CN115557900B - 一种3-取代哒嗪衍生物的合成方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/12—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
本发明属于有机化工医药领域,涉及一种3‑取代哒嗪衍生物的合成方法。本发明以哒嗪‑3‑酮衍生物、芳基重氮化合物为原料,铑盐作为催化剂,再加入适量的溶剂,密封充氩气反应,在室温附近反应一定时间,反应结束后减压蒸去溶剂,产物经硅胶柱层析或重结晶分离得到目标产物;实现了3‑取代哒嗪衍生物的合成。本方法优点有:原料易得、底物适应性广、反应操作简单、反应效率高、原子经济性高,较符合绿色化学的要求。
Description
技术领域
本发明属于有机化工医药领域,涉及一种以哒嗪-3-酮衍生物和芳基重氮化合物为原料,金属铑盐为催化剂合成3-位是季碳中心取代的哒嗪衍生物。
背景技术
哒嗪是存在于许多已知药物或者新合成具有特殊生物药物活性先导分子中的关键母核(Chang,Y.,et al.J.Med.Chem.2019,62,8951–8952.Lu,Y.,etal.J.Med.Chem.2021,64,15214–15249.)。鉴于3-或6-取代哒嗪广泛分布于生物分子中(Chelini,A.,et al.M.J.Med.Chem.2017,60,5216–5221.Chelini,A.,etal.J.Med.Chem.2017,60,5216–5221.),具有非常特殊的生物活性,开发合成结构更复杂哒嗪衍生物的新方法,是其可被用于进一步进行高效药物筛选的前提。
取代哒嗪衍生物的合成最常用的方法主要是[4+2]环化反应(Wu,Q.,et al.RSCAdv.2019,9,21507-21512.Gao,Q.,et al.J.Org.Chem.2012,77,9865-9870.),该方法在合成出具有不同取代基的哒嗪衍生物方面已经取得了很大的成就。除此之外,也可以利用aza-Diels-Alder反应制备具有高区域选择性的取代吡嗪衍生物(Takayuki K.,etal.J.Org.Chem.2021,86,8926-8932),该方法具有很好的官能团相融性。尽管合成取代哒嗪衍生物的方法已经有很多,在常用的哒嗪原料上发生杂环环上的取代反应,实现3-烷基取代哒嗪的直接构建3-季碳中心难以实现。而哒嗪酮有两个氮,在3-位通过重排反应,存在选择性困难,直接引入季碳中心的方法目前还没有。
发明内容
针对背景技术中的问题,本发明提供了一种以哒嗪-3-酮衍生物和芳基重氮化合物为原料,金属铑盐为催化剂合成3-取代哒嗪衍生物的方法。本发明以哒嗪-3-酮衍生物和芳基重氮化合物为原料,在Rh的催化下,形成铑卡宾,进一步插入C=O后形成叶立德、随后进行环氧化和分子内重排,实现了使用廉价易得的原料合成3-位是季碳中心取代的哒嗪衍生物,该方法具有原料易得、底物适应性广、反应操作简单、反应效率高、原子经济性高等优点,较符合绿色化学的要求。特别是当使用手性铑催化剂时,可以得到具有中等对映选择性的手性3-取代哒嗪衍生物,极大的丰富了3-取代哒嗪衍生物的结构,高效构造该类结构的候选药物筛选分子库。
为了实现上述技术目的,采用的技术方案为:
本发明涉及一种3-取代的哒嗪衍生物的合成方法。反应首先加入哒嗪-3-酮衍生物,芳基重氮化合物以及铑催化剂,再加入适量的溶剂并用氩气保护,在20℃-35℃下反应15~60分钟,待反应结束后减压蒸去溶剂,以硅胶吸附,通过柱层析或混合溶剂重结晶分离得到目标产物;实现了以哒嗪-3-酮衍生物、芳基重氮化合物为原料,以铑盐为催化剂合成在3-位引入了季碳中心的3-取代哒嗪衍生物。所有产物其结构经1H NMR、13C NMR、HRMS和熔点确证。该反应投料的方式简便,底物适应性较广。
反应后用柱色谱分离方法提纯,以石油醚与乙酸乙酯的混合溶剂为洗脱剂或者以乙酸乙酯/石油醚体系为重结晶溶剂,对产物进行提纯以得到纯净的具有3-取代哒嗪衍生物产物。
具有3-取代哒嗪衍生物合成方法为:
所用的铑催化剂包括:Rh2(OAc)4、Rh2(PTTL)4、Rh2(esp)2、Rh2(Oct)4、Rh2(OPiv)4、Rh2(S-TFPTTL)4,其用量为哒嗪-3-酮衍生物摩尔数的0.5~2%,其中最佳催化剂为Rh2(OAc)4,最佳用量为哒嗪-3-酮化合物摩尔数的1%。
哒嗪-3-酮衍生物为下述结构:
芳基重氮化合物包括下述结构:
芳基重氮化合物的用量为哒嗪-3-酮衍生物用量的1~2.5当量。
先加入哒嗪-3-酮衍生物、芳基重氮化合物以及铑催化剂,再加入适量的溶剂,密封充氩气保护,在20℃-35℃下反应15~60分钟,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到产物,或者用EA/PE体系进行重结晶提纯。
所述反应溶剂为有机溶剂。具体的有机溶剂为二氯甲烷、正己烷、乙腈、乙醚、氯仿、甲苯、四氢呋喃、1,2-二氯乙烷中的一种。
哒嗪-3-酮衍生物在溶剂中的浓度为0.05~0.2mol/L。
本发明通过对哒嗪-3-酮衍生物和芳基重氮化合物为原料的结构设计,细致的反应条件筛选,在Rh的催化下合成了全新的3-取代哒嗪衍生物,可以高效在3-位引入了季碳中心,极大的丰富了3-取代哒嗪衍生物的结构。
有益效果:
1).反应原料易得,容易制备。
2).反应条件较为温和,特别是反应时间较短,效率高。
3).底物适应性广,产率中等至较高,部分产物有中等的对映选择性,高效在3-位引入了季碳中心,甚至手性季碳中心,极大的丰富了3-取代哒嗪衍生物的结构,为进一步的哒嗪衍生物药物筛选提供了分子库。
附图说明
图1为实施例1得到的3aa的1H-NMR(核磁氢谱);
图2为实施例1得到的3aa的13C-NMR(核磁碳谱);
图3为实施例1得到的3aa的HRMS(高分辨质谱)。
具体实施方式
下面结合实施例对本发明做进一步描述,但不限于此。
实施例1
向50ml反应管中加入3-羟基-6-氯哒嗪492mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1a 782mg,收率85%;m.p.70-72℃;1H NMR(300MHz,CDCl3)δ7.19(d,J=9.9Hz,1H),6.93(d,J=9.9Hz,1H),1.63(s,9H).13C NMR(75MHz,CDCl3)δ157.0,148.9,138.4,134.5,134.0,87.2,27.6.HRMS(ESI)m/z:[M+Na]+Calcd for C9H11ClN2NaO3253.0350;Found 253.0349.
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 68.9mg,收率82%;m.p.:135-137℃;1HNMR(400MHz,CDCl3)δ7.93(d,J=9.2Hz,1H),7.53-7.44(m,2H),7.40(d,J=9.2Hz,1H),7.37-7.28(m,3H),1.54(s,9H),1.51(s,9H).13C NMR(100MHz,CDCl3)δ167.4,159.5,156.2,152.1,137.3,130.0,128.8,128.7,127.5,126.2,84.4,83.9,83.6,27.8.HRMS(ESI)m/z:[M+H]+Calcd for C21H26ClN2O5421.1525;Found 421.1529.
实施例1-1
放大反应:向100ml反应管中依次加入哒嗪-3-酮衍生物1a 690.0mg(3.0mmol),苯基重氮甲酯2a 1.31g(6.0mmol),随后加入催化剂Rh2(OAc)413.3mg(0.03mmol),60mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,重结晶纯化得到白色固体3aa 1.02g,收率81%。放大反应效果较好,拥有一定的工业生产价值。
实施例2
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(PTTL)42.4mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 26.9mg,收率32%。
实施例3
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(esp)21.5mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 57.1mg,收率68%。
实施例4
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(Oct)41.4mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 58.8mg,收率70%。
实施例5
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a65.4mg(0.3mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 17.6mg,收率21%。
实施例6
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.44mg(0.001mmol),4mL DCM。密封充氩气反应。反应在30℃下反应1h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 24.4mg,收率29%。
实施例7
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)41.76mg(0.004mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 47.1mg,收率56%。
实施例8
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL正己烷。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 36.1mg,收率43%。
实施例9
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL乙醚。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3aa 15.1mg,收率18%。
实施例10
向50ml反应管中加入3-羟基-6-溴哒嗪776mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1b 630mg,收率63%;m.p.:52-54℃;1H NMR(400MHz,CDCl3)δ7.25(d,J=9.6Hz,1H),6.82(d,J=9.6Hz,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ156.9,149.0,137.2,133.6,127.5,87.2,27.6.HRMS(ESI)m/z:[M+Na]+Calcd for C9H11BrN2NaO3296.9845;Found 296.9847.
向反应管中依次加入哒嗪-3-酮衍生物1b 54.8mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ba 81.7mg,收率88%;m.p.:158-160℃;1HNMR(300MHz,CDCl3)δ7.81(d,J=9.0Hz,1H),7.54(d,J=9.0Hz,1H),7.51-7.42(m,2H),7.38-7.24(m,3H),1.54(s,9H),1.51(s,9H).13C NMR(75MHz,CDCl3)δ167.3,159.7,152.1,147.7,137.2,130.8,129.7,128.8,128.7,126.2,84.4,83.9,83.6,27.8.HRMS(ESI)m/z:[M+H]+Calcd for C21H26BrN2O5465.1020,Found 465.1022.
实施例11
向50ml反应管中加入3-羟基-5,6-二氯哒嗪656mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1c528mg,收率50%;m.p.:79-81℃;1H NMR(400MHz,CDCl3)δ7.12(s,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ156.2,148.2,140.4,137.4,131.2,87.7,27.6.HRMS(ESI)m/z:[M+Na]+Calcd for C9H10Cl2N2NaO3286.9961;Found 286.9959.
向反应管中依次加入哒嗪-3-酮衍生物1c 52.8mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到黄色油3ca66.3mg,收率73%;1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.56-7.44(m,2H),7.40-7.28(m,3H),1.54(s,9H),1.51(s,9H).13C NMR(100MHz,CDCl3)δ167.2,160.1,154.8,152.1,137.0,136.9,129.4,129.0,128.9,126.0,84.2,83.9,83.8,27.7.HRMS(ESI)m/z:[M+H]+Calcd for C21H25Cl2N2O5455.1135;Found455.1138.
实施例12
向50ml反应管中加入3-羟基-6-氯哒嗪1.0g(7.7mmol),二甲氨基甲酰氯1.65g(15.4mmol),K2CO32.7 g(19.3mmol),nBu4NHSO426.2 mg(0.077mmol),20mL DCM,反应在室温下反应24h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1d 870mg,收率56%;m.p.:68-70℃;1H NMR(300MHz,CDCl3)δ7.63(d,J=9.0Hz,1H),7.46(d,J=9.0Hz,1H),3.17(s,3H),3.04(s,3H).13C NMR(75MHz,CDCl3)δ161.4,154.4,152.7,131.0,124.5,36.8,36.7.HRMS(ESI)m/z:[M+H]+Calcd forC7H9ClN3O 202.0378;Found 202.0378.
向反应管中依次加入哒嗪-3-酮衍生物1d 40.2mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到黄色油3da29.7mg,收率38%;1H NMR(400MHz,CDCl3)δ7.44-7.33(m,5H),7.18(d,J=9.6Hz,1H),6.95(d,J=9.6Hz,1H),3.01(s,3H),2.48(s,3H),1.53(s,9H).13C NMR(100MHz,CDCl3)δ165.1,163.7,159.7,136.2,133.8,132.3,132.2,129.4,128.7,128.1,84.0,82.2,39.4,37.7,27.8.HRMS(ESI)m/z:[M+H]+Calcd forC19H23ClN3O4392.1372;Found 392.1373.
实施例13
向50ml反应管中加入3-羟基-6-碘哒嗪888mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到黄色油状物1e 219mg,收率17%;1H NMR(400MHz,CDCl3)δ7.36(d,J=9.6Hz,1H),6.62(d,J=9.6Hz,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ157.0,142.7,142.0,132.8,131.5,87.2,27.7.HRMS(ESI)m/z:[M+Na]+Calcd for C9H11IN2NaO3344.9707;Found 344.9706.
向反应管中依次加入哒嗪-3-酮衍生物1e 64.4mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ea86.0mg,收率84%;m.p.:186-188℃.1H NMR(300MHz,CDCl3)δ7.74(d,J=9.0Hz,1H),7.60(d,J=9.0Hz,1H),7.52-7.44(m,2H),7.38-7.26(m,3H),1.54(s,9H),1.51(s,9H).13C NMR(100MHz,CDCl3)δ167.3,159.7,152.1,137.3,136.5,128.8,128.7,128.6,126.2,124.7,84.5,83.9,83.6,27.78,27.77.HRMS(ESI)m/z:[M+H]+Calcd for C21H26IN2O5513.0881;Found 513.0885.
实施例14
向50ml反应管中加入3-羟基-6-苯基哒嗪688mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1f588mg,收率54%;m.p.:51-53℃.1H NMR(400MHz,CDCl3)δ7.84-7.78(m,2H),7.67(d,J=9.6Hz,1H),7.48-7.42(m,3H),7.01(d,J=9.6Hz,1H),1.67(s,9H).13C NMR(100MHz,CDCl3)δ158.1,150.4,144.6,134.0,132.2,131.2,130.0,129.0,126.3,86.5,27.7.HRMS(ESI)m/z:[M+Na]+Calcd for C15H16N2NaO3295.1053;Found 295.1054.
向反应管中依次加入哒嗪-3-酮衍生物1f54.4 mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到无色油状物3fa 74.9mg,收率81%;1H NMR(400MHz,CDCl3)δ8.07-7.99(m,3H),7.75(d,J=9.2Hz,1H),7.62-7.54(m,2H),7.51-7.40(m,3H),7.37-7.23(m,3H),1.54(s,9H),1.52(s,9H).13C NMR(75MHz,CDCl3)δ167.6,159.0,158.3,152.2,137.9,136.1,130.0,129.0,128.51,128.47,127.6,127.2,126.3,123.5,84.7,83.5,83.4,27.8.HRMS(ESI)m/z:[M+H]+Calcd for C27H31N2O5463.2227;Found 463.2233.
实施例15
向50ml反应管中加入3-羟基-6-氯哒嗪1.0g(7.7mmol),二乙氨基甲酰氯2.1g(15.4mmol),K2CO32.7 g(19.3mmol),nBu4NHSO426.2 mg(0.077mmol),20mL DCM,反应在室温下反应24h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到无色油状物1g 500mg,收率28%;1H NMR(400MHz,CDCl3)δ7.61(d,J=9.0Hz,1H),7.47(d,J=9.0Hz,1H),3.52(q,J=7.2Hz,2H),3.41(q,J=7.2Hz,2H),1.30(t,J=7.2Hz,3H),1.22(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.5,154.4,152.1,130.9,124.5,42.5,42.3,14.2,13.1.HRMS(ESI)m/z:[M+H]+Calcd forC9H13ClN3O2230.0691;Found 230.0691.
向反应管中依次加入哒嗪-3-酮衍生物1g 45.8mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到黄色油状物3ga 21.8mg,收率26%;1H NMR(400MHz,CDCl3)δ7.41-7.28(m,5H),7.23(d,J=9.6Hz,1H),6.98(d,J=9.6Hz,1H),3.60-3.41(m,1H),3.35-3.16(m,1H),3.01-2.72(m,2H),1.48(s,9H),1.16(t,J=7.2Hz,3H),0.30(t,J=6.8Hz,3H).13C NMR(75MHz,CDCl3)δ165.2,164.0,159.7,136.7,133.9,132.4,132.1,129.1,128.1,127.6,83.6,83.1,42.8,40.5,27.8,11.6,11.2.HRMS(ESI)m/z:[M+H]+Calcdfor C21H27ClN3O4420.1685;Found 420.1684.
实施例16
向50ml反应管中加入3-羟基-6-氯哒嗪1.0g(7.7mmol),1-哌啶酰氯2.3g(15.4mmol),K2CO32.7 g(19.3mmol),nBu4NHSO426.2 mg(0.077mmol),20mL DCM,反应在室温下反应24h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到白色固体1h 800mg,收率43%;m.p.:85-87℃;1H NMR(400MHz,CDCl3)δ7.60(d,J=9.2Hz,1H),7.45(d,J=9.2Hz,1H),3.75-3.61(m,2H),3.59-3.47(m,2H),1.75-1.55(m,6H).13C{1H}NMR(100MHz,CDCl3)δ161.5,154.4,151.5,130.9,124.5,45.9,45.4,25.8,25.4,24.0.HRMS(ESI)m/z:[M+H]+Calcd for C10H13ClN3O2242.0691;Found242.0688.
向反应管中依次加入哒嗪-3-酮衍生物1h 48.2mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到黄色油状物3ha 37.1mg,收率43%;1H NMR(300MHz,CDCl3)δ7.44-7.30(m,5H),7.22(d,J=9.6Hz,1H),6.96(d,J=9.6Hz,1H),3.74-3.47(m,2H),3.00-2.77(m,2H),1.49(s,9H),1.49-1.34(m,4H),1.06-0.87(m,1H),0.80-0.56(m,1H).13C NMR(75MHz,CDCl3)δ164.9,164.2,163.9,159.6,136.4,133.8,132.3,129.2,128.3,127.7,83.7,82.8,48.6,44.8,27.8,25.3,24.1,24.0.HRMS(ESI)m/z:[M+H]+Calcdfor C22H27ClN3O4432.1685;Found 432.1687.
实施例17
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2b94.4mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ab 57.0mg,收率65%;m.p.:132-134℃;1HNMR(300MHz,CDCl3)δ7.95(d,J=9.3Hz,1H),7.57-7.46(m,2H),7.44(d,J=9.0Hz,1H),7.11-6.95(m,2H),1.53(s,9H),1.50(s,9H).13C NMR(75MHz,CDCl3)δ167.1,162.7(d,J=247.5Hz),159.6,156.3,151.9,133.2(d,J=3.8Hz),129.7,128.3(d,J=8.3Hz),127.6,115.6(d,J=21.8Hz),84.0,83.9,83.8,27.7.19F NMR(282MHz,CDCl3)δ-112.8.HRMS(ESI)m/z:[M+H]+Calcd for C21H25ClFN2O5439.1431;Found 439.1434.
实施例18
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2c92.8mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ac 54.7mg,收率63%;m.p.:134-136℃;1HNMR(300MHz,CDCl3)δ7.90(d,J=9.3Hz,1H),7.42-7.31(m,3H),7.13(d,J=8.1Hz,2H),2.30(s,3H),1.54(s,9H),1.51(s,9H).13C NMR(75MHz,CDCl3)δ167.5,159.5,156.1,152.2,138.8,134.4,130.0,129.4,127.4,126.1,84.4,83.8,83.5,27.8,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C22H28ClN2O5435.1681;Found 435.1684.
实施例19
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2d100.8mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ad 69.9mg,收率77%;m.p.:106-108℃;1HNMR(300MHz,CDCl3)δ7.96(d,J=9.2Hz,1H),7.58-7.53(m,1H),7.45(d,J=9.2Hz,1H),7.42-7.35(m,1H),7.31-7.25(m,2H),1.53(s,9H),1.50(s,9H).13C NMR(75MHz,CDCl3)δ166.8,159.4,156.4,151.8,139.1,134.7,129.9,129.6,129.0,127.7,126.6,124.4,84.2,84.0,83.8,27.7.HRMS(ESI)m/z:[M+H]+Calcd for C21H25Cl2N2O5455.1135;Found455.1135.
实施例20
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2e94.4mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ae 64.8mg,收率74%;m.p.:134-136℃;1HNMR(400MHz,CDCl3)δ7.97(d,J=9.2Hz,1H),7.83-7.72(m,1H),7.45(d,J=9.2Hz,1H),7.36-7.28(m,1H),7.22-7.13(m,1H),7.05-6.94(m,1H),1.51(s,9H),1.49(s,9H).13C NMR(100MHz,CDCl3)δ166.2,159.03,159.0(d,J=248.0Hz),156.4,151.7,130.9(d,J=8.0Hz),129.9(d,J=2.0Hz),129.3(d,J=2.0Hz),127.4,125.3(d,J=11.0Hz),124.4(d,J=3.0Hz),116.6,116.4,84.1,83.8,82.4,27.71,27.68.19F NMR(282MHz,CDCl3)δ-110.3.HRMS(ESI)m/z:[M+H]+Calcd for C21H25ClFN2O5439.1431;Found 439.1434.
实施例21
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2f114.4mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3af79.1 mg,收率81%;m.p.:160-162℃;1HNMR(400MHz,CDCl3)δ7.98(d,J=9.1Hz,1H),7.69(d,J=2.0Hz,1H),7.48(d,J=9.1Hz,1H),7.44-7.32(m,2H),1.53(s,9H),1.49(s,9H).13C NMR(75MHz,CDCl3)δ166.4,159.5,156.5,151.6,137.3,133.1,132.9,130.4,129.3,128.5,127.9,125.7,84.4,84.2,83.4,27.7.HRMS(ESI)m/z:[M+H]+Calcd for C21H24Cl3N2O5489.0745;Found 489.0749.
实施例22
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2g100.8mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体3ag 50.0mg,收率55%;m.p.:160-162℃;1HNMR(400MHz,CDCl3)δ7.94(d,J=9.2Hz,1H),7.49-7.43(m,2H),7.41(d,J=9.2Hz,1H),7.36-7.25(m,8H),5.34(d,J=12.4Hz,1H),5.25(d,J=12.4Hz,1H),1.42(s,9H).13C NMR(100MHz,CDCl3)δ168.6,159.4,156.4,152.0,136.8,134.7,129.6,129.0,128.8,128.7,128.54,128.52,127.8,126.2,84.4,84.1,68.2,27.6.HRMS(ESI)m/z:[M+H]+Calcd forC24H24ClN2O5455.1368;Found 455.1369.
实施例23
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2h87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到黄色油3ah73.9mg,收率88%;1H NMR(400MHz,CDCl3)δ7.96(d,J=9.1Hz,1H),7.53-7.46(m,2H),7.43(d,J=9.1Hz,1H),7.38-7.28(m,3H),4.40-4.18(m,2H),1.70-1.58(m,2H),1.51(s,9H),1.40-1.28(m,2H),0.89(t,J=7.6Hz,3H).13CNMR(100MHz,CDCl3)δ168.8,159.5,156.3,152.1,137.0,129.7,129.0,128.7,127.7,126.2,84.4,83.9,66.4,30.4,27.7,19.0,13.6.HRMS(ESI)m/z:[M+H]+Calcd forC21H26ClN2O5421.1525;Found 421.1528.
实施例24
向反应管中依次加入哒嗪-3-酮衍生物1a 46.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(S-TFPTTL)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/5]纯化得到白色固体(R)-3aa 59.7mg,收率71%,76%ee;m.p.:135-137℃;HPLC(IA,n-hexane/i-PrOH=80/20,flow rate=1.0mL/min,I=225nm)tR=4.45min(major),5.38min(minor),76%ee.[α]D 20:-11.6(c=0.50,CHCl3;76%ee).1HNMR(400MHz,CDCl3)δ7.93(d,J=9.2Hz,1H),7.53-7.44(m,2H),7.40(d,J=9.2Hz,1H),7.37-7.28(m,3H),1.54(s,9H),1.51(s,9H).13C NMR(100MHz,CDCl3)δ167.4,159.5,156.2,152.1,137.3,130.0,128.8,128.7,127.5,126.2,84.4,83.9,83.6,27.8.HRMS(ESI)m/z:[M+H]+Calcd for C21H26ClN2O5421.1525;Found 421.1529.
对比例1
向50ml反应管中加入3-羟基-6-甲基哒嗪440mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O 1.1g(5.2mmol),20mL THF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到无色油状物588mg,收率70%;1H NMR(400MHz,CDCl3)δ7.10(d,J=9.6Hz,1H),6.84(d,J=9.6Hz,1H),2.36(s,3H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ158.0,150.7,145.0,134.2,131.7,86.2,27.6,20.9.HRMS(ESI):calculated for C10H15N2NaO3[M+Na]+:233.0897;Found:233.0894.
向反应管中依次加入哒嗪-3-酮衍生物42.0mg(0.2mmol),苯基重氮化合物2a87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后检测反应发现哒嗪-3-酮衍生物完全不反应,无产物。
对比例2
向50ml反应管中加入哒嗪-3-酮384mg(4.0mmol),DMAP 48.8mg(0.4mmol),Boc2O1.1g(5.2mmol),20mLTHF,反应在30℃下反应4h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/3]纯化得到棕色固体306mg,收率39%;1H NMR(400MHz,CDCl3)δ7.81(dd,J=3.6,1.6Hz,1H),7.20(dd,J=9.6,3.6Hz,1H),6.94(dd,J=10.0,1.6Hz,1H),1.64(s,9H).13C NMR(100MHz,CDCl3)δ158.5,150.2,136.5,132.2,131.8,86.6,27.6.HRMS(ESI):calculated for C9H12N2NaO3[M+Na]+:219.0740;Found:219.0739.
向反应管中依次加入哒嗪-3-酮39.2mg(0.2mmol),苯基重氮化合物2a 87.2mg(0.4mmol),随后加入催化剂Rh2(OAc)40.88mg(0.002mmol),4mL DCM。密封充氩气反应。反应在30℃下反应0.5h,反应结束后检测反应发现反应很杂,生成很多副产物,原料转化率大概在50%,但产物产率<5%。产率太低,没有拿到产物。
Claims (5)
1.一种3-取代哒嗪衍生物的合成方法,其特征在于:反应首先加入哒嗪-3-酮衍生物,芳基重氮化合物/>以及铑催化剂,再加入溶剂并用氩气保护,在20℃~35℃下反应15 ~ 60 分钟,待反应结束后减压蒸去溶剂,以硅胶吸附,通过柱层析分离得到3-取代哒嗪衍生物目标产物/>;
其中,R1为6-氯、6-溴、5,6-二氯、6-碘或6-苯基;R2为叔丁氧羰基、N,N-二甲基甲酰基、N,N-二乙基甲酰基或哌啶-1-基酰基;R3为苯基、4-氟苯基、4-甲基苯基、3-氯苯基、2-氟苯基或3,4-二氯苯基;R4为叔丁基、苄基或正丁基;
所述铑催化剂为Rh2(OAc)4、Rh2(PTTL)4、Rh2(esp)2、Rh2(Oct)4、Rh2(OPiv)4、Rh2(S-TFPTTL)4中的一种,用量为哒嗪-3-酮衍生物摩尔数的0.5~2%。
2.如权利要求1所述的3-取代哒嗪衍生物的合成方法,其特征在于:所述的哒嗪-3-酮衍生物为以下结构式中的一种:
。
3.如权利要求1所述的3-取代哒嗪衍生物的合成方法,其特征在于:所述的芳基重氮化合物为以下结构式中的一种:
。
4.如权利要求1所述的3-取代哒嗪衍生物的合成方法,其特征在于:芳基重氮化合物的用量为哒嗪-3-酮衍生物用量的1~2.5当量。
5.如权利要求1所述的3-取代哒嗪衍生物的合成方法,其特征在于:所用溶剂为二氯甲烷、正己烷、乙腈、乙醚、氯仿、甲苯、四氢呋喃、1,2-二氯乙烷中的一种,哒嗪-3-酮衍生物在溶剂中的浓度为0.05~0.2mol/L。
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"3,6-双取代哒嗪的合成和介晶性";熊俊如等;《应用化学》;第20卷(第11期);第1088-1092页 * |
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