CN105985292A - 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 - Google Patents

一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 Download PDF

Info

Publication number
CN105985292A
CN105985292A CN201510075076.5A CN201510075076A CN105985292A CN 105985292 A CN105985292 A CN 105985292A CN 201510075076 A CN201510075076 A CN 201510075076A CN 105985292 A CN105985292 A CN 105985292A
Authority
CN
China
Prior art keywords
amide compound
preparation
otf
unsaturation
nitropyrazole
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.)
Granted
Application number
CN201510075076.5A
Other languages
English (en)
Other versions
CN105985292B (zh
Inventor
冯小明
姚乾
刘小华
林丽丽
张宇恒
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.)
Zhejiang Jiuzhou Pharmaceutical Co Ltd
Original Assignee
Zhejiang Jiuzhou Pharmaceutical Co Ltd
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 Zhejiang Jiuzhou Pharmaceutical Co Ltd filed Critical Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority to US15/511,243 priority Critical patent/US10464899B2/en
Priority to EP15844037.0A priority patent/EP3199525A4/en
Priority to PCT/CN2015/081341 priority patent/WO2016045415A1/zh
Priority to JP2017512956A priority patent/JP2017530956A/ja
Publication of CN105985292A publication Critical patent/CN105985292A/zh
Application granted granted Critical
Publication of CN105985292B publication Critical patent/CN105985292B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
    • C07D231/16—Halogen atoms or nitro radicals
    • 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
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D409/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，采用硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，

Description

一种不对称催化合成γ-硝基吡唑酰胺化合物的方法
技术领域
本发明涉及手性氧化胺-稀土金属络合物催化α,β-不饱和吡唑酰胺与硝基烷烃的不对称Michael加成反应合成γ-硝基吡唑酰胺的方法。
背景技术
γ-硝基吡唑酰胺化合物在有机合成中占有很重要的地位，它不但可以在碱的催化下与甲醇发生甲酯化反应，操作简单，合成效率高，还可以通过简单的化学反应转化为γ-氨基酸、2-吡啶酮以及2-吡咯烷酮等具有生物活性的化合物。目前已有一些不对称催化合成γ-硝基吡唑酰胺的报道。
Carlos F.Barbas III等利用硫脲衍生物XIV为手性催化剂，氯仿为溶剂，在-20℃下实现了下列硝基烯与吡唑酰胺的不对称Michael加成反应，产物可获得34％-99％的收率、10:1->20:1的d.r值(d.r值：含有两个及以上手性中心的化合物的非对映选择性)和78％-97％的ee值(Angew.Chem.Int.Ed.2012,51,5381)。
Long Lu等利用硫脲衍生物2d为手性催化剂，甲苯为溶剂，在室温下实现了下列硝基烷烃与三氟甲基取代的吡唑酰胺的不对称Michael加成反应，产物可获得71％-91％的收率、4.4:1–9.9:1的d.r值(d.r值：含有两个及以上手性中心的化合物的非对映选择性)和80％-93％的ee值(ACS Catal.2013,3,502)。
Shuji Kanemasa等利用R,R-DBFOX/Ph*Ni(ClO4)2*3H2O(A)和2,2,6,6-tetramethylpiperidine(TMP)作为组合催化剂，硝基甲烷与四氢呋喃(v/v＝1/1)为混合溶剂，在-20℃至室温下实现了下列硝基甲烷对不饱和吡唑酰胺的不对称Michael加成反应，产物可获得39％-97％的收率和77％-97％的ee值(J.Am.Chem.Soc.2002,124,13394)。
综上所述，Carlos F.Barbas III的催化反应体系中，反应须在-20℃进行，会耗费很多能量；Long Lu的催化反应体系中，α,β-不饱和酰胺扩展的底物都是端位有三氟甲基取代的，限制比较大；Shuji Kanemasa的催化反应体系中，反应前需要在-78℃活化，并且扩展的16个底物中，有11个底物的反应温度为-20℃，3个底物需要0℃，仅仅只有两个底物可以在室温下反应，有11个底物的反应时间需要96h，其中有6个底物反应时间需要168h，并且收率也并不理想，反应完成后需先用饱和氯化铵洗涤产品后才柱层析分离纯化，反应条件苛刻，操作复杂，硝基甲烷的用量太大(0.1mmolα,β-不饱和吡唑酰胺化合物需要用9.1mmol硝基甲烷)，最重要的是所得的反应结果并不好。所以一种高效、操作简单、节约能源并利于环境的方法亟需被发展。
发明内容
本发明的目的是发展不对称催化α,β-不饱和吡唑酰胺化合物与硝基烷烃的Michael加成反应，提供一种高效、操作简单、节约能源并利于环境的合成γ-硝基吡唑酰胺化合物的方法。
本发明的方案是：一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，其特征在于以硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，得手性γ-硝基吡唑酰胺化合物，其中：
硝基烷烃的结构为RCH2NO2，R＝H,CH3,Et,Bn；
α,β-不饱和吡唑酰胺化合物的结构为：
R1＝C6H5,4-FC6H4,4-ClC6H4,4-BrC6H4,4-MeC6H4,4-MeOC6H4,3-BrC6H4,3-MeC6H4,2-BrC6H4,2-MeOC6H4,3,4–Cl2C6H3,3,4-(MeO)2C6H3,2-Furyl,2-Thienyl,CH3,Pr,Pent,iBu,EtO,EtOOC；R2＝CH3,Ph；R3＝H,Cl,Br,I；
γ-硝基吡唑酰胺化合物具有如下结构：
其中R，R1，R2，R3的定义与上文定义相同。
手性氧化胺配体的结构为：
n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
所述的反应溶剂选自烷烃类，如戊烷、己烷、庚烷等；卤代烃类，如二氯乙烷、氯仿等；芳烃类，如甲苯、乙苯、异丙苯；醚类，如四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃等，酯类，如乙酸乙酯、乙酸异丙酯等。
优选的，反应温度为25-50℃。
优选的，本发明的方案是：一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，其特征在于以硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，二氯甲烷为溶剂，于25-50℃，常压下反应12-120h，得手性γ-硝基吡唑酰胺化合物。
上述方法TLC检测反应终点，利用硅胶柱层析分离得到手性γ-硝基吡唑酰胺化合物。
稀土金属化合物为：三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钪[Sc(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]、三氟甲磺酸钇[Y(OTf)3]；
硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比是1.86:1-55.8:1,最佳摩尔比是9.3:1。
反应的最佳催化剂是手性氧化胺L6(n＝2，R＝2,6-iPr2C6H3-)与三氟甲磺酸钆[Gd(OTf)3]形成的络合物，手性氧化胺与稀土金属化合物的摩尔比为0.8:1.0-1.5:1.0,最佳摩尔比是1.2:1.0；
分子筛450℃下活化3小时，0.1mmol的α,β-不饱和吡唑酰胺对应的分子筛量为10-100mg；
二氯甲烷经GaH2回流干燥处理，0.1mmol的α,β-不饱和吡唑酰胺对应的量为6.2mmol；
反应温度为30℃；
反应时间为72-96h。
进一步地，经上述方法制备得到的γ-硝基吡唑酰胺化合物在有机碱存在下与甲醇反应得到酯化产物。
所述的酯化产物具有如下结构：
其中R，R1的定义与前文相同。
所述有机碱选自三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺，1,8-二氮杂环[5,4,0]十一烯-7(DBU)。
与背景技术相比，本发明具有如下突出优势：
1.操作简便，催化剂不需要活化，产物易与催化剂、添加剂、原料分离。
2.反应转化率和对映选择性高，反应收率高达99％，对映选择性高达99％ee。
3.反应体系简单清洁，无需酸、碱添加剂。
4.反应条件温和，常压30℃下反应。
5.硝基烷烃的用量较少，节约原料。
具体实施方式
实施例1：手性氧化胺与稀土金属络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
在反应容器中加入稀土金属化合物(序号1-11:0.01mmol,序号12-16:0.0075mmol)、手性氧化胺配体(序号1-11:0.012mmol,序号12-16:0.009mmol)、α,β-不饱和吡唑酰胺1a(0.1mmol)、分子筛30mg、搅拌子，置换氮气3次后加入二氯甲烷(6.2mmol)、硝基甲烷(序号1-11:5.6mmol,序号12-16:0.93mmol)，于25-50℃搅拌12-120h。TLC监测反应。柱层析分离纯化，产物的对映体过量用高效液相色谱(Daicel chiralcel IE，V正己烷:V异丙醇＝90：10，流速1.0mL/min)测定，见表1。反应式和手性氧化胺配体结构如下：
表一.手性氧化胺与稀土金属络合物催化不对称α,β-不饱和吡唑酰胺和硝基甲烷的不对称Michael加成反应条件优化(n.d.：未检测)
实施例2：手性氧化胺L6-Gd(OTf)3络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
在反应容器中加入Gd(OTf)3(序号1-16,20-23,25-27:0.0075mmol,序号17-19,24:0.01mmol)、手性氧化胺L6(序号1-16,20-23,25-27:0.009mmol,序号17-19,24:0.012mmol)(手性氧化胺L6与三氟甲磺酸钆(Gd(OTf)3)的摩尔比为1.2:1.0)、α,β-不饱和酰胺(0.1mmol)、分子筛(序号1-16,20-27:30mg,序号18:100mg,序号17,19:60mg)、搅拌子，置换氮气3次后加入6.2mmol二氯甲烷和0.93mmol硝基烷烃，30℃下搅拌72h。柱层析分离纯化，产物的对映体过量用手性高效液相色谱测定，反应式如下：
反应结果见表2：(d.r:含有两个及以上手性中心的化合物的非对映选择性)
表2.手性氧化胺L6-Gd(OTf)3络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
序号 R,R1,R2,R3 收率(％) 对映选择性(％ee)
1 H,C6H5,CH3,H 99 99
2 H,4-FC6H4,CH3,H 99 99
3 H,4-ClC6H4,CH3,H 98 98
4 H,4-BrC6H4,CH3,H 96 98
5 H,4-MeC6H4,CH3,H 95 99
6 H,4-MeOC6H4,CH3,H 89 99
7 H,3-BrC6H4,CH3,H 98 98
8 H,3-MeC6H4,CH3,H 96 99
9 H,2-BrC6H4,CH3,H 99 99
10 H,2-MeOC6H4,CH3,H 99 99
11 H,3,4–Cl2C6H3,CH3,H 96 99
12 H,3,4-(MeO)2C6H3,CH3,H 83 99
13 H,2-Furyl,CH3,H 56 97
14 H,2-Thienyl,CH3,H 58 98
15 H,CH3,CH3,H 69 98
16 H,Pr,CH3,H 87 98
17 H,Pent,CH3,H 65 98
18 H,iBu,CH3,H 77 98
19 H,EtO,CH3,H 53 95
20 H,EtOOC,CH3,H 67 95
21 H,4-ClC6H4,CH3,Cl 94 99
22 H,4-ClC6H4,CH3,Br 96 99
23 H,4-ClC6H4,CH3,I 97 99
24 H,4-ClC6H4,C6H5,H 39 81
25 CH3,4-ClC6H4,CH3,H 94 98/98(d.r.1.6/1)
26 Et,4-ClC6H4,CH3,H 87 99/98(d.r.1.2/1)
27 PhCH2,4-ClC6H4,CH3,H 98 99/98(d.r.1.1/1)
实施例3：手性氧化胺与稀土金属络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
在反应容器中加入稀土金属化合物(序号1-11:0.01mmol,序号12-16:0.0075mmol)、手性氧化胺配体(序号1-11:0.012mmol,序号12-16:0.009mmol)、α,β-不饱和吡唑酰胺1a(0.1mmol)、分子筛30mg、搅拌子，置换氮气3次后加入二氯甲烷(6.2mmol)、硝基甲烷(序号1-11:5.6mmol,序号12-16:0.93mmol)，于25-50℃搅拌12-120h。TLC监测反应。柱层析分离纯化，产物的对映体过量用高效液相色谱(Daicel chiralcel IE，V正己烷:V异丙醇＝90：10，流速1.0mL/min)测定，见表1。反应式和手性氧化胺配体结构如下：
表3.手性氧化胺L6-Gd(OTf)3络合物在不同溶剂和温度下催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
实施例4：放大量实验1
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.24mmol)、三氟甲磺酸钆(0.2mmol)、序号2中不饱和酰胺(0.976g，4mmol)、分子筛1.2g，抽换氮气3次，然后加入186mmol二氯甲烷、37.2mmol硝基甲烷，30℃下搅拌96h。硅胶柱层析分离，得到催化产物为白色固体，1.217g，收率：99％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异 丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值99％。
实施例5：放大量实验2
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.36mmol)、三氟甲磺酸钆(0.3mmol)、序号3中不饱和酰胺(1.04g，4mmol)、分子筛1.2g，抽换氮气3次，然后加入186mmol二氯甲烷、37.2mmol硝基甲烷，30℃下搅拌72h。硅胶柱层析分离，得到催化产物为白色固体，1.278g，收率：99％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异 丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值98％。
实施例6：放大量实验3
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.72mmol)、三氟甲磺酸钆(0.6mmol)、序号18中不饱和酰胺(1.236g，6mmol)、分子筛6.5g，抽换氮气3次，然后加入325.5mmol二氯甲烷、55.8mmol硝基甲烷，30℃下搅拌72h。硅胶柱层析分离，得到催化产物为无色液体，1.34g，收率：83％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值99％。
γ-硝基吡唑酰胺化合物在合成中的应用：
实施例7：催化产物的酯化反应
催化反应完成后(起始α,β-不饱和吡唑酰胺为0.1mmol)，往盛有3b和3a反应液的试管中分别加入DBU(0.067mmol)和甲醇(2.5mmol),在室温下搅拌过夜。柱层析分离纯化，利用高效液相色谱分析(3a:Daicel chiralcel IB，V正己烷:V异丙醇＝90:10，流速1.0mL/min)、(3b:Daicel chiralcel IC，V正己烷:V异丙醇＝95:5，流速0.8mL/min)。结果如下：
5a和5b可以按照文献报道的方法合成药物分子，巴氯芬和帕罗西汀(Org.Lett.2012,14,1516)。
催化反应完成后(起始α,β-不饱和吡唑酰胺为0.1mmol)，往盛有3b反应液的试管中分别加入三乙胺(0.067mmol)和甲醇(2.5mmol),在室温下搅拌过夜。柱层析分离纯化，利用高效液相色谱分析(3a:Daicel chiralcel IB，V正己烷:V异丙醇＝90:10，流速1.0mL/min)、(3b:Daicel chiralcel IC，V正己烷:V异丙醇＝95:5，流速0.8mL/min)，得到(S)-5b，94.2％收率，99％ee。
催化反应完成后(起始α,β-不饱和吡唑酰胺为0.1mmol)，往盛有3a反应液的试管中分别加入二甲基苯胺(0.08mmol)和甲醇(2.5mmol),在室温下搅拌过夜。柱层析分离纯化，利用高效液相色谱分析(3a:Daicel chiralcel IB，V正己烷:V异丙醇＝90:10，流速1.0mL/min)、(3b:Daicel chiralcel IC，V正己烷:V异丙醇＝95:5，流速0.8mL/min)，得到(S)-5a，92％收率，98.6％ee。
由于脂肪类的酯类化合物不便于检测和分离纯化，所以采取了分步的方式来完成酯化的过程：在反应容器中加入3t(46.2mg,0.173mmol，98％ee，)，然后依次加入7.8mmol二氯甲烷、DBU(0.1mmol)、甲醇(3.72mmol)，室温下搅拌5h。柱层析分离纯化，利用高效液相色谱分析(Daicel chiralcel IE，V正己烷:V异丙醇＝95:5，流速1.0mL/min)，产物收率95％，对映体选择性98％ee。结果如下：
实施例8：普瑞巴林的合成
中国科学院成都有机化学有限公司公布了消旋的5c转化为消旋的6c的方法。他们用的是雷尼镍-H2作为氢化试剂对5c进行了还原关环，以97％的收率得到6c，虽然结果很好，但是操作复杂，并且过程中用到雷尼镍、氢气这些危险的试剂(CN 102115449A.06,07,2011)。
在这里我们提供了下列由5c合成6c的方法：该法反应条件温和、操作简单、反应高效
在装有磁力搅拌装置的圆底烧瓶中，加入5c(68.82mg,0.34mmol)、NiCl2·6H2O(80.6mg,0.34mmol)、EtOH(33.9mmol)，然后置于冰浴中5分钟，然后慢慢加入NaBH4(140.9mg,3.74mmol)，反应溶液继续在冰浴下搅拌2小时。然后加入1mL乙醇淬灭反应，回到室温，往反应液中加入1mL 6mol/L的氢氧化钠溶液，继续搅拌1h。1h后，往反应液中加入2mol/L的盐酸溶液，调节PH值小于7，然后用二氯甲烷(4x 6mL)萃取，合并有机层，用无水硫酸钠干燥，接着抽滤旋干既得产物6c，收率：95％，利用高效液相色谱分析(Daicel chiralcelAD-H，V正己烷:V异丙醇＝96：4，流速1.0mL/min)，得到产物的对映选择性ee值97％。
化合物6c按照文献的报道(Tetrahedron,2011,67,636)，在6mol/L盐酸中，100℃下回流10小时，便可以以95％的收率拿到普瑞巴林的盐酸盐并且ee值得到保持。

Claims (10)

1.一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，其特征在于以硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，反应后得到手性γ-硝基吡唑酰胺化合物，其中：
硝基烷烃的结构为RCH2NO2，R＝H,CH3,Et,Bn；
α,β-不饱和吡唑酰胺化合物的结构为：
γ-硝基吡唑酰胺化合物具有如下结构：
手性氧化胺配体的结构为：
其中R1＝C6H5,4-FC6H4,4-ClC6H4,4-BrC6H4,4-MeC6H4,4-MeOC6H4,3-BrC6H4,3-MeC6H4,2-BrC6H4,2-MeOC6H4,3,4–Cl2C6H3,3,4-(MeO)2C6H3,2-Furyl,2-Thienyl,CH3,Pr,Pent,iBu,EtO,EtOOC；R2＝CH3,Ph；R3＝H,Cl,Br,I；
n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
稀土金属化合物为：三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钪[Sc(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]、三氟甲磺酸钇[Y(OTf)3]。
2.根据权利要求1所述的制备方法，在如下溶剂中进行反应：戊烷、己烷、二氯乙烷、氯仿、甲苯、乙苯、异丙苯、四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃、乙酸乙酯或乙酸异丙酯。
3.根据权利要求1所述的制备方法，反应温度为25-50℃。
4.根据权利要求1所述的制备方法，其特征在于以硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，二氯甲烷为溶剂，于25-50℃，常压下反应12-120h，得手性γ-硝基吡唑酰胺化合物。
5.根据权利要求1或4所述的制备方法，硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比是1.86:1-55.8:1；手性氧化胺与稀土金属化合物的摩尔比为0.8:1.0-1.5:1.0；分子筛的 量为:0.1mmol的α,β-不饱和吡唑酰胺需分子筛为10-100mg。
6.根据权利要求1或4所述的制备方法，所述的稀土金属化合物是三氟甲磺酸钆[Gd(OTf)3]。
7.根据权利要求1或4所述的制备方法，所述的手性氧化胺配体中n＝2,R＝2,6-iPr2C6H3-。
8.根据权利要求1或4所述的制备方法，所述的α,β-不饱和吡唑酰胺化合物与稀土金属化合物的摩尔比为20:1-10:1。
9.根据权利要求1或4所述的制备方法，其特征在于0.1mmolα,β-不饱和吡唑酰胺化合物需要分子筛30-100mg。
10.根据权利要求1～4任一权利要求所述的制备方法，进一步地包括如下步骤：
γ-硝基吡唑酰胺化合物在有机碱存在下与甲醇反应得到酯化产物；
所述的酯化产物具有如下结构：
其中R，R1的定义与权利要求1相同。
所述有机碱选自三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7。
CN201510075076.5A 2014-09-22 2015-02-12 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 Active CN105985292B (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/511,243 US10464899B2 (en) 2014-09-22 2015-06-12 Asymmetrically catalyzed synthesis method of nitropyrazole amide compound
EP15844037.0A EP3199525A4 (en) 2014-09-22 2015-06-12 Method for asymmetrically catalyzed synthesis of nitropyrazole amide compound
PCT/CN2015/081341 WO2016045415A1 (zh) 2014-09-22 2015-06-12 一种不对称催化合成硝基吡唑酰胺化合物的方法
JP2017512956A JP2017530956A (ja) 2014-09-22 2015-06-12 ニトロピラゾールアミド化合物の不斉触媒合成方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2014104862093 2014-09-22
CN201410486209.3A CN104262255A (zh) 2014-09-22 2014-09-22 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法

Publications (2)

Publication Number Publication Date
CN105985292A true CN105985292A (zh) 2016-10-05
CN105985292B CN105985292B (zh) 2019-05-10

Family

ID=52153873

Family Applications (3)

Application Number Title Priority Date Filing Date
CN201410486209.3A Pending CN104262255A (zh) 2014-09-22 2014-09-22 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法
CN201510075076.5A Active CN105985292B (zh) 2014-09-22 2015-02-12 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法
CN201510291876.0A Active CN105418502B (zh) 2014-09-22 2015-06-01 一种用于合成帕罗西汀的中间体及其制备方法和用途

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201410486209.3A Pending CN104262255A (zh) 2014-09-22 2014-09-22 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201510291876.0A Active CN105418502B (zh) 2014-09-22 2015-06-01 一种用于合成帕罗西汀的中间体及其制备方法和用途

Country Status (5)

Country Link
US (2) US10464899B2 (zh)
EP (2) EP3199525A4 (zh)
JP (2) JP2017530956A (zh)
CN (3) CN104262255A (zh)
WO (1) WO2016045416A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876328A (zh) * 2021-01-15 2021-06-01 四川大学 一种不对称催化合成γ-氰基酰胺化合物及采用该化合物手性药物的方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262255A (zh) * 2014-09-22 2015-01-07 四川大学 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法
WO2016045415A1 (zh) * 2014-09-22 2016-03-31 浙江九洲药业股份有限公司 一种不对称催化合成硝基吡唑酰胺化合物的方法
CN106748949B (zh) * 2017-01-13 2019-04-09 厦门大学 一种合成α,β不饱和酰胺化合物的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102531815A (zh) * 2011-12-22 2012-07-04 四川大学 一种不对称催化α,β-不饱和羰基化合物环氧化反应方法
CN104262255A (zh) * 2014-09-22 2015-01-07 四川大学 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3680184D1 (de) * 1985-08-10 1991-08-14 Beecham Group Plc Verfahren zur herstellung von arylpiperidincarbinol.
WO2009005647A2 (en) * 2007-06-27 2009-01-08 Bioverdant, Inc. Compounds and process to prepare chiral intermediates for synthesis of paroxetine
CN102531825B (zh) * 2010-12-29 2014-04-23 中国科学院大连化学物理研究所 一种促进丙烷转化制芳烃的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102531815A (zh) * 2011-12-22 2012-07-04 四川大学 一种不对称催化α,β-不饱和羰基化合物环氧化反应方法
CN104262255A (zh) * 2014-09-22 2015-01-07 四川大学 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASAYUKI HASEGAWA，ET AL.: "Molecular sieves 4A work to mediate the catalytic metal enolization of nucleophile precursors: application to catalyzed enantioselective Michael addition reactions", 《TETRAHEDRON LETTERS》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876328A (zh) * 2021-01-15 2021-06-01 四川大学 一种不对称催化合成γ-氰基酰胺化合物及采用该化合物手性药物的方法

Also Published As

Publication number Publication date
JP2017529343A (ja) 2017-10-05
EP3199525A4 (en) 2018-02-14
US20170291876A1 (en) 2017-10-12
US9796675B1 (en) 2017-10-24
EP3199526A1 (en) 2017-08-02
JP2017530956A (ja) 2017-10-19
CN105418502B (zh) 2018-12-14
WO2016045416A1 (zh) 2016-03-31
CN105985292B (zh) 2019-05-10
CN104262255A (zh) 2015-01-07
EP3199525A1 (en) 2017-08-02
CN105418502A (zh) 2016-03-23
EP3199526A4 (en) 2018-02-14
US20170283380A1 (en) 2017-10-05
US10464899B2 (en) 2019-11-05

Similar Documents

Publication Publication Date Title
Xu et al. Transition‐metal‐based Lewis acid catalysis of Aza‐type Michael additions of amines to α, β‐unsaturated electrophiles in water
CN105985292A (zh) 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法
Singh et al. New benzimidazolium-based chiral ionic liquids: synthesis and application in enantioselective sodium borohydride reductions in water
Murtinho et al. Enantioselective ethylation of aldehydes with 1, 3-N-donor ligands derived from (+)-camphoric acid
Nakayama et al. Asymmetric Morita–Baylis–Hillman reactions of 2-cyclohexen-1-one catalyzed by chiral biaryl-based bis (thiourea) organocatalysts
Song et al. Nickel-Catalyzed Remote C (sp3)–N/O Bond Formation of Alkenes with Unactivated Amines and Alcohols
Lou et al. Cinchona-derived prolinamide in Brønsted acidic ionic liquids: a novel and recyclable catalytic system for asymmetric aldol reaction
EP3045459B1 (en) Method for preparing intermediate compound of sitagliptin
CN102197021A (zh) 氟代硫酸酯类的制造方法
Li et al. Synergistic Ag (I)/nBu4NBr-catalyzed fixation of CO2 to β-oxopropyl carbonates via propargylic alcohols and monohydric alcohols
Deng et al. Recent progress on photocatalytic synthesis of ester derivatives and reaction mechanisms
CN102850153B (zh) 一种催化α,β-不饱和烯酮及饱和酮的不对称还原反应方法
Shibatomi et al. Lewis acid-catalyzed asymmetric fluorinations of β-keto esters: dramatic improvement in enantioselectivity by changing the operation sequence
JP2015501282A (ja) 光学活性β−ヒドロキシ−α−アミノカルボン酸エステルの製造方法
Choi et al. α, β-Unsaturated acyl cyanide synthesis via triethylamine catalyzed redox cyanation
CN104030984B (zh) 一种吡唑衍生物的制备方法
CN113200856B (zh) 一种三氟甲基丙烯基类化合物及其制备方法与应用
Lee et al. Ytterbium (III) triflate-catalyzed one-pot Mannich-type reaction in ionic liquid
WO2016045415A1 (zh) 一种不对称催化合成硝基吡唑酰胺化合物的方法
Sui et al. Cu (II)‐Catalyzed Enantioselective Conjugate Reduction for the Synthesis of N‐Aryl β‐Amino Acid Esters
Handique et al. Reduction of α, β unsaturated carbonyl compounds by Ni2+–BH4−
CN114516796A (zh) 一种制备5-氧代己酸酯的方法
Yazaki Development of catalytic reactions for precise control of chemoselectivity
Saidalimu et al. Activation of Trifluoromethylthio Moiety by Appending Iodonium Ylide under Copper Catalysis for Electrophilic Trifluoromethylation Reaction
Zheng et al. Catalytic, Conjugate Reduction‐Aldol Addition Reaction of β′‐Oxoalkyl α, β‐Unsaturated Carboxylates

Legal Events

Date Code Title Description
C06 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