CN105985292B - 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

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CN105985292B
CN105985292B CN201510075076.5A CN201510075076A CN105985292B CN 105985292 B CN105985292 B CN 105985292B CN 201510075076 A CN201510075076 A CN 201510075076A CN 105985292 B CN105985292 B CN 105985292B
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冯小明
姚乾
刘小华
林丽丽
张宇恒
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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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,C<sub>6</sub>H<sub>5</sub>,CH<sub>3</sub>,H 99 99
2 H,4-FC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 99 99
3 H,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 98 98
4 H,4-BrC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 96 98
5 H,4-MeC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 95 99
6 H,4-MeOC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 89 99
7 H,3-BrC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 98 98
8 H,3-MeC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 96 99
9 H,2-BrC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 99 99
10 H,2-MeOC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 99 99
11 H,3,4–Cl<sub>2</sub>C<sub>6</sub>H<sub>3</sub>,CH<sub>3</sub>,H 96 99
12 H,3,4-(MeO)<sub>2</sub>C<sub>6</sub>H<sub>3</sub>,CH<sub>3</sub>,H 83 99
13 H,2-Furyl,CH<sub>3</sub>,H 56 97
14 H,2-Thienyl,CH<sub>3</sub>,H 58 98
15 H,CH<sub>3</sub>,CH<sub>3</sub>,H 69 98
16 H,Pr,CH<sub>3</sub>,H 87 98
17 H,Pent,CH<sub>3</sub>,H 65 98
18 H,<sup>i</sup>Bu,CH<sub>3</sub>,H 77 98
19 H,EtO,CH<sub>3</sub>,H 53 95
20 H,EtOOC,CH<sub>3</sub>,H 67 95
21 H,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,Cl 94 99
22 H,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,Br 96 99
23 H,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,I 97 99
24 H,4-ClC<sub>6</sub>H<sub>4</sub>,C<sub>6</sub>H<sub>5</sub>,H 39 81
25 CH<sub>3</sub>,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 94 98/98(d.r.1.6/1)
26 Et,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,H 87 99/98(d.r.1.2/1)
27 PhCH<sub>2</sub>,4-ClC<sub>6</sub>H<sub>4</sub>,CH<sub>3</sub>,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(Daicelchiralcel AD-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 (11)

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α,β-不饱和吡唑酰胺和硝基烷烃为原料，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，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：
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；
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-；
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；
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。
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：二氯甲烷。
3.按权利要求1所述的方法，其特征在于硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比为9.3:1。
4.按权利要求1所述的方法，其特征在于稀土金属化合物是三氟甲磺酸钆[Gd(OTf)3]。
5.按权利要求1所述的方法，其特征在于手性氧化胺配体是n＝2,R＝2,6-iPr2C6H3-。
6.按权利要求1所述的方法，其特征在于手性氧化胺配体和三氟甲磺酸钆[Gd(OTf)3]的摩尔比为1.2:1。
7.按权利要求1所述的方法，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。
8.按权利要求1所述的方法，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。
9.按权利要求1所述的方法，其特征在于0.1mmolα,β-不饱和吡唑酰胺化合物需要二氯甲烷6.2mmol。
10.按权利要求1所述的方法，其特征在于反应温度为30℃。
11.按权利要求1所述的方法，其特征在于反应时间为72-96h。
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