)的乙醚溶液。
10.根据权利要求1所述的制备方法，其特征在于，步骤3中所述反应在60℃下搅拌反应过夜。
11.根据权利要求1所述的制备方法，其特征在于，步骤3中所述碱2’为碳酸钾。
12.根据权利要求1所述的制备方法，其特征在于，步骤4中所述有机溶剂2’与无机溶剂的体积比为10:1至1:1。
13.根据权利要求1所述的制备方法，其特征在于，步骤4中所述反应液在90-140℃搅拌反应过夜。
14.根据权利要求1所述的制备方法，其特征在于，步骤4中所述有机溶剂2’为甲苯。
15.根据权利要求1所述的制备方法，其特征在于，步骤4中所述有机溶剂2’与无机溶剂的体积比为8:1至2:1。
16.根据权利要求1所述的制备方法，其特征在于，步骤4中所述有机溶剂2’与无机溶剂的体积比为5:1。
17.根据权利要求1所述的制备方法，其特征在于，步骤4中所述反应液在110℃搅拌反应过夜。
18.根据权利要求1所述的制备方法，其特征在于，步骤4中所述碱3’为磷酸钾。
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Denomination of invention: Preparation method of compound serving as farnesoid X receptor (FXR) Effective date of registration: 20190711 Granted publication date: 20181109 Pledgee: Pudong Shanghai technology financing Company limited by guarantee Pledgor: All create (Shanghai) Pharmaceutical Technology Co., Ltd Registration number: 2019310000039 |
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