CN107311940B - 一种嘧啶二酮类化合物的制备方法 - Google Patents

一种嘧啶二酮类化合物的制备方法 Download PDF

Info

Publication number
CN107311940B
CN107311940B CN201710618708.7A CN201710618708A CN107311940B CN 107311940 B CN107311940 B CN 107311940B CN 201710618708 A CN201710618708 A CN 201710618708A CN 107311940 B CN107311940 B CN 107311940B
Authority
CN
China
Prior art keywords
solvent
alkyl
preparation
hybar
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201710618708.7A
Other languages
English (en)
Other versions
CN107311940A (zh
Inventor
魏晔
梁洪文
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Third Military Medical University TMMU
Original Assignee
Third Military Medical University TMMU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Third Military Medical University TMMU filed Critical Third Military Medical University TMMU
Priority to CN201710618708.7A priority Critical patent/CN107311940B/zh
Publication of CN107311940A publication Critical patent/CN107311940A/zh
Application granted granted Critical
Publication of CN107311940B publication Critical patent/CN107311940B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种嘧啶二酮类化合物的制备方法，在溶剂中，惰性气体保护下，以环状肟脂类化合物和异氰类化合物作为反应原料，在一价银化物催化作用下，高效合成嘧啶二酮类化合物。本发明所述制备方法原料廉价易得、步骤简短、方法原子经济性高（100%），反应条件温和，可大规模工业应用，通过利用环状肟酯N‑O键断裂，一步、高效构建嘧啶二酮类化合物，实现了该体系化学合成的突破性进展，并促进该体系相关药物化学研究的深层次扩展。

Description

一种嘧啶二酮类化合物的制备方法
技术领域
本发明涉及有机化合物合成领域，具体为嘧啶二酮类化合物的制备方法。
背景技术
嘧啶二酮结构广泛存于天然化合物中，如RNA特有的碱基尿嘧啶，此外，嘧啶二酮结构也是多种药物分子的核心骨架，具有独特的生物活性，如具有抗代谢、抗肿瘤活性的药物——5-氟尿嘧啶，以及世界上第一个获得美国FDA批准生产的抗艾滋病药物齐多夫定。嘧啶二酮结构还是一种重要的有机合成中间体，可以用来合成其他许多有机化合物。
目前嘧啶二酮类化合物的合成方法主要有以下两种方式：(1)β酮酯类化合物与尿素在回流下反应生成嘧啶二酮类化合物(U.S.PatAppl.Publ.20070048752)；
(2)β酮酯类化合物与尿素在微波条件下下反应生成嘧啶二酮类化合物(Tetrahedron Letters.2012,53,2639–2642)，两者的反应式如下：
(1)
(2)
上述两种合成方法均是通过化学反应在尿素分子式上添加官能团得到嘧啶二酮类化合物，然而，在尿素分子式上添加官能团较为困难，导致这两种合成方法的合成效率较低，此外，采用第一种合成方法合成得到的嘧啶二酮类化学物种类单一，无法有效满足药物、功能材料对嘧啶二酮类化合物的需求，采用第二种合成方法需在微波条件下进行，无法大规模工业化生产。
因此，研发一种简洁、高效、环保、实用的合成嘧啶二酮类化合物的方法，为药物研发、小分子药物的高通量筛选以及功能材料的合成提供切实可靠的基础，具有十分重要的研究意义和应用前景。
发明内容
本发明的目的提供一种嘧啶二酮类化合物的制备方法，以一价银化物为催化剂，利用环状肟脂类化合物和异氰类化合物反应一步构建成嘧啶二酮类化合物，是一种简洁、高效、易于操作的制备方法，利于工业应用。
本发明的技术方案是：一种嘧啶二酮类化合物的制备方法，具有以下步骤：
取环状肟酯类化合物1、异氰类化合物2作为原料，以一价银化物作为催化剂，在惰性气体氛围加入到有机溶剂中，在40-180℃条件下反应，反应完毕后，降至室温，过滤，取滤液蒸馏、层析，得到嘧啶二酮类化合物3，其反应式为：
其中，环状肟酯类化合物1：异氰类化合物2：一价银化物的摩尔比为1-5：1-5：0.05-1。
所述环状肟酯类化合物1中R1为烷基、含杂原子烷基、芳基、卤素、烯基、杂芳基或环烷基；R2为烷基、芳基、烯基；所述异氰类化合物2中R3为烷基、含杂原子烷基、芳基、磺酰基、叔丁基、杂芳基或卤素。
所述嘧啶二酮类化合物3中的R1为烷基、含杂原子烷基、芳基、卤素、烯基、杂芳基或环烷基，R2为烷基、芳基、烯基，R3为烷基、含杂原子烷基、芳基、磺酰基、叔丁基、杂芳基或卤素。
有机溶剂中还有浓度为0.05mmol/L-5mmol/L的碱性化合物作为添加剂，其添加剂优选为三乙胺、吡啶，碱性化合物：环状肟酯类化合物1的摩尔比为1-5：1-5。
所述环状肟酯类化合物1的浓度为0.05mmol/L-5mmol/L，所述异氰类化合物2的浓度为0.05mmol/L-5mmol/L。
所述一价银化物为Ag2O、AgTFA、Ag2CO3、AgNO3、AgSbF6、AgOTf、AgCN、AgPF6、AgClO4、AgF、AgOAc的任意一种或几种混合。
所述有机溶剂为脂肪烃类溶剂、芳烃类溶剂、卤代烷类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、亚砜类溶剂、酰胺类溶剂、腈类溶剂、杂环类溶剂的任意一种或几种混合，优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲醇、异丙醇、四氢呋喃、1,4-二氧六环、甲苯、乙腈、二氯乙烷、氯仿、丙酮、二甲亚砜的任意一种或几种混合。
过滤得到的沉淀用乙酸乙酯冲洗数次，冲洗液合并入滤液中。
蒸馏通过旋转蒸发仪进行，通过TLC检测原料消失后判定反应完毕。
过滤时采用硅藻土过滤。
本发明制备方法利用一价银离子催化环状肟酯类化合物N-O键断裂，高效构建成嘧啶二酮类化合物，步骤简短、原子经济性高(100％)，整个反应条件温和，利于大规模工业生产。通过添加三乙胺、吡啶作为添加剂，能有效提高产物嘧啶二酮类化合物的合成效率，通过申请人实验验证，能有效提高合成率至92％。
本发明的有益效果为，反应体系的各原料简单易得，均为工业化商品，来源广泛、价格低廉，并且性质稳定，保存条件不苛刻；其次，本发明反应体系的合成路线简短，原料的原子经济性高(100％)、效能优越，产物嘧啶二酮类化合物的反应产率高达92％，实现了该体系化学合成的突破性进展，并促进该体系相关药物化学研究的深层次扩展。
具体实施方式
现结合具体实施例，对本发明作进一步的详细说明。
应当指出的是，下述实施例的反应条件、试剂、实验方法等，除特别提及的内容之外，均属于本领域技术人员的公知常识。下述实施例所给出的数据包括具体操作和反应条件及产物，产物纯度通过核磁鉴定。
本发明所用试剂均采用市售的分析纯试剂。
实施例1
取规格为10ml的反应管，加入1,4-二氧六环(2mL)作为溶剂，称量肟酯类化合物1a(0.2mmol)、异氰类化合物2a(0.3mmol)、氧化银(0.01mmol)、吡啶(0.2mmol)，在惰性气体保护下，分别加反应管中,密封反应管。80℃油浴条件下搅拌反应6小时，TLC检测，反应完毕后，降至室温，用硅藻土过滤得滤液，过滤得到的固体颗粒用乙酸乙酯冲洗数次，将冲洗液合并在滤液中，再通过旋蒸仪蒸馏，去除1,4-二氧六环和乙酸乙酯，得3aa粗品，3aa粗品通过快速柱层析得产物3aa纯品，产率92％。1H NMR(600MHz,CDCl3):δ9.97(s,1H),7.65(d,J＝7.6Hz,2H),7.56(t,J＝7.2Hz,1H),7.51(t,J＝7.5Hz,2H),6.06(d,J＝1.4Hz,1H),4.69(s,2H),4.21(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):13C NMR(150MHz,CDCL3)δ167.65,162.62,152.54,150.64,131.72,131.18,129.33,126.26,98.49,61.64,41.39,14.12；HRMS(ESI):计算值C14H14N2O4[M+Na]+297.0851,实际值297.0853。
实施例2
取规格为10ml的反应管，加入丙酮(2mL)作为溶剂，称量肟酯类化合物1a(0.2mmol)、异氰类化合物2a(0.6mmol)、AgNO3(0.01mmol)、三乙胺(0.2mmol)，在惰性气体保护下，分别加反应管中,密封反应管。60℃油浴条件下搅拌反应6小时，TLC检测，反应完毕后，降至室温，用硅藻土过滤得滤液，过滤得到的固体颗粒用乙酸乙酯冲洗数次，将冲洗液合并在滤液中，再通过旋蒸仪蒸馏，去除丙酮和乙酸乙酯，得3aa粗品，3aa粗品通过快速柱层析得产物3aa纯品，产率79％。1H NMR(600MHz,CDCl3):δ9.41(s,1H),7.60–7.56(m,2H),7.03–6.99(m,2H),5.99(d,J＝1.5Hz,1H),4.70(s,2H),4.22(d,J＝7.1Hz,2H),3.88(s,3H),1.28(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):δ167.7,162.7,162.4,152.3,150.1,127.7,123.2,114.8,97.1,61.655.5,41.4,14.1；HRMS(ESI):计算值C15H16N2O5[M+Na]+327.0957,实际值325.0962。
实施例3
取规格为10ml的反应管，加入四氢呋喃(2mL)作为溶剂，称量肟酯类化合物1a(0.2mmol)、异氰类化合物2a(0.3mmol)、AgF(0.01mmol)、吡啶(0.2mmol)，在惰性气体保护下，分别加反应管中,密封反应管。100℃油浴条件下搅拌反应6小时，TLC检测，反应完毕后，降至室温，用硅藻土过滤得滤液，过滤得到的固体颗粒用乙酸乙酯冲洗数次，将冲洗液合并在滤液中，再通过旋蒸仪蒸馏，去除四氢呋喃和乙酸乙酯，得3aa粗品，3aa粗品通过快速柱层析得产物3aa纯品，产率65％。1H NMR(600MHz,d6-DMSO):δ11.74(s,1H),7.93(d,J＝8.2Hz,2H),7.84(d,J＝8.3Hz,2H),6.10(s,1H),4.52(s,2H),4.11(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H).；13C NMR(150MHz,d6-DMSO):δ168.3,162.6,151.7,150.6,135.6,131.4(q,2JC-F＝31.8Hz),128.6,126.1(q,3JC-F＝3.8Hz),125.2(q,1JC-F＝271.0Hz),99.0,61.5,41.4,14.5；HRMS(ESI):计算值C15H13F3N2O4[M+Na]+365.0725,实际值365.0723。
实施例4
取规格为10ml的反应管，加入1,4-二氧六环(2mL)作为溶剂，称量肟酯类化合物1a(0.2mmol)、异氰类化合物2a(0.3mmol)、AgSbF6(0.02mmol)、吡啶(0.2mmol)，在惰性气体保护下，分别加反应管中,密封反应管。120℃油浴条件下搅拌反应6小时，TLC检测，反应完毕后，降至室温，用硅藻土过滤得滤液，过滤得到的固体颗粒用乙酸乙酯冲洗数次，将冲洗液合并在滤液中，再通过旋蒸仪蒸馏，去除1,4-二氧六环和乙酸乙酯，得3aa粗品，3aa粗品通过快速柱层析得产物3aa纯品，产率78％。1H NMR(600MHz,d6-DMSO):δ11.63(s,1H),7.73–7.65(m,4H),6.04(s,1H),4.52(s,2H),4.12(q,J＝7.1Hz,2H),1.18(t,J＝7.1Hz,3H)；13CNMR(150MHz,d6-DMSO):δ168.3,162.6,151.8,150.9,132.3,130.8,129.6,125.4,98.0,61.5,41.4,14.5；HRMS(ESI):计算值C14H13BrN2O4[M+Na]+374.9956,实际值374.9952。
实施例5
操作步骤同实施例1，产率65％。1H NMR(600MHz,d6-DMSO):δ11.62(s,1H),7.75(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),6.03(s,1H),4.51(s,2H),4.11(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H)；13C NMR(150MHz,d6-DMSO):δ168.3,162.6,151.8,150.8,136.6,130.4,129.4,129.3,98.0,61.5,41.4,14.5.HRMS(ESI):计算值C14H13ClN2O4[M+Na]+331.0462,实际值331.0459。
实施例6
操作步骤同实施例1，产率91％。1H NMR(600MHz,CDCl3):δ9.87(s,1H),7.38–7.34(m,1H),7.31–7.23(m,3H),5.70(d,J＝1.3Hz,1H),4.56(s,2H),4.16(q,J＝7.1Hz,2H),2.37(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):δ167.6,162.6,152.2,151.7,135.8,131.9,131.1,130.6,128.3,126.2,101.3,61.6,41.219.9,14.1；HRMS(ESI):计算值C15H16N2O4[M+Na]+311.1008,实际值311.1011。
实施例7
操作步骤同实施例1，产率82％。1H NMR(600MHz,d6-DMSO):δ11.63(s,1H),7.96(s,1H),7.73(t,J＝8.9Hz,2H),7.44(t,J＝7.9Hz,1H),6.08(s,1H),4.53(s,2H),4.12(q,J＝7.1Hz,2H),1.18(t,J＝7.1Hz,3H)；13C NMR(150MHz,d6-DMSO):δ168.3,162.6,151.7,150.4,134.4,133.8,131.3,130.2,126.7,122.5,98.4,61.5,41.4,14.5；HRMS(ESI):计算值C14H13BrN2O4[M+Na]+374.9956,实际值374.9955。
实施例8
操作步骤同实施例1，产率75％。1H NMR(600MHz,d6-DMSO):δ11.48(s,1H),8.38(s,1H),7.67(dd,J＝17.0,3.6Hz,2H),6.18(s,1H),4.50(s,2H),4.10(q,J＝7.0Hz,2H),1.16(t,J＝7.0Hz,3H)；13C NMR(150MHz,d6-DMSO):δ168.4,163.0,151.8,146.1,132.8,128.5,128.1,126.6,96.4,61.4,41.3,14.5；HRMS(ESI):计算值C12H12N2O4S[M+Na]+303.0415,实际值303.0417。
实施例9
操作步骤同实施例1，产率86％。1H NMR(600MHz,d6-DMSO):δ11.15(s,1H),7.02(s,1H),6.72–6.66(m,1H),6.12–6.06(m,1H),5.72(s,1H),4.47(s,2H),4.08(q,J＝7.1Hz,2H),3.70(s,3H),1.15(t,J＝7.1Hz,3H)；13C NMR(150MHz,d6-DMSO):δ168.5,162.6,151.7,143.9,129.9,124.2,114.3,108.6,95.9,61.4,41.2,36.3,14.4；HRMS(ESI):计算值C13H15N3O4[M+Na]+300.0960,实际值300.0962。
实施例10
操作步骤同实施例1，产率89％。1H NMR(600MHz,d6-DMSO):δ11.68(s,1H),7.98(s,1H),7.52(d,J＝3.5Hz,1H),6.73(dd,J＝3.4,1.6Hz,1H),5.96(s,1H),4.51(s,2H),4.11(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):δ168.3,162.5,151.6,147.5,144.7,141.2,114.6,113.3,93.4,61.5,41.3,14.5；HRMS(ESI):计算值C12H12N2O5[M+Na]+287.0644,实际值287.0641。
实施例11
操作步骤同实施例1，产率89％。1H NMR(600MHz,d6-DMSO):δ11.44(s,1H),7.35(s,1H),7.32(dd,J＝8.2,1.5Hz,1H),7.02(d,J＝8.2Hz,1H),6.10(s,2H),5.98(s,1H),4.51(s,2H),4.11(q,J＝7.1Hz,2H),1.18(t,J＝7.1Hz,3H)；13C NMR(150MHz,d6-DMSO):δ168.4,162.7,151.8,151.3,150.3,148.3,125.2,122.3,108.9,107.6,102.4,96.7,61.4,41.3,14.5；HRMS(ESI):计算值C15H14N2O6[M+Na]+341.0750,实际值341.0752。
实施例12
操作步骤同实施例1，产率92％。1H NMR(600MHz,d6-DMSO):δ11.71(s,1H),8.42(s,1H),8.07–7.94(m,3H),7.82(d,J＝8.5Hz,1H),7.65–7.55(m,2H),6.18(s,1H),4.56(s,2H),4.14(q,J＝7.0Hz,2H),1.19(t,J＝7.1Hz,3H)；13C NMR(150MHz,d6-DMSO):δ134.4,132.7,129.3,129.0,128.8,128.4,128.1,127.8,127.5,124.2,98.0,61.5,41.4,14.5；HRMS(ESI):计算值C18H16N2O4[M+Na]+347.1008,实际值347.1010。
实施例13
操作步骤同实施例1，产率73％。1H NMR(600MHz,CDCl3):δ9.33(s,1H),7.34(t,J＝7.4Hz,1H),7.26(dd,J＝10.2,5.2Hz,2H),7.20(dd,J＝10.0,5.2Hz,5H),7.09(dd,J＝6.5,3.0Hz,2H),4.70(s,2H),4.21(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):δ167.7,162.7,151.2,147.6,132.4,132.1,131.3,130.3,128.7,128.6,128.0,127.5,112.4,61.6,41.9,14.1,；HRMS(ESI):计算值C20H18N2O4[M+Na]+373.1164,实际值373.1166。
实施例14
操作步骤同实施例1，产率79％。1H NMR(600MHz,d6-DMSO):δ8.66(t,J＝5.7Hz,1H),7.50(dd,J＝6.4,2.8Hz,2H),7.45–7.36(m,3H),4.10(dd,J＝14.0,7.0Hz,2H),3.97(d,J＝6.0Hz,2H),1.89(s,3H),1.14(t,J＝7.0Hz,3H)；13C NMR(150MHz,d6-DMSO):δ169.8,162.2,161.5,157.2,137.8,129.9,129.0,128.4,102.7,61.0,42.9,14.5,12.9；HRMS(ESI):计算值C15H16N2O4[M+Na]+311.1008,实际值311.1010。
实施例15
操作步骤同实施例1，产率79％。1H NMR(600MHz,d6-DMSO):δ11.50(s,1H),7.62(d,J＝8.0Hz,2H),7.26(d,J＝7.9Hz,2H),5.96(s,1H),4.50(s,2H),4.09(q,J＝7.0Hz,2H),2.31(s,3H),1.15(t,J＝7.1Hz,3H).；13C NMR(150MHz,d6-DMSO):δ168.41(s),162.7,151.9,151.8,141.9,129.9,128.7,127.4,97.0,61.4,41.3,21.3,14.5；HRMS(ESI):计算值C15H16N2O4[M+Na]+311.1008,实际值311.1011。
实施例16
操作步骤同实施例1，产率73％。1H NMR(600MHz,CDCl3):δ10.46(s,1H),5.61(s,1H),4.63(s,2H),4.21(q,J＝7.1Hz,2H),2.14(s,3H),1.27(t,J＝7.1Hz,3H).；13C NMR(150MHz,CDCl3):δ167.8,162.6,153.0,150.7,100.0,77.2,77.0,76.8,61.6,41.2,18.8,14.1；HRMS(ESI):计算值C9H12N2O4[M+Na]+235.0695,实际值235.0693。
实施例17
操作步骤同实施例1，产率74％。1H NMR(600MHz,CDCl3):δ10.26(s,1H),4.66(s,2H),4.21(q,J＝7.1Hz,2H),2.38–2.33(m,2H),2.14(s,3H),1.40(dd,J＝10.3,4.8Hz,2H),1.35–1.31(m,2H),1.27(t,J＝7.1Hz,3H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3):δ167.9,163.0,152.4,145.3,111.2,61.5,41.6,31.0,25.1,22.6,16.5,14.1,13.9；HRMS(ESI):计算值C13H20N2O4[M+Na]+291.1321,实际值291.1320。
实施例18
操作步骤同实施例1，产率82％。1H NMR(600MHz,CDCl3):δ10.43(s,1H),7.25(dd,J＝9.3,5.8Hz,2H),7.20–7.13(m,3H),4.67(s,2H),4.20(q,J＝7.1Hz,2H),3.75(s,2H),2.15(s,3H)；13C NMR(150MHz,CDCl3):δ167.8,163.1,152.4,147.1,139.3,128.5,128.0,126.2,110.1,77.2,77.0,76.8,61.6,41.7,30.7,17.0,14.1；HRMS(ESI):计算值C16H18N2O4[M+Na]+325.1164,实际值325.1162。
实施例19
操作步骤同实施例1，产率91％。1H NMR(600MHz,CDCl3):δ9.98(s,1H),4.65(s,2H),4.21(dd,J＝14.1,7.0Hz,2H),2.46(s,2H),2.40(t,J＝6.5Hz,2H),1.73(d,J＝17.3Hz,3H),1.47–1.35(m,11H),1.27(t,J＝7.0Hz,5H).；13C NMR(150MHz,CDCl3):δ168.0,163.3,152.4,149.5,110.9,61.5,41.5,27.1,26.3,25.5,25.3,24.9(two signals areoverlapped),23.7,23.1,22.7,21.7,14.1；HRMS(ESI):计算值C18H28N2O4[M+Na]+359.1947,实际值359.1949。
实施例20
操作步骤同实施例1，产率83％。1H NMR(600MHz,CDCl3):δ10.39(s,1H),5.47(d,J＝1.5Hz,1H),4.62(s,2H),4.20(q,J＝7.1Hz,2H),1.65–1.59(m,1H),1.27(t,J＝7.1Hz,3H),1.08–1.04(m,2H),0.96–0.92(m,2H)；13C NMR(150MHz,CDCl3):δ167.8,162.5,156.9,152.9,95.9,61.6,41.2,14.1,13.2,8.7；HRMS(ESI):计算值C11H14N2O4[M+Na]+261.0851,实际值261.0853。
实施例21
操作步骤同实施例1，产率79％。1H NMR(600MHz,CDCl3):δ10.04(s,1H),5.69(s,1H),4.62(s,2H),4.20(q,J＝7.1Hz,2H),3.75(s,3H),3.44(s,2H),1.27(t,J＝7.1Hz,3H)；13C NMR(150MHz,CDCl3):δ167.9,167.7,162.4,151.9,146.1,101.5,61.7,52.9,41.3,37.4,14.1；HRMS(ESI):计算值C11H14N2O6[M+Na]+293.0750,实际值293.0752。
实施例22
操作步骤同实施例1，产率40％。1H NMR(600MHz,d6-DMSO):δ11.68(s,1H),8.05–8.00(m,2H),7.85(d,J＝7.2Hz,2H),7.66–7.50(m,8H),6.15(s,1H)；13C NMR(150MHz,d6-DMSO):δ163.7,152.4,152.2,134.3,132.7,131.9,131.8,130.3,129.3,129.1,128.7,127.6,127.4,126.7,126.2,122.6,98.4；HRMS(ESI):计算值C20H14N2O2[M+Na]+377.0953,实际值337.0955。
实施例23
操作步骤同实施例1，产率60％。1H NMR(600MHz,CDCl3):δ9.87(s,1H),7.63(d,J＝7.3Hz,2H),7.55(d,J＝7.2Hz,1H),7.50(t,J＝7.4Hz,2H),7.45(d,J＝6.1Hz,2H),7.27(m,3H),6.03(d,J＝2.0Hz,1H),5.12(s,2H).；13C NMR(150MHz,CDCl3):δ163.2,150.1,136.6,131.6,131.3,129.4,129.0,128.4,127.7,126.2,98.9,43.7；HRMS(ESI):计算值C17H14N2O2[M+Na]+301.0953,实际值301.0955。
实施例24
操作步骤同实施例1，产率92％。1H NMR(600MHz,CDCl3):δ10.49(s,1H),7.71–7.64(m,2H),7.53(m,3H),6.05(d,J＝1.7Hz,1H),4.59(s,2H),1.44(s,9H)；13C NMR(150MHz,CDCl3):δ166.7,162.7,152.9,150.7,131.6,131.2,129.2,126.4,98.5,82.3442.128.0；HRMS(ESI):计算值C14H16N2O2[M+Na]+267.1109,实际值267.1110。
实施例25
操作步骤同实施例1，产率78％。1H NMR(600MHz,d6-DMSO):δ11.65(s,1H),7.72(dd,J＝7.7,4.6Hz,4H),7.53(d,J＝7.2Hz,1H),7.48(t,J＝7.5Hz,2H),7.41(d,J＝8.1Hz,2H),6.00(s,1H),5.32(s,2H),2.38(s,3H)；13C NMR(150MHz,d6-DMSO):δ161.7,152.2,151.2,145.1,137.3,131.9,131.4,130.2,129.3,128.5,127.5,97.3,60.8,21.6.；HRMS(ESI):计算值C18H16N2O4S[M+Na]+379.0728,实际值379.0725。
实施例26
操作步骤同实施例1，产率82％。1H NMR(600MHz,d6-DMSO):δ11.59(s,1H),7.74(d,J＝7.7Hz,2H),7.54(t,J＝7.2Hz,1H),7.49(t,J＝7.5Hz,2H),6.02(s,1H),4.24(d,J＝11.9Hz,2H),4.10–3.98(m,4H),1.21(t,J＝7.0Hz,6H)；13C NMR(150MHz,d6-DMSO):δ162.4,151.6,131.7,131.6,129.3,127.5,97.5,62.3,36.035.0,16.6；HRMS(ESI):计算值C13H14N2O5P[M+Na]+361.0929,实际值361.0929。

Claims (8)

1.一种嘧啶二酮类化合物的制备方法，其特征在于，具有以下步骤：
取环状肟酯类化合物1、异氰类化合物2作为原料，以一价银化物作为催化剂，在惰性气体氛围加入到有机溶剂中，在40-180℃条件下反应，反应完毕后，降至室温，过滤，取滤液蒸馏、层析，得到嘧啶二酮类化合物3，其反应式为：
其中，环状肟酯类化合物1：异氰类化合物2：一价银化物的摩尔比为1-5：1-5：0.05-1；
有机溶剂中还有浓度为0.05mmol/L-5mmol/L的碱性化合物作为添加剂，其添加剂为三乙胺、吡啶，碱性化合物：环状肟酯类化合物1的摩尔比为1-5：1-5；
所述环状肟酯类化合物1中R1为烷基、含杂原子的烷基、芳基、卤素、烯基、杂芳基或环烷基；R2为烷基、芳基、烯基；所述异氰类化合物2中R3为烷基、含杂原子的烷基、芳基、磺酰基、杂芳基或卤素；
所述嘧啶二酮类化合物3中的R1为烷基、含杂原子的烷基、芳基、卤素、烯基、杂芳基或环烷基，R2为烷基、芳基、烯基，R3为烷基、含杂原子的烷基、芳基、磺酰基、杂芳基或卤素。
2.根据权利要求1所述的制备方法，其特征在于：所述环状肟酯类化合物1的浓度为0.05mmol/L-5mmol/L，所述异氰类化合物2的浓度为0.05mmol/L-5mmol/L。
3.根据权利要求1所述的制备方法，其特征在于：所述一价银化物为Ag2O、AgTFA、Ag2CO3、AgNO3、AgSbF6、AgOTf、AgCN、AgPF6、AgClO4、AgF、AgOAc的任意一种或几种混合。
4.根据权利要求1所述的制备方法，其特征在于：所述有机溶剂为脂肪烃类溶剂、芳烃类溶剂、卤代烷类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、亚砜类溶剂、酰胺类溶剂、腈类溶剂、杂环类溶剂的任意一种或几种混合。
5.根据权利要求4所述的制备方法，其特征在于：所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲醇、异丙醇、四氢呋喃、1,4-二氧六环、甲苯、乙腈、二氯乙烷、氯仿、丙酮、二甲亚砜的任意一种或几种混合。
6.根据权利要求1所述的制备方法，其特征在于：过滤得到的沉淀用乙酸乙酯冲洗数次，冲洗液合并入滤液中。
7.根据权利要求1所述的制备方法，其特征在于：蒸馏通过旋转蒸发仪进行，通过TLC检测原料消失后判定反应完毕。
8.根据权利要求1所述的制备方法，其特征在于：过滤时采用硅藻土过滤。
CN201710618708.7A 2017-07-26 2017-07-26 一种嘧啶二酮类化合物的制备方法 Expired - Fee Related CN107311940B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710618708.7A CN107311940B (zh) 2017-07-26 2017-07-26 一种嘧啶二酮类化合物的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710618708.7A CN107311940B (zh) 2017-07-26 2017-07-26 一种嘧啶二酮类化合物的制备方法

Publications (2)

Publication Number Publication Date
CN107311940A CN107311940A (zh) 2017-11-03
CN107311940B true CN107311940B (zh) 2019-08-30

Family

ID=60175025

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710618708.7A Expired - Fee Related CN107311940B (zh) 2017-07-26 2017-07-26 一种嘧啶二酮类化合物的制备方法

Country Status (1)

Country Link
CN (1) CN107311940B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113336702B (zh) * 2021-06-01 2022-06-14 西南大学 2-氨基稠合吡啶类化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007122634A2 (en) * 2006-04-24 2007-11-01 Jubilant Biosys Limited Pyrimidinediones as tyrosine kinase inhibitors
CN102361557A (zh) * 2009-03-26 2012-02-22 Mapi医药公司 制备阿格列汀的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070048752A1 (en) * 2004-07-12 2007-03-01 Applera Corporation Mass tags for quantitative analyses

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007122634A2 (en) * 2006-04-24 2007-11-01 Jubilant Biosys Limited Pyrimidinediones as tyrosine kinase inhibitors
CN102361557A (zh) * 2009-03-26 2012-02-22 Mapi医药公司 制备阿格列汀的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Nataraj Poomathi，et al.Reaction of isatins with 6-amino uracils and isoxazoles: isatin ring-opening vs. annulations and regioselective synthesis of isoxazole fused quinoline sca ffolds in water.《Green Chemistry》.2015,第17卷(第6期),第3362-3372页.
Studies on total synthesis of cylindrospermopsin: new constructions of uracils from a,b-unsaturated esters;Stephen P. Keen，et al;《Tetrahedron Letters》;20001231;第41卷(第22期);第4307-4310页

Also Published As

Publication number Publication date
CN107311940A (zh) 2017-11-03

Similar Documents

Publication Publication Date Title
Martín et al. Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds
Agnihotri et al. Mild and efficient method for the cleavage of benzylidene acetals using HClO4–SiO2 and direct conversion of acetals to acetates
CN102276673A (zh) 一种2-脱氧-β-D-吡喃葡萄糖基三唑类化合物的制备方法
CN103274987A (zh) 3,3-二取代氧化吲哚衍生物及其合成方法和应用
CN107488139B (zh) 一种含硫3-芳亚甲基异吲哚啉酮衍生物制备方法
CN107311940B (zh) 一种嘧啶二酮类化合物的制备方法
Inoue et al. Catalytic Asymmetric Intramolecular Cyclopropanation of α-Diazo-α-Silyl Acetate
CN104892682A (zh) 含对氨基苯磺酸的金属配位聚合物的合成及其催化活性
Ohba et al. A highly efficient macrolactonization method via ethoxyvinyl ester
CN113105468B (zh) 一种含苯并吡喃酮的多环螺吲哚酮类化合物及其制备方法和应用
CN102343258B (zh) 三唑基键合环糊精-硅胶手性固定相及其制备方法
CN110483483A (zh) 一种手性多齿氮配体化合物及其制备方法和应用
CN114014872A (zh) 青蒿琥酯衍生物及其制备方法和应用
Fenlon et al. Synthesis of epi-chloranthalactones A, B, D and E
CN113045479B (zh) 一种可见光促进3-羟基异吲哚-1-酮类化合物的合成方法
CN108191736B (zh) 一种2,3-二取代吲哚类衍生物及其制备方法
CN108440466B (zh) 5-芳基-3-(2-氨基磺酸酯基-5-取代亚苄基)丁烯内酯化合物及制备方法、应用
CN102389782A (zh) 三唑基单键合全取代环糊精-硅胶手性固定相及其制备方法
CN107954966B (zh) 一种Sc(III)催化合成2,3-二取代-4H-苯并吡喃的制备方法
CN107556301B (zh) 一种他司美琼中间体的合成方法
CN112812015B (zh) 一种含四元环的杂二萜类化合物、其制备方法和应用，以及药物组合物
CN108727373A (zh) 一种c-3位芳基硒代咪唑并吡啶类化合物的催化合成方法
Kim et al. New radical approaches to 3-deoxy-D-oct-2-ulosonic acids (KDO)
CN108530405A (zh) 非金属路易斯酸催化烯烃分子内加成c-o键合成苯并呋喃衍生物的方法
CN108558974A (zh) 一种糖衍生吡啶三氮唑镍催化剂的制备及应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20190830