CN113423690B - 吡唑衍生物 - Google Patents

吡唑衍生物 Download PDF

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CN113423690B
CN113423690B CN202080012471.8A CN202080012471A CN113423690B CN 113423690 B CN113423690 B CN 113423690B CN 202080012471 A CN202080012471 A CN 202080012471A CN 113423690 B CN113423690 B CN 113423690B
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J·A·莫里斯
S·E·拉塞尔
S·恩济
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Abstract

本发明涉及具有下式的硝基‑乙烯基‑吡唑化合物，其中环A、RB2和RB3是如权利要求1中所定义的；以及此类化合物的制造及其随后在农用化学品和/或药物的生产中的用途。

Description

吡唑衍生物
本发明涉及如本文所述的具有式(B)和式(C)的吡唑衍生物，其是在农用化学品和药物的生产中的有价值的中间体。本发明扩展到此类吡唑衍生物的制造，及其随后在农用化学品和/或药物的制造中的用途。
在第一方面，提供了一种具有式(B)的化合物
其中环A是二取代的吡唑，在环氮上被RB2取代并在环碳上被RB3取代，其中RB2是C1-C3烷基或C1-C3氟烷基并且RB3是卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基。
在第二方面，提供了一种具有式(C)的化合物
其中环A是二取代的吡唑，在环氮上被RB2取代并在环碳上被RB3取代，其中RB2是C1-C3烷基或C1-C3氟烷基，并且RB3是卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基。
具有式(B)和(C)的化合物可以用作在包括吡唑并-吡咯烷酮基序的药物和农用化学品的制造中的中间体。例如，US 2007/0123508描述了用作PAR2抑制剂的2-氧代-1-吡咯烷酮衍生物，具有式(B)、(C)、(D)和(E)的化合物可以在其中US 2007/0123508的化合物的R1是取代的吡唑的此类化合物的合成中使用。本文还描述了使用具有式(B)和(C)的化合物制造新颖的除草化合物。
具有式(B)的化合物可以由具有式(A)的卤化吡唑其中环A、RB2和RB3是如以上所定义的，并且Hal是选自碘、溴和氯的卤素，通过使具有式(A)的化合物与异丙基氯化镁-氯化锂在合适的溶剂(如四氢呋喃)中在-20℃下反应来制备。两小时后，添加1-二甲基氨基-2-硝基乙烯并在一小时的时间内将反应物缓慢温热至室温。在处理和纯化后，这得到了具有式(B)的所希望的硝基乙烯基吡唑(反应方案1)。具有式(A)的化合物是已知的，或者可以根据本领域熟知的方法制备。
反应方案1
具有式(B)的硝基乙烯基吡唑化合物还可以通过在合适的溶剂中用合适的碱使相应的吡唑醛(x)和硝基甲烷一起反应随后进行脱水步骤来制备，如下面的反应方案1.1所示。此类方法报告于WO 2016/100050和WO 2019/169153中。
反应方案1.1
然后使具有式(B)的硝基乙烯基吡唑化合物在合适的溶剂(如甲苯)中在对映选择性镍催化下与丙二酸酯(如丙二酸二乙酯)反应，如J.Am.Chem.Soc.[美国化学会志]2005,127,9958-9959中所述，以得到为具有式(C)的化合物的对映体富集的丙二酸酯加成产物，如反应方案2所示。
反应方案2
在具有式(A)、(B)和(C)的化合物中，如本文所述，环A是带有两个取代基的吡唑部分，其中所述取代基中的一个(RB2)由环氮携带，并且第二个取代基(RB3)在环碳原子上携带。显然在这种构型下，A是与相应分子的其余部分连接的碳。
当A是二取代的并且RB3在邻近取代的环氮原子的环碳原子上携带时，所述RB3取代基可以定义为RB3SN。为了避免疑问，RB3SN是仅用于表示吡唑部分内的位置布局的RB3的子定义，并且因此RB3SN也选自由以下组成的组：卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基和C1-C3烷基。因此，当A是二取代的时，它可以由基团A1、A2、A3、A4、或A5表示，如下所示，其中RB2、RB3和RB3SN是如以上所定义的，并且锯齿状线表示与相关分子的其余部分的附接点。
基团A1和A2是特别优选的，其中A2是最优选的二取代吡唑。
优选地，RB2选自由以下组成的组：甲基、乙基、正丙基、氟甲基、三氟甲基、氟乙基、二氟乙基和三氟乙基。更优选地，RB2选自由以下组成的组：甲基、乙基、正丙基、三氟甲基和二氟乙基。还更优选地，RB2选自由以下组成的组：甲基、乙基和二氟乙基。
优选地，RB3(以及因此还有RB3SN)选自氯、氟、溴、甲基、乙基、二氟甲基、三氟甲基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基。
下表1和2提供了用于本发明的具有式(B)和(C)的化合物的具体实例。
表1根据本发明的具有式B的化合物
表2根据本发明的具有式C的化合物
如本文所述的具有式(B)和(C)的化合物可以用于合成具有式(D)的吡唑并-内酰胺-甲酸酯，
其中环A、RB2和RB3是如本文所定义的，以及具有式(E)的吡唑并-内酰胺-甲酸衍生物，
同样其中环A、RB2和RB3是如本文所定义的。这些新颖的化合物构成本发明的又另外的方面。
使用合适的还原剂(如硼氢化钠)，用合适的催化剂(如氯化镍)，在合适的溶剂(如乙醇)中，将具有式(C)化合物还原环化得到具有式(D)的吡唑并-内酰胺-甲酸酯(下面的反应方案3)。
反应方案3
具有式(D)的化合物然后可以在水性氢氧化物/乙醇混合物中水解以得到适当的具有式(E)的吡唑并-内酰胺-3-甲酸衍生物，如反应方案4所示。
反应方案4
具有式(D)和式(E)的化合物也是在吡唑并-内酰胺除草剂的生产中的有价值的中间体，特别是因为它们产生优选的除草对映异构体。下表3和4提供了用于本发明的具有式(D)和(E)的化合物的具体实例。
表3根据本发明的具有式(D)的化合物
表4根据本发明的具有式(E)的化合物
由具有式(E)的化合物制造具有式(G)的新颖的吡唑并-内酰胺除草剂的方法在下面在反应方案5和6中进行了概括地描述，并对于实例中的具体的除草化合物进行了描述。
反应方案5
使用过量的碱(如叔丁醇钾)，用碘甲烷或替代性甲基化试剂，在合适的溶剂(如四氢呋喃)中将具有式(E)的化合物在内酰胺氮上甲基化(以上反应方案5)。
使用标准酰胺偶联条件，如丙烷膦酸酐在合适的溶剂(如二氯甲烷)中，用合适的碱，将具有式(F)的3-羧基取代的N-甲基内酰胺与具有式R2-NH2(其中R2是如下文所定义的)的苯胺偶联以得到具有式(G)的除草的吡唑并-内酰胺甲酰胺(反应方案6)。
反应方案6
对于具有式R2-NH2的苯胺和具有式(G)的除草化合物，R2取代基包括氢、C1-C6烷基、-Cr烷氧基Cs烷基、C1-C6卤代烷基、-Cr烷氧基Cs卤代烷基、C2-C6烯基、C2-C6炔基、以及-(CR21R22)tR20，其中每个R20独立地是-C(O)OR23、-OC(O)R23、-C3-C6环烷基、或-芳基、-芳氧基、-杂芳基、-杂芳氧基或-杂环基环，其中所述环任选地被1至3个独立的R25取代；r是1、2、3、4、或5的整数，s是1、2、3、4、或5的整数，并且r+s之和小于或等于6；t是0、1、2、3、4、5或6的整数，每个R21独立地是氢或C1-C2烷基；每个R22独立地是氢或C1-C2烷基；R23是氢或C1-C4烷基。
在某些实施例中，其中R2是任选地被1至3个R25取代的芳基或杂芳基环，并且所述芳基或杂芳基环选自由以下组成的组：苯基、吡啶基和噻吩基环系统，它可以由以下通用结构表示
其中环B是苯基、吡啶基、或噻吩基环，P是0、1、2、或3的整数，并且锯齿状线表示环与分子的其余部分的附接点，在这种情况下通过酰胺氮。
在某些实施例中，R2选自由以下组成的组：R2-1、R2-2、R2-3、R2-4、R2-5和R2-6，其中p和锯齿状线是如先前所述的，并且每个R25独立地是卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氰基、硝基、C1-C6烷硫基、C1-C6烷基亚磺酰基、或C1-C6烷基磺酰基
更优选地，每个R25独立地是卤素、C1-C4烷基、C1-C3卤代烷基、C1-C3烷氧基、或C1-C3卤代烷氧基；甚至更优选地，氯、氟、溴、C1-C2卤代烷基、C1-C2卤代烷氧基、或C1-C2烷氧基；还更优选地，氟、乙基、三氟甲基、二氟乙基、甲氧基、二氟甲氧基、或三氟甲氧基。如本文所述，p的值是1、2或3。优选地，p是0、1、或2并且每个R25被环碳原子携带。
具有式R2-NH2的苯胺是已知的，或者可以根据本领域熟知的方法制备。
下面所示的反应方案1a、2a、3a、4a和5a例示了如以上对于一组优选的实施例所述的本发明的化合物和方法，其中具有式(A)的化合物中的吡唑环具有上文描述为A2的结构。除非另有说明，否则RB2、RB3、Hal和R2是如上文所定义的。
反应方案1a
反应方案2a
反应方案3a
反应方案4a
反应方案5a
反应方案6a
现在将通过举例更详细地说明本发明的不同方面和实施例。应当理解的是，在不偏离本发明范围的情况下，可以对细节做出修改。
为了避免疑问，在本申请的正文中引用文献参考、专利申请、或专利时，将所述引用的全文通过援引并入本文。
实例
实例1：`除草化合物(3S,4R)-N-(2,3-二氟苯基)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酰胺的制备
步骤3中使用的镍催化剂，其催化不对称丙二酸酯加成至硝基烯烃，可以如J.Am.Chem.Soc.[美国化学会志]2005,127,9958-9959中制备。
步骤1 3-碘-1-甲基-5-(三氟甲基)吡唑
将化合物1-甲基-5-(三氟甲基)吡唑-3-胺(5.00g，30.3mmol)在9M硫酸(818mmol，91mL)中在500mL烧杯中，使用顶置式搅拌器在0℃(冰浴)下搅拌，直到产生均匀的混合物。然后在5分钟内逐滴添加在10mL水中的亚硝酸钠(60.6mmol，4.18g)，得到无色溶液并将反应物在0℃下再搅拌20分钟。将在20mL水中的碘化钾(75.7mmol，12.6g)逐滴添加到反应物中，并且然后将混合物再搅拌4小时。将反应物用饱和硫代硫酸钠淬灭，直到混合物变得澄清。然后将混合物用二氯甲烷稀释并且分离相。将水溶液进一步用二氯甲烷萃取，并将合并的有机萃取物用水洗涤、干燥(MgSO4)、过滤并在真空下浓缩，以得到淡黄色油状物。通过柱色谱法(EtOAc/己烷梯度洗脱)纯化粗产物，以得到呈无色油状物的3-碘-1-甲基-5-(三氟甲基)吡唑，3.9g，(47％)。
1H NMR(400MHz,CDCl3)δ＝6.76(s,1H)4.01(d,J＝0.61Hz,3H)。
步骤2 1-甲基-3-[(E)-2-硝基乙烯基]-5-(三氟甲基)吡唑
在-20℃下将THF中的异丙基氯化镁-氯化锂(23.55mmol，1.3mol/L)逐滴添加到THF(90mL)中的3-碘-1-甲基-5-(三氟甲基)吡唑(5.0g，18.12mmol)中并将混合物搅拌2小时。添加1-二甲基氨基-2-硝基乙烯(27.17mmol，3.321g)并在1小时内将反应物缓慢温热至室温。然后将反应混合物小心地用2M HCl淬灭，并用乙酸乙酯萃取。将有机萃取物用盐水洗涤、干燥(MgSO4)、过滤、浓缩并通过色谱法(EtOAc/环己烷梯度洗脱)纯化，以得到呈黄色油状物的1-甲基-3-[(E)-2-硝基乙烯基]-5-(三氟甲基)吡唑(74.6％)，2.99g(74.6％)。
1H NMR(400MHz,CDCl3)δ＝7.89(d,J＝13.7Hz,1H),7.63(d,J＝13.7Hz,1H),6.88(s,1H),4.05(d,J＝0.6Hz,3H)。
步骤3 2-[(1S)-1-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-硝基-乙基]丙二酸二乙酯
向甲苯(19.5mL)中的1-甲基-3-[(E)-2-硝基乙烯基]-5-(三氟甲基)吡唑(0.650g，2.94mmol)溶液中添加丙二酸二乙酯(0.676mL，4.41mmol)，然后添加镍(II)双[(1R,2R)-N1,N2-双(苯基甲基)-1,2-环己烷二胺-N1,N2]二溴化物(0.0588mmol，0.0472g)，并将混合物在环境温度下搅拌20小时。
将反应混合物用水(2x10mL)洗涤并将有机相分离、浓缩并通过色谱法(EtOAc/环己烷梯度洗脱)纯化，以得到呈淡黄色油状物的2-[(1S)-1-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-硝基-乙基]丙二酸二乙酯，1.07g(95％)。
1H NMR(400MHz,CDCl3)δ＝6.53(s,1H),5.01(dd,1H),4.88(dd,J＝4.3,13.9Hz,1H),4.35(ddd,J＝4.4,7.7,9.0Hz,1H),4.22(q,2H),4.16(q,J＝7.1Hz,2H),3.90(s,3H),3.89(d,1H),1.26(t,3H),1.20(t,J＝7.2Hz,3H)。
步骤4(3R,4R)-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸乙酯
向在氮气下的冷却至0℃-5℃(冰浴)的乙醇(42.1mL)中的2-[(1R)-1-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-硝基-乙基]丙二酸二乙酯(1.07g，2.81mmol)溶液中添加二氯化镍六水合物(2.95mmol，0.700g)。然后将硼氢化钠(8.42mmol，0.325g)分批添加到淡绿蓝色的溶液中。30分钟后，除去冷却，并使反应混合物温热至环境温度。搅拌5小时后，在环境温度下，将反应混合物在冰-水浴中冷却到5℃-10℃，并缓慢地用氯化铵溶液淬灭，并将混合物再搅拌20分钟。然后将混合物用EtOAc(20mL)稀释，并通过硅藻土床过滤，用分批的水和EtOAc洗涤。将收集的两相混合物浓缩以除去大部分溶剂，并将残余物转移到分液漏斗中、用EtOAc(20mL)稀释并将有机相分离。将水相进一步用EtOAc(2x 25mL)萃取，并将所有的有机萃取物合并，通过相分离浓缩并通过色谱法(EtOAc/己烷梯度洗脱)纯化，以得到淡黄色油状物，0.61g(77％)，其在静置后结晶。
1H NMR(400MHz,CDCl3)δ＝6.91(br s,1H),6.47(s,1H),4.28(q,J＝7.2Hz,2H),4.14(q,1H),3.94(d,3H),3.80(dt,J＝1.0,9.0Hz,1H),3.63(d,J＝9.3Hz,1H),3.52(dd,J＝8.2,9.5Hz,1H),1.32(t,J＝7.2Hz,3H)。
步骤5(3R,4R)-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸
在0℃(冰浴)下向乙醇(6.0mL)和水(2.0mL)中的(3R,4R)-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸乙酯(0.61g，2.0mmol)溶液中添加2M氢氧化钠(3mL，6.0mmol)。将反应混合物在0℃下搅拌30分钟并且然后用水(15mL)稀释并用EtOAc(25mL)萃取。将有机萃取物用水(10mL)洗涤，并将水性萃取物合并并且用稀HCl酸化至pH2。然后将酸化的水性萃取物用EtOAc(3x 20mL)再萃取，并将这些有机萃取物穿过相分离筒并浓缩，得到淡黄色油状物，0.54g(定量)，其在静置后结晶。
1H NMR(400MHz,CDCl3)δ＝6.59(s,1H),4.09(q,1H),3.94(s,3H),3.85-3.77(m,1H),3.72(d,J＝10.0Hz,1H),3.66-3.58(m,1H)。
步骤6(3R,4R)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸
在氮气氛下，在室温下，向四氢呋喃(16mL)中的(3R,4R)-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸(0.57g，2.1mmol，0.57g)搅拌溶液中添加叔丁醇钾(1.0M在THF中)(4.5mL，4.5mmol)，得到淡黄色精细悬浮液。向此悬浮液中添加碘甲烷(0.19mL，3.1mmol)，并在室温下继续搅拌20h。将搅拌的反应混合物用稀HCl酸化至pH 2，并将混合物用水(10mL)稀释并用EtOAc(3x 30mL)萃取。将合并的有机萃取物用盐水(15mL)洗涤、经硫酸镁干燥、过滤并将滤液浓缩，得到透明的琥珀色胶状物，0.63g(定量)。
1H NMR：(400MHz,CDCl3)δ＝6.68(s,1H),3.97(q,1H),3.94(s,3H),3.76-3.68(m,3H),2.99(s,3H)。
步骤7(3S,4R)-N-(2,3-二氟苯基)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酰胺
向二氯甲烷(15mL)中的(3R,4R)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酸(0.61g，2.1mmol)溶液中添加2,3-二氟苯胺(0.21mL，2.1mmol)。然后添加乙酸乙酯中的丙基膦酸酐(50质量％)(2.3g，3.6mmol，2.1mL)，并且然后将反应混合物浸入室温的水浴中。逐滴添加N,N-二异丙基乙胺(1.1mL，6.3mmol)，并将反应物在室温下搅拌2.5小时。将反应混合物通过添加水(15mL)淬灭并转移到相分离筒中。将水溶液进一步用DCM(2x 10mL)萃取并将合并的有机萃取物浓缩并通过色谱法(EtOAc/己烷梯度洗脱)纯化，以得到粉色油状物。用异己烷研磨得到淡粉色固体398mg(47％)。
1H NMR：(400MHz,CDCl3)δ＝10.16(br s,1H),8.08-8.01(m,1H),7.02(ddt,J＝2.1,5.9,8.3Hz,1H),6.93-6.84(m,1H),6.69(s,1H),4.09(q,1H),3.94(s,3H),3.78(d,J＝9.5Hz,1H),3.76-3.65(m,2H),2.98(s,3H)。
通过上述方法进行的手性HPLC分析确认对映异构体比率为97:3。
实例2(3S,4S)-N-(2,3-二氟苯基)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-4-基]-2-氧代-吡咯烷-3-甲酰胺的制备
除草化合物(3S,4S)-N-(2,3-二氟苯基)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-4-基]-2-氧代-吡咯烷-3-甲酰胺以与以上对于以上实例1中的(3S,4R)-N-(2,3-二氟苯基)-1-甲基-4-[1-甲基-5-(三氟甲基)吡唑-3-基]-2-氧代-吡咯烷-3-甲酰胺所述的完全类似的方式制造。单一对映异构体的NMR数据如下：
1HNMR(CDCl3)δ＝10.05(br s,1H),8.04-7.97(m,1H),7.46(s,1H),7.01(ddt,J＝2.1,5.9,8.3Hz,1H),6.93-6.84(m,1H),4.21(q,J＝8.8Hz,1H),4.00(s,3H),3.75(t,J＝9.5Hz,1H),3.64(d,J＝9.4Hz,1H),3.27(dd,J＝8.1,9.9Hz,1H),2.97(s,3H)。

Claims (11)

1.一种具有式(B)的化合物
其中环A是二取代的吡唑，在环氮上被RB2取代并在环碳上被RB3取代，其中RB2是C1-C3烷基或C1-C3氟烷基并且每个RB3是卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基，
条件是所述化合物不是(i)1,3-二甲基-4-(2-硝基乙烯基)吡唑或(ii)1,5-二甲基-4-(2-硝基乙烯基)吡唑。
2.一种具有式(C)的化合物
其中环A、RB2和RB3是如权利要求1中所定义的。
3.如权利要求1或权利要求2所述的化合物，其中，环A是A1、A2、A3、A4或A5，
其中RB3SN是位于与被RB2取代的氮原子紧邻的碳原子上的RB3取代基，并且锯齿状线表示与硝基乙烯基部分的附接处。
4.如权利要求1或2所述的化合物，其中，RB2选自由以下组成的组：甲基、乙基、正丙基、氟甲基、三氟甲基、氟乙基、二氟乙基和三氟乙基。
5.如权利要求3所述的化合物，其中，RB2选自由以下组成的组：甲基、乙基、正丙基、氟甲基、三氟甲基、氟乙基、二氟乙基和三氟乙基。
6.如权利要求1或2所述的化合物，其中，RB3选自由以下组成的组：氯、氟、溴、甲基、乙基、二氟甲基、三氟甲基、C1-C3卤代烷氧基、C1-C3烷氧基和C1-C3烷基。
7.如权利要求3所述的化合物，其中，RB3选自由以下组成的组：氯、氟、溴、甲基、乙基、二氟甲基、三氟甲基、C1-C3卤代烷氧基、C1-C3烷氧基和C1-C3烷基。
8.如权利要求4所述的化合物，其中，RB3选自由以下组成的组：氯、氟、溴、甲基、乙基、二氟甲基、三氟甲基、C1-C3卤代烷氧基、C1-C3烷氧基和C1-C3烷基。
9.如权利要求5所述的化合物，其中，RB3选自由以下组成的组：氯、氟、溴、甲基、乙基、二氟甲基、三氟甲基、C1-C3卤代烷氧基、C1-C3烷氧基和C1-C3烷基。
10.一种用于制造具有式(D)的化合物的对映选择性方法
其中环A是二取代的吡唑，在环氮上被RB2取代并在环碳上被RB3取代，其中RB2是C1-C3烷基或C1-C3氟烷基并且每个RB3是卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基，
所述对映选择性方法包括：
(i)使具有式(A)的卤化吡唑，
其中Hal是选自碘、溴和氯的卤素；
与异丙基氯化镁-氯化锂在合适的溶剂中反应并且随后添加1-二甲基氨基-2-硝基乙烯以得到具有式(B)的化合物
(ii)使来自步骤(i)的所述具有式(B)的化合物与丙二酸酯在溶剂中在对映选择性镍催化下反应以得到具有式(C)的化合物
；
以及
(iii)使来自步骤2的所述具有式(C)的化合物与还原剂在溶剂中在催化剂存在下反应以得到所述具有式(D)的化合物
11.一种用于制造具有式(E)的化合物的对映选择性方法
其中环A是二取代的吡唑，在环氮上被RB2取代并在环碳上被RB3取代，其中RB2是C1-C3烷基或C1-C3氟烷基并且每个RB3是卤素、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3氟烷基、C1-C3卤代烷氧基、C1-C3烷氧基、或C1-C3烷基，
(i)所述对映选择性方法包括：使具有式(A)的卤化吡唑，
其中Hal是选自碘、溴和氯的卤素；
与异丙基氯化镁-氯化锂在合适的溶剂中反应并且随后添加1-二甲基氨基-2-硝基乙烯以得到具有式(B)的化合物
(ii)使来自步骤(i)的所述具有式(B)的化合物与丙二酸酯在溶剂中在对映选择性镍催化下反应以得到具有式(C)的化合物
(iii)使来自步骤2的所述具有式(C)的化合物与还原剂在溶剂中在催化剂存在下反应以得到具有式(D)的化合物
以及
(iv)在水性氢氧化物/乙醇混合物中水解来自步骤(iii)的所述具有式(D)的化合物以得到所述具有式(E)的化合物
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