CN118047802A - 氮杂螺环类化合物、其中间体及其制备方法 - Google Patents
氮杂螺环类化合物、其中间体及其制备方法 Download PDFInfo
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及氮杂螺环类化合物、其中间体及其制备方法。本发明方法克服了现有技术中存在的缺陷,所得产物纯度好、收率高、工艺可操作性强,工艺安全性高,且可工业化生产。
Description
技术领域
本发明属于化学医药领域,具体涉及氮杂螺环类化合物、其中间体及其制备方法。
背景技术
Suzuki偶联反应是一个工业中常用于构建碳-碳键的有机偶联反应,反应是在零价钯配合物催化下,芳基或烯基硼酸或硼酸酯与氯、溴、碘代芳烃或烯烃发生交叉偶联。该反应由铃木章在1979年首先报道,在有机合成中的用途很广,具有较强的底物适应性及官能团容忍性,常用于合成多烯烃、苯乙烯和联苯的衍生物,从而应用于众多天然产物、有机材料的合成中。
其中,经典合成单取代芳基硼酸的方法是用格氏试剂或锂试剂和硼酸酯反应来制备。用这种经典方法的缺点是单取代芳基硼酸酯有进一步生成二取代硼酸,甚至三烷基硼的可能,因此反应须在低温下进行。解决这个问题的一个有效的办法是使用硼酸三异丙酯和有机锂试剂反应;可以避免二烷(芳)基硼烷和三烷(芳)基硼烷的产生。反应完后通常加入稀盐酸酸化直接高收率地得到芳基硼酸。然而,对于分子中带有酯基、氰基、硝基、羰基等官能团的芳香卤代物来说,无法通过有机金属试剂来制备相应的芳基硼酸。GaryA.Molander于2012年报道了以四羟基二硼为硼化试剂,在钯催化条件下完成芳基硼酸的制备。(J.Am.Chem.Soc.2012,134,11667-11673)
发明内容
为了解决现有技术中存在的问题,本发明提供一种医药制备中间体及其制备方法。
具体而言,本发明提供一种式(II)化合物及其药学上可接受的盐:
R1,R2和R3选自氘、卤素、氢、羟基、C1-3烷基,优选氘。
本发明还提供制备式(II)化合物及其药学上可接受的中间体,其特征在于如式(I)化合物所示:
R1,R2和R3选自氘、卤素、氢、羟基、C1-3烷基,优选氘;
X选自卤素和三氟甲磺酸酯,优选Br。
本发明还提供制备式(II)或式(I)化合物的中间体,其特征在于如式(A)所示:
R1,R2和R3选自氘、卤素、氢、羟基、C1-3烷基,优选氘;X选自卤素和三氟甲磺酸酯,优选Br。
本发明还提供制备式(II)化合物的方法,其特征在于,包括步骤b:
所述硼酸化是在催化剂存在下进行的;
优选地,所述催化剂试剂选自氯[(三环己基膦)-2-(2-氨基联苯)]钯(II)和三环己基膦体系,2-双环己基膦-2',4',6'-三异丙基联苯和氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)体系,二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II),优选2-双环己基膦-2',4',6'-三异丙基联苯和氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)体系;
优选地,所述催化剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II):2-双环己基膦-2',4',6'-三异丙基联苯的用量配比为1:2;
优选地,所述催化试剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)的质量占式(I)化合物的质量百分比为0.1%~0.5%,优选0.175%;2-双环己基膦-2',4',6'-三异丙基联苯的质量占式(I)化合物的质量百分比为0.2%~0.7%,优选0.35%。
优选地,所述催化试剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)占式(I)化合物游离态的质量百分比为0.1%~0.5%,优选0.25%;2-双环己基膦-2',4',6'-三异丙基联苯占式(I)化合物游离态的质量百分比为0.2%~0.7%,优选0.5%。
优选地,所述反应还需要加入碱,选自N,N-二异丙基乙胺、三乙胺、N-甲基吗啉或乙酸钾,优选N,N-二异丙基乙胺。
优选地,所述反应溶剂为甲醇、乙醇、2甲基-四氢呋喃或丙酮中的一种或多种试剂,优选甲醇和丙酮的组合。
本发明还提供制备式(I)化合物的方法,包括步骤a:
优选地,所述反应是在碱和四丁基氯化铵,四丁基碘化铵,四丁基硫酸氢铵存在下进行的,
优选地,所述碱为氢氧化钠、氢氧化钾;
优选地,所述有机反应溶剂为二氯甲烷,乙酸乙酯,甲苯,醋酸异丙酯,优选甲苯;
优选地,所述酸选自酒石酸,樟脑磺酸,对甲苯磺酸,HCl(二氧六环)溶液,草酸,更优选草酸。
本发明通过探索新的反应中间体,以及催化剂的使用,避免了柱层析的后处理过程,实现了反应工艺的工业化生产。通过使用新的催化剂体系,降低了催化剂用量,反应体系干净,并且后续处理简单,避免柱层析和降低成本。
具体实施方式
下面结合实施例对本发明做进一步详细、完整地说明,但决非限制本发明,本发明的保护与公开范围并非仅局限于实施例的内容。
实施例1II-a化合物的制备
将60g中间体I-a用乙酸乙酯(210mL)和水(126mL)溶解。控制内温低于30℃,滴加20%氢氧化钠水溶液调节pH=7~8,控制内温25-35℃搅拌0.5-1.0小时;过滤,滤饼用乙酸乙酯(50mL)浸泡洗涤,抽干,滤液分层,水相用乙酸乙酯(50mL)萃取一次,合并有机相;所得有机相用饱和食盐水(126mL*2)洗两次,无水硫酸钠干燥;过滤,低于45℃减压浓缩至干,反应釜中依次加入I-a游离态(42g),四羟基二硼(22.3g),N,N-二异丙基乙胺(38.2g),甲醇(420mL),丙酮(168mL)氮气置换;加入2-双环己基膦-2',4',6'-三异丙基联苯(0.21g),氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)2(0.105g);升温至40℃,反应5h;降温至10-20℃;控温不超过20℃,加入乙酸乙酯和半饱和食盐水,搅拌2-5分钟,分出水相;再次加入半饱和食盐水,搅拌2-5分钟,分出水相,饱和氯化钠水溶液洗涤,分液;有机相干燥浓缩至干得32.8g棕黑色固体(收率85%,纯度90%)。
MS m/z(ESI):389.4[M+H]+;1H NMR(400MHz,CDCl3)δ7.32(t,J=7.5Hz,1H),7.27(d,J=7.7Hz,1H),7.16(s,1H),7.07(dt,J=7.4,1.5Hz,1H),4.50(s,2H),3.54(q,J=7.0Hz,2H),2.35-2.27(m,2H),2.07-1.92(m,6H),1.83(dd,J=7.1,4.7Hz,3H),1.62-1.52(m,2H),1.33(dd,J=15.0,7.4Hz,2H),1.26(dd,J=11.1,4.1Hz,3H),0.87(t,J=7.3Hz,3H).
实施例2中间体I-a的制备
开启反应釜搅拌,加入氢氧化钠(13g),水(30mL),搅拌溶清,降温至15~25℃;加入甲苯(126mL),B(29.8g)和四丁基氯化铵(1.8g),搅拌10-20分钟;将A-a(42g)和甲苯(126mL)加入反应体系中;保持内温25~35℃反应2~3小时;垫硅藻土,过滤,乙酸乙酯洗涤滤饼;反应液中加入水,搅拌5-10分钟静置分层,留置有机相;有机相用饱和食盐水洗两次,无水硫酸钠干燥;过滤,用乙酸乙酯洗涤滤饼;将无水草酸和乙酸乙酯加入所得有机相中;加热至60~70℃搅拌溶清,溶清后搅拌1~2小时;氮气保护下缓慢降温,保持内温-5~5℃搅拌2-4小时;抽滤,滤饼用冰的乙酸乙酯淋洗;滤饼在45~55℃真空干燥至恒重,得到I-a约66g白色固体,(收率84.6%,纯度98%)。
MS m/z(ESI):423.2[M+H]+;1H NMR(400MHz,CDCl3)δ7.48(d,J=8.2Hz,1H),7.34-7.17(m,1H),6.93(dd,J=8.2,2.3Hz,1H),4.52(s,2H),3.60(q,J=7.0Hz,2H),2.40-2.22(m,2H),2.13-1.89(m,6H),1.81(td,J=6.4,1.9Hz,3H),1.64-1.45(m,2H),1.41-1.20(m,5H),0.87(t,J=7.3Hz,3H)。
Claims (8)
1.一种式(II)化合物及其药学上可接受的盐:
R1,R2和R3选自氘、卤素、氢、羟基、C1-3烷基,优选氘。
2.制备权利要求1所述化合物及其药学上可接受的中间体,其特征在于如式(I)化合物所示:
R1,R2和R3的定义与权利要求1相同;
X选自卤素和三氟甲磺酸酯,优选Br。
3.制备权利要求1所述式(II)化合物或权利要求2所述式(I)化合物的中间体,其特征在于如式(A)所示:
R1,R2和R3的定义与权利要求1相同;X的定义与权利要求2相同。
4.制备权利要求1所述式(II)化合物的方法,其特征在于,包括步骤b:
所述硼酸化是在催化剂存在下进行的;
优选地,所述催化试剂选自氯[(三环己基膦)-2-(2-氨基联苯)]钯(II)和三环己基膦体系、2-双环己基膦-2',4',6'-三异丙基联苯和氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)体系、二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II),优选2-双环己基膦-2',4',6'-三异丙基联苯和氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)体系;
优选地,所述反应还需要加入碱,选自N,N-二异丙基乙胺、三乙胺、N-甲基吗啉或乙酸钾,更优选N,N-二异丙基乙胺;
优选地,所述反应溶剂选自甲醇、乙醇、2甲基-四氢呋喃或丙酮中的一种或多种试剂,更优选甲醇和丙酮的组合。
5.根据权利要求4所述制备式(II)化合物的方法,其特征在于,所述催化试剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II):2-双环己基膦-2',4',6'-三异丙基联苯的用量配比为1:2。
6.根据权利要求4所述制备式(II)化合物的方法,其特征在于,所述催化试剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)的质量占式(I)化合物的质量百分比为0.1%~0.5%,优选0.175%;2-双环己基膦-2',4',6'-三异丙基联苯的质量占式(I)化合物的质量百分比为0.2%~0.7%,优选0.35%。
7.根据权利要求4所述制备式(II)化合物的方法,其特征在于,所述催化试剂氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)占式(I)化合物游离态的质量百分比为0.1%~0.5%,优选0.25%;2-双环己基膦-2',4',6'-三异丙基联苯占式(I)化合物游离态的质量百分比为0.2%~0.7%,优选0.5%。
8.制备权利要求2所述式(I)化合物的方法,包括步骤a:
优选地,所述反应是在碱和四丁基氯化铵存在下进行的,
优选地,所述碱为氢氧化钠、氢氧化钾;
优选地,所述有机反应溶剂选自二氯甲烷、乙酸乙酯、甲苯、醋酸异丙酯中的一种或多种,优选甲苯;
优选地,所述酸选自酒石酸、樟脑磺酸、对甲苯磺酸、HCl(二氧六环)溶液、草酸,优选草酸。
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