CN110872232B - 相转移催化β-酮酸酯不对称α-二氟甲基化的方法 - Google Patents

相转移催化β-酮酸酯不对称α-二氟甲基化的方法 Download PDF

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CN110872232B
CN110872232B CN201911085955.0A CN201911085955A CN110872232B CN 110872232 B CN110872232 B CN 110872232B CN 201911085955 A CN201911085955 A CN 201911085955A CN 110872232 B CN110872232 B CN 110872232B
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王亚坤
房立真
从梅
段迎超
高飞宇
陈依帆
崔静雯
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Abstract

本发明公开了一种相转移催化β‑酮酸酯不对称α‑二氟甲基化的方法，将β‑酮酸酯类化合物IIIa、相转移催化剂、TMSCF2Br和碱在溶剂中于‑78~60℃搅拌反应，薄层色谱跟踪反应直至反应结束后混合液分层，收集有机层并旋干溶剂，柱层析分离得到手性α‑二氟甲基‑β‑酮酸酯类化合物IIIb。本发明的有效性体现在通过使用廉价易得的金鸡纳碱季铵盐作为相转移催化剂，并通过相转移催化的方法首次成功实现了β‑酮酸酯类化合物的不对称的α‑二氟甲基化，为合成具有光学活性的α‑二氟甲基‑β‑酮酸酯类化合物的合成提供了新颖且有效的途径。

Description

相转移催化β-酮酸酯不对称α-二氟甲基化的方法
技术领域
本发明属于有机合成技术领域，具体涉及一种相转移催化β-酮酸酯不对称α-二氟甲基化的方法。
背景技术
含氟化合物在制药、农用化学品和材料科学中发挥着引人注目和日益重要的作用，广泛的存在于天然产物，手性医药及农药中间体中。其中，二氟甲基(CF2H)基团因其作为OH/SH的生物电子等排体和亲脂氢键供体而备受关注(J.Med.Chem.2019,62,5628-5637)。正因为如此，含有二氟甲基的有机分子已被应用于许多已上市的药物中，如PDE4抑制剂Roflumilast和质子泵抑制剂潘托普拉唑。
近些年来，人们开发了许多方法来获得含二氟甲基的化合物。过渡金属催化是二氟甲基化的有效手段(Chem.Eur.J.2017,23,14676-14701)。除此之外，亲电二氟甲基化是一种强有力的策略，利用二氟卡宾实现的二氟甲基化已经引起了人们广泛的关注(Chem.Rev.2014,115,765-825)。β-酮酸酯是应用广泛的亲核试剂，而该类化合物的α-二氟甲基反应已经被Hu(Angew.Chem.Int.Ed.2019,131,6471-6476.)，Shibata(Chem.Commun.2018,54,8881-8884),Shen(Chin.J.Chem.2018,36,1069-1074)和Liu课题组(Org.Lett.2018,20,6925-6929.)利用不同的二氟甲基化试剂实现。在不对称氟化学领域，羰基化合物的不对称氟化反应(Org.Lett.2002,4,545-547)，不对称全氟烷基化反应(J.Am.Chem.Soc.2015,137,5678-5681)，不对称三氟甲基化反应(J.Am.Chem.Soc.2010,132,4986-4987)已经实现。然而，目前还没有一例通过不对称合成直接实现亲核试剂的不对称二氟甲基化反应。因此，开发一种简单直接的方法直接实现β-酮酸酯的不对称α-二氟甲基化反应是一种具有挑战性且意义重大的工作。
另一方面，不对称相转移催化被认为是绿色、可持续的手段，而金鸡纳碱衍生的手性相转移催化剂已经在手性药物分子的合成中获得了广泛的应用(Angew.Chem.Int.Ed.2013,52,4312-4348；J.Tan,N.Yasuda,Org.Process Res.Dev.2015,19,1731-1746.)。本申请人开发了一系列的金鸡纳碱衍生的手性相转移催化剂，并成功实现了β-酮酸酯的不对称α-光氧化反应(Green Chem.2016,18,5493-5499；J.Org.Chem.2016,81,7042-7050)，不对称α-酰氧化反应(J.Org.Chem.2018,83,2263-2273；Tetrahedron 2018,74,4126-4133)以及不对称α-烷基化反应(Org.Biomol.Chem.2019,17,573-584)。在此基础上，本申请人利用相转移催化策略，通过催化剂的筛选，反应条件的优化，成功实现了首例相转移催化β-酮酸酯不对称α-二氟甲基化反应。
发明内容
本发明解决的技术问题是提供一种相转移催化β-酮酸酯不对称α-二氟甲基化的方法，即通过相转移催化的方法实现β-酮酸酯的不对称α-二氟甲基化，最终制得手性α-二氟甲基-β-酮酸酯类化合物。
本发明为解决上述技术问题采用如下技术方案，相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于具体过程为：将β-酮酸酯类化合物IIIa、相转移催化剂、TMSCF2Br和碱在溶剂中于-78～60℃搅拌反应，薄层色谱跟踪反应直至反应结束后混合液分层，收集有机层并旋干溶剂，柱层析分离得到手性α-二氟甲基-β-酮酸酯类化合物IIIb；制备过程中的反应方程式为：
Figure GDA0003366917370000021
其中R7为烷基、环烷基、芳环或苄基，n为1或2，R8、R9、R10为氢原子、卤素、烷基、烷氧基或环烷基；
所述相转移催化剂为金鸡纳碱辛可宁衍生物催化剂Ia，其化学式如下：
Figure GDA0003366917370000022
其中R1为氢、苯基、4-三氟甲基苯基、3-三氟甲基苯基或1-萘基；R2、R3、R4、R5、R6为氢原子、卤素、烷基、烷氧基或芳基。
进一步优选，所述金鸡纳碱辛可宁衍生物催化剂Ia的合成路线为：
Figure GDA0003366917370000031
该金鸡纳碱辛可宁衍生物催化剂Ia的具体合成过程为：使用正丁基锂与R1Br发生锂卤素交换反应后，与辛可宁发生反应得到C-2`位取代的辛可宁，之后再与取代苄溴在氯仿/甲醇混合溶液中反应得到金鸡纳碱辛可宁衍生物催化剂Ia。
进一步优选，所述碱为有机碱水溶液或无机碱水溶液；所述溶剂为卤代烃、芳香烃、烷烃或醚。
进一步优选，所述无机碱水溶液为碳酸钠、磷酸氢二钾、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、甲醇钠或乙醇钠中一种或多种水溶液组合。
进一步优选，所述无机碱水溶液优选为质量浓度为30％的碳酸钾水溶液、质量浓度为50％的氢氧化钠水溶液、质量浓度为50％的氢氧化钾水溶液、质量浓度为30％的碳酸铯水溶液、质量浓度为50％的磷酸氢二钾水溶液或质量浓度为50％的乙醇钠水溶液。
进一步优选，所述溶剂优选为甲苯、三氟甲苯、氯仿、乙醚、乙酸乙酯、对二甲苯、均三甲苯、正己烷或体积比为1:1的甲苯与氯仿的混合溶液。
进一步优选，所述相转移催化剂与β-酮酸酯类化合物的投料摩尔比为0.0001～0.5:1，TMSCF2Br与β-酮酸酯类化合物的投料摩尔比为1～3:1。
进一步优选，所述相转移催化剂与β-酮酸酯类化合物的投料摩尔比优选为0.01～0.05:1。
进一步优选，反应温度优选为-40～0℃。
与现有技术相比，本发明具有以下有益效果：本发明的有效性体现在通过使用廉价易得的金鸡纳碱季铵盐作为相转移催化剂，并通过相转移催化的方法首次成功实现了β-酮酸酯类化合物的不对称的α-二氟甲基化，为实现光学活性的α-二氟甲基-β-酮酸酯类化合物的合成提供了新颖且有效的途径。
具体实施方式
以下通过实施例对本发明的上述内容作进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Ia-1的制备(Ia中，R1为H，R2-R5为H)
Figure GDA0003366917370000041
在50mL三口烧瓶中加入辛可宁1.47g，四氢呋喃50mL，苄溴1.27g，氩气保护下回流反应16小时。反应结束后冷却至室温，混合液倒入50mL乙醚中，过滤，固体用甲醇/乙醚重结晶，得到Ia-1，收率88％。
实施例2
Ia-2的制备(Ia中，R1为4-三氟甲基苯基，R2-R5为H)
Figure GDA0003366917370000042
称取辛可宁5.88g(10mmol)，加入75mL干燥的甲基叔丁基醚溶液中，氩气保护。在-20℃下，向甲基叔丁基醚溶剂的4-溴三氟甲苯(11.26g,50mmol)中滴加15mL甲基叔丁基醚，通过锂-卤素交换反应制备4-三氟甲基苯基锂试剂。制备的有机锂试剂迅速加入辛可宁溶液中，在-20℃下搅拌1小时。随后混合物升至室温，继续搅拌2小时。反应结束后，用30mL乙酸淬灭体系，加入60mL水和60mL乙酸乙酯。随后加入固体碘5g，剧烈搅拌使其溶解。随后，加入20mL水溶解的硫代硫酸钠2g淬灭碘。混合液用氨水调节pH＝10，水层用乙酸乙酯萃取两次，收集有机层，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥。旋干溶剂后，粗品柱层析分离(乙酸乙酯/甲醇＝9:1)得到橘黄色固体Cn'(4.35g,收率48％).随后，在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，苄溴0.25g。在氩气保护下，反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，固体用甲醇/乙醚重结晶，得到Ia-2,收率71％。1H NMR(400MHz,CDCl3)δ8.45(d,J＝8.4Hz,1H),8.33(d,J＝7.7Hz,3H),7.81(d,J＝8.1Hz,2H),7.65–7.60(m,2H),7.20–7.01(m,5H),6.76(d,J＝5.7Hz,1H),6.59–6.49(m,1H),6.15(d,J＝11.8Hz,1H),5.85(ddd,J＝17.4,10.5,7.1Hz,1H),5.41(d,J＝11.8Hz,1H),5.30–5.10(m,2H),4.46(ddd,J＝12.4,9.1,2.3Hz,1H),4.30–4.04(m,2H),3.31(t,J＝11.5Hz,1H),2.76(q,J＝10.1Hz,1H),2.28(q,J＝9.0Hz,1H),2.18–1.99(m,1H),1.75(dt,J＝32.2,12.0Hz,6H),0.81(t,J＝7.5Hz,1H)。
实施例3
Ia-3的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为CF3，R4-R6为H)
Figure GDA0003366917370000051
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-三氟甲基苄溴0.46g。反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品用二氯甲烷/甲醇＝15:1柱层析分离，随后用甲醇/乙醚重结晶，得到Ia-3，收率53％。1H NMR(400MHz,CD3OD)δ8.56(d,J＝1.6Hz,2H),8.49–8.33(m,4H),8.22(s,1H),8.16–8.09(m,1H),7.89–7.71(m,4H),6.63(d,J＝2.5Hz,1H),6.09(ddd,J＝17.4,10.4,7.2Hz,1H),5.59–5.44(m,1H),5.43–5.22(m,3H),4.56(ddd,J＝11.7,8.4,2.7Hz,1H),4.17(dt,J＝9.9,5.3Hz,2H),3.69–3.47(m,1H),3.13(dt,J＝11.6,9.1Hz,1H),2.76–2.41(m,2H),2.03–1.76(m,3H),1.15–1.02(m,1H)。
实施例4
Ia-4的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为OMe，R4-R6为H)
Figure GDA0003366917370000052
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-甲氧基苄溴0.46g。反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品用二氯甲烷/甲醇＝12:1柱层析分离，随后用甲醇/乙醚重结晶，得到Ia-4，收率53％。1H NMR(400MHz,CD3OD)δ8.49–8.27(m,4H),8.18–8.05(m,1H),7.83(d,J＝8.2Hz,2H),7.79–7.64(m,2H),6.95(d,J＝2.3Hz,2H),6.71–6.54(m,2H),6.06(ddd,J＝17.4,10.5,7.2Hz,1H),5.35–5.22(m,2H),5.15(d,J＝12.1Hz,1H),4.99(d,J＝12.1Hz,1H),4.40(td,J＝10.2,9.4,4.8Hz,1H),4.19–4.01(m,2H),3.84(s,6H),3.70(t,J＝11.5Hz,1H),3.11(dt,J＝11.9,9.3Hz,1H),2.63–2.42(m,2H),1.98–1.70(m,3H),1.16–0.96(m,1H)。
实施例5
Ia-5的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为叔丁基，R4-R6为H)
Figure GDA0003366917370000061
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-二叔丁基苄溴0.50g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-5，收率45％。1H NMR(400MHz,CDCl3)δ8.44–8.24(m,3H),8.19–8.10(m,1H),7.94(dd,J＝7.9,1.9Hz,1H),7.75(d,J＝8.0Hz,2H),7.66(dd,J＝11.3,1.7Hz,2H),7.53–7.33(m,3H),6.57(s,1H),5.89(ddd,J＝17.5,10.4,7.4Hz,1H),5.59–5.37(m,2H),5.24–4.95(m,2H),4.52(t,J＝10.8Hz,1H),4.29–3.97(m,2H),3.51(t,J＝11.5Hz,1H),2.91(q,J＝7.1Hz,3H),2.51–2.21(m,2H),1.90–1.62(m,3H),1.31(s,18H),1.27–1.19(m,6H)。
实施例6
Ia-6的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为苯基，R4-R6为H)
Figure GDA0003366917370000062
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-苯基苄溴0.52g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-6，收率78％。1H NMR(400MHz,CD3OD)δ8.38(t,J＝7.0Hz,4H),8.20–8.06(m,1H),7.98(d,J＝34.4Hz,3H),7.88–7.67(m,8H),7.53–7.29(m,6H),6.65(d,J＝11.4Hz,1H),6.19–5.95(m,1H),5.51–5.07(m,4H),4.56–4.40(m,1H),4.24–4.03(m,2H),3.76–3.52(m,3H),3.16(d,J＝12.7Hz,1H),2.79–2.36(m,2H),2.02–1.63(m,4H),1.26(s,2H),1.13–0.76(m,3H)。
实施例7
Ia-7的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为氟，R4-R6为H)
Figure GDA0003366917370000071
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-二氟苄溴0.43g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-7，收率83％。1H NMR(400MHz,CD3OD)δ8.42(d,J＝8.4Hz,4H),8.21(d,J＝8.1Hz,1H),7.96–7.70(m,4H),7.57–7.48(m,2H),7.24(t,J＝2.4Hz,1H),6.63(d,J＝2.5Hz,1H),6.10(ddd,J＝17.3,10.4,7.1Hz,1H),5.41–5.19(m,3H),5.06(d,J＝12.7Hz,1H),4.46(ddd,J＝11.9,8.4,2.7Hz,1H),4.15–3.92(m,2H),3.67(t,J＝11.3Hz,1H),3.25–3.07(m,1H),2.77–2.39(m,2H),1.90(dd,J＝29.7,15.9Hz,3H),1.14(q,J＝13.1,9.4Hz,1H)。
实施例8
Ia-8的制备(Ia中，R1为4-三氟甲基苯基，R2-R3为溴，R4-R6为H)
Figure GDA0003366917370000072
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3,5-二溴苄溴0.46g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-8，收率78％。1H NMR(400MHz,CD3OD)δ8.40(d,J＝8.6Hz,4H),8.17(dd,J＝8.0,1.5Hz,1H),8.05(d,J＝1.7Hz,2H),7.96(d,J＝1.6Hz,1H),7.91–7.70(m,4H),6.60(d,J＝2.5Hz,1H),6.09(ddd,J＝17.4,10.4,7.1Hz,1H),5.37–5.18(m,3H),5.03(d,J＝12.4Hz,1H),4.45(ddd,J＝11.8,8.5,2.6Hz,1H),4.20–3.99(m,2H),3.60(t,J＝11.3Hz,1H),3.14(dt,J＝11.8,9.3Hz,1H),2.76–2.45(m,2H),2.02–1.80(m,3H),1.19–1.02(m,1H)。
实施例9
Ia-9的制备(Ia中，R1为4-三氟甲基苯基，R2为苯基，R3-R6为H)
Figure GDA0003366917370000081
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3-苯基苄溴0.37g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-9，收率69％。1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.31(d,J＝8.0Hz,3H),7.94–7.73(m,3H),7.64(t,J＝9.3Hz,2H),7.53(d,J＝7.4Hz,2H),7.39(dt,J＝13.0,7.1Hz,3H),7.16(q,J＝7.7,6.5Hz,1H),7.00(q,J＝7.9Hz,2H),6.83(dd,J＝20.4,6.0Hz,1H),6.59(s,1H),6.33(d,J＝11.9Hz,1H),5.84(ddd,J＝17.4,10.4,7.2Hz,1H),5.59(d,J＝11.8Hz,1H),5.25–5.10(m,2H),4.50(ddd,J＝12.1,9.0,2.4Hz,1H),4.28–4.01(m,2H),3.35(t,J＝11.6Hz,1H),2.80(q,J＝10.2Hz,1H),2.38–2.04(m,2H),1.82–1.61(m,3H),1.53–1.17(m,3H)。
实施例10
Ia-10的制备(Ia中，R1为4-三氟甲基苯基，R2为三氟甲基，R3-R6为H)
Figure GDA0003366917370000082
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3-苯基苄溴0.37g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-10，收率69％。1H NMR(400MHz,CD3OD)δ8.50–8.32(m,4H),8.28–8.14(m,2H),8.08(d,J＝7.8Hz,1H),7.97–7.75(m,6H),6.66(d,J＝9.5Hz,1H),6.11(ddd,J＝17.4,10.6,7.2Hz,1H),5.33–5.23(m,2H),5.25–5.03(m,1H),4.49(ddd,J＝11.8,8.5,2.7Hz,1H),4.25–4.03(m,2H),3.76–3.53(m,1H),3.16–2.99(m,1H),2.74–2.38(m,2H),1.99–1.78(m,3H),1.20–1.07(m,1H)。
实施例11
Ia-11的制备(Ia中，R1为4-三氟甲基苯基，R2为溴，R3-R6为H)
Figure GDA0003366917370000091
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，3-溴苄溴0.38g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-11，收率85％。1H NMR(400MHz,CD3OD)δ8.50–8.31(m,4H),8.22(d,J＝8.2Hz,1H),8.02(s,1H),7.91–7.72(m,6H),7.52(td,J＝7.9,1.7Hz,1H),6.65(s,1H),6.11(ddd,J＝17.5,10.5,7.4Hz,1H),5.36–5.23(m,2H),5.20–4.96(m,2H),4.45(ddd,J＝11.8,8.4,2.7Hz,1H),4.14–3.89(m,2H),3.63(t,J＝11.3Hz,1H),3.13(q,J＝9.9Hz,1H),2.73–2.44(m,2H),1.98–1.80(m,3H),1.20–1.08(m,1H)。
实施例12
Ia-12的制备(Ia中，R1为4-三氟甲基苯基，R2、R3、R5、R6为H，R4为三氟甲基)
Figure GDA0003366917370000092
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，4-三氟甲基苄溴0.35g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-12，收率65％。1H NMR(400MHz,CDCl3)δ8.43(d,J＝8.5Hz,1H),8.40–8.25(m,3H),7.83(dd,J＝14.5,7.8Hz,4H),7.61(d,J＝8.3Hz,1H),7.41(d,J＝7.9Hz,2H),7.01(dt,J＝43.8,7.5Hz,2H),6.86–6.73(m,1H),6.62–6.40(m,2H),5.84(ddd,J＝17.4,10.4,7.2Hz,1H),5.46(dd,J＝24.3,11.8Hz,1H),5.29–5.10(m,2H),4.51(ddd,J＝12.1,8.9,2.5Hz,1H),4.32–4.03(m,2H),3.23–3.03(m,2H),2.66(dd,J＝15.2,6.5Hz,1H),2.32(q,J＝8.9Hz,1H),2.11(d,J＝52.3Hz,1H),1.85–1.68(m,3H),1.56–1.44(m,1H),1.26(s,3H)。
实施例13
Ia-13的制备(Ia中，R1为4-三氟甲基苯基，R2、R3、R5、R6为H，R4为叔丁基)
Figure GDA0003366917370000101
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，4-叔丁基苄溴0.36g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-13，收率71％。1H NMR(400MHz,CD3OD)δ8.43(d,J＝6.6Hz,3H),8.35(d,J＝8.2Hz,1H),8.23(d,J＝8.3Hz,1H),7.95–7.76(m,4H),7.73–7.56(m,4H),6.73–6.57(m,1H),6.26–5.90(m,1H),5.30–5.23(m,1H),5.16–4.95(m,2H),4.51–4.31(m,1H),4.16–3.85(m,2H),3.74–3.51(m,1H),2.76–2.43(m,2H),2.01–1.75(m,4H),1.38(s,9H),1.10(t,J＝7.3Hz,2H)。
实施例14
Ia-14的制备(Ia中，R1为4-三氟甲基苯基，R2、R3、R4、R5、R6为F)
Figure GDA0003366917370000102
在50mL三口烧瓶中加入Cn'0.43g，氯仿8mL，甲醇4mL，2,3,4,5,6-5氟苄溴0.42g。氩气保护下反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，粗品直接用甲醇/乙醚重结晶，得到Ia-14，收率88％。1H NMR(400MHz,CD3OD)δ8.44(d,J＝7.3Hz,4H),8.23(d,J＝8.4Hz,1H),7.85(dd,J＝32.4,7.9Hz,4H),6.75–6.59(m,1H),6.11(ddd,J＝17.4,10.6,7.3Hz,1H),5.36–5.24(m,3H),5.17(d,J＝13.7Hz,1H),4.47(t,J＝9.8Hz,1H),4.24(t,J＝10.4Hz,1H),3.93(q,J＝13.5,12.2Hz,1H),3.66–3.50(m,2H),2.73(q,J＝8.8Hz,1H),2.52(t,J＝12.1Hz,1H),1.97(dd,J＝16.3,8.9Hz,4H),1.48–1.14(m,5H),1.09–0.90(m,2H)。
实施例15
Ia-15的制备(Ia中，R1为苯基，R2-R3为溴，R4-R6为H)
Figure GDA0003366917370000111
称取辛可宁5.88g(10mmol)，加入75mL干燥的甲基叔丁基醚溶液中，氩气保护。在-20℃下，向甲基叔丁基醚溶剂的4-溴甲苯(7.8g,50mmol)中滴加15mL甲基叔丁基醚，通过锂-卤素交换反应制备苯基锂试剂。制备的有机锂试剂迅速加入辛可宁溶液中，在-20℃下搅拌1小时。随后混合物升至室温，继续搅拌2小时。反应结束后，用30mL乙酸淬灭体系，加入60mL水和60mL乙酸乙酯。随后加入固体碘5g，剧烈搅拌使其溶解。随后，加入20mL水溶解的硫代硫酸钠2g淬灭碘。混合液用氨水调节pH＝10，水层用乙酸乙酯萃取两次，收集有机层，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥。旋干溶剂后，粗品柱层析分离(乙酸乙酯/甲醇＝9:1)，随后用乙酸乙酯重结晶，得到白色固体Cn-2(2.07g,收率28％)。随后，在50mL三口烧瓶中加入Cn-2 0.37g，氯仿8mL，甲醇4mL，3,5-二溴苄溴0.43g。在氩气保护下，反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，固体用甲醇/乙醚重结晶，得到Ia-15,收率83％。1H NMR(400MHz,CD3OD)δ8.31(d,J＝5.9Hz,2H),8.18(ddd,J＝13.7,8.2,1.2Hz,3H),8.01(dd,J＝9.3,1.7Hz,3H),7.92–7.73(m,2H),7.65–7.40(m,3H),6.60(d,J＝2.5Hz,1H),6.08(ddd,J＝17.4,10.5,7.1Hz,1H),5.37–5.27(m,2H),5.14(d,J＝12.5Hz,1H),5.00(d,J＝12.6Hz,1H),4.46(ddd,J＝11.8,8.5,2.7Hz,1H),4.11–3.84(m,2H),3.68–3.50(m,1H),3.14(dd,J＝11.8,9.2Hz,1H),2.68(t,J＝8.8Hz,1H),2.58–2.44(m,1H),1.99–1.83(m,3H),1.34–1.26(m,1H),1.20–1.06(m,1H)。
实施例16
Ia-16的制备(Ia中，R1为3-三氟甲基苯基，R2-R3为溴，R4-R6为H)
Figure GDA0003366917370000112
称取辛可宁5.88g(10mmol)，加入75mL干燥的甲基叔丁基醚溶液中，氩气保护。在-20℃下，向甲基叔丁基醚溶剂的3-溴三氟甲苯(11.26g,50mmol)中滴加15mL甲基叔丁基醚，通过锂-卤素交换反应制备3-三氟甲基苯基锂试剂。制备的有机锂试剂迅速加入辛可宁溶液中，在-20℃下搅拌1小时。随后混合物升至室温，继续搅拌2小时。反应结束后，用30mL乙酸淬灭体系，加入60mL水和60mL乙酸乙酯。随后加入固体碘5g，剧烈搅拌使其溶解。随后，加入20mL水溶解的硫代硫酸钠2g淬灭碘。混合液用氨水调节pH＝10，水层用乙酸乙酯萃取两次，收集有机层，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥。旋干溶剂后，粗品柱层析分离(乙酸乙酯/甲醇＝9:1)得到橘黄色固体Cn-3(4.21g,收率45％)，随后，在50mL三口烧瓶中加入Cn-3 0.43g，氯仿8mL，甲醇4mL，3,5-二溴苄溴0.43g。在氩气保护下，反应加热至50℃，反应16小时。反应结束后冷却至室温，倒入50mL乙醚中，过滤，固体用甲醇/乙醚重结晶，得到Ia-16，收率78％。1H NMR(400MHz,CD3OD)δ8.54(s,1H),8.47(d,J＝7.5Hz,1H),8.37(d,J＝12.2Hz,2H),8.23(dt,J＝8.7,2.0Hz,1H),8.08–7.96(m,3H),7.91–7.77(m,4H),6.62(d,J＝2.5Hz,1H),6.10(ddd,J＝17.4,10.5,7.2Hz,1H),5.42–5.11(m,3H),5.02(d,J＝12.4Hz,1H),4.55–4.43(m,1H),4.18–3.90(m,2H),3.61(t,J＝11.4Hz,1H),3.16(q,J＝9.7Hz,1H),2.78–2.45(m,2H),2.04–1.81(m,3H),1.20–1.03(m,1H)。
实施例17
(S)-2-二氟甲基-1-茚酮-2-甲酸甲酯IIIb-1的制备
Figure GDA0003366917370000121
称取0.1mmol 1-茚酮-2-甲酸金刚酯IIIa-1，加入5mol％相转移催化剂Ia-1，0.2mol TMSCF2Br，放入10mL单口反应管，加入30wt％K2CO3水溶液0.5mL，4mL甲苯，-5℃下搅拌反应。反应6小时后，加入饱和氯化铵，混合液用乙酸乙酯萃取2次，水洗2次，无水硫酸钠干燥，过滤，旋干。粗品柱层析分离(石油醚：乙酸乙酯＝50:1，v/v)得到不对称二氟甲基化产物IIIb-1(收率46％,15％ee,C/O选择性＝90:10)。1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.7Hz,1H),7.72–7.53(m,2H),7.40(t,J＝7.4Hz,1H),6.54(t,J＝55.4Hz,1H),3.67(d,J＝17.4Hz,1H),3.49(d,J＝17.4Hz,1H),2.22–2.06(m,9H),1.73–1.56(m,6H).HPLCconditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/12,0.6mL/min,254nm,τR(major)＝12.25min,τR(minor)＝10.99min。
实施例18-32所实施的发明过程与实施例17相同，但使用下表中所列的相转移催化剂代替实施例17中的相转移催化剂Ia-1，结果见表1。
表1使用不同相转移催化剂制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1a)
Figure GDA0003366917370000131
Figure GDA0003366917370000132
a)The reactions were performed with 1a(0.1mmol),TMSCF2Br(0.2mmol),catalyst(0.005mmol),and 30％K2CO3(0.5mL)in toluene(2mL)at-5℃.b)Yields shownare of isolated products.c)Determined bychiral HPLC(Chiralcel AD-H).d)19F NMRwith trifluorotoluene as the internal standard。
实施例33-41所实施的发明过程与实施例18相同，但使用下表中所列的碱代替实施例18中的碱，结果见表2。
表2使用不同碱制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1
Figure GDA0003366917370000141
实施例42-32所实施的发明过程与实施例37相同，但使用下表中所列的溶剂代替实施例37中的溶剂甲苯，结果见表3。
表3使用不同溶剂制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1
Figure GDA0003366917370000142
实施例50-55所实施的发明过程与实施例45相同，但使用下表中所列的温度代替实施例45的反应温度-5℃，结果见表4。
表4在不同温度下制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1
Figure GDA0003366917370000143
Figure GDA0003366917370000151
实施例56-60所实施的发明过程与实施例34相同，但使用下表中所列的相转移催化剂用量代替实施例34所记载的原有相转移催化剂用量，结果见表5。
表5使用不同催化剂量的IIb-2制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1
Figure GDA0003366917370000152
实施例61-60所实施的发明过程与实施例58相同，但使用下表中所列的反应时间代替实施例58中所记载的原有反应时间，结果见表6。
表6不同反应时间制备2-二氟甲基-1-茚酮-2-甲酸金刚酯IIIb-1
Figure GDA0003366917370000153
实施例68-65所实施的发明过程与实施例41相同，但使用下表中所列的β-酮酸酯类化合物IIIa-2-IIIa-22代替实施例41中记载的原底物β-酮酸酯类化合物IIIa-1，结果见表7。
表7使用不同β-酮酸酯IIIa-2—IIIa-17制备其光学活性的α-苯甲酰化产物IIIb-2—IIIb-17
Figure GDA0003366917370000161
Figure GDA0003366917370000162
Figure GDA0003366917370000171
IIIb-2：[α]D 25 63.2(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.7Hz,1H),7.66(td,J＝7.5,1.2Hz,1H),7.55(dd,J＝7.8,1.0Hz,1H),7.44–7.35(m,1H),6.54(t,J＝55.4Hz,1H),3.68(d,J＝17.5Hz,1H),3.50(d,J＝17.5Hz,1H),1.45(s,9H).13C NMR(101MHz,CDCl3)δδ196.31(d,J＝6.6Hz),164.75(d,J＝11.4Hz),154.03,135.95,134.17(d,J＝3.6Hz),127.94,126.44,125.17,115.70(dd,J＝246.5,240.8Hz),83.91,65.52(dd,J＝23.0,21.2Hz),27.77.19F NMR(376MHz,CDCl3)δ-126.65(dd,J＝286.8,55.1Hz,1F),-128.71(dd,J＝286.8,55.1Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.6mL/min,254nm,τR(major)＝9.26min,τR(minor)＝8.24min.HRMS Calcd.for[C15H16F2O3+Na]+requires m/z 305.0965,found m/z 305.0962。
IIIb-3：[α]D 25 56.3(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.7Hz,1H),7.67(td,J＝7.5,1.2Hz,1H),7.57(d,J＝7.7Hz,1H),7.42(t,J＝7.4Hz,1H),6.59(t,J＝55.3Hz,1H),5.09(p,J＝6.3Hz,1H),3.71(d,J＝17.6Hz,1H),3.54(d,J＝17.5Hz,1H),1.26(dd,J＝10.5,6.3Hz,6H).13C NMR(101MHz,CDCl3)δ195.95(d,J＝7.0Hz),165.38(d,J＝12.0Hz),153.98,136.03,134.08(d,J＝3.6Hz),128.00,126.47,125.24,117.97,115.55(d,J＝6.1Hz),113.12,70.66,66.90–59.15(m),29.81(t,J＝2.7Hz),21.47(d,J＝7.5Hz).19F NMR(376MHz,CDCl3)δ-126.33(dd,J＝287.1,55.0Hz,1F),-129.11(dd,J＝287.1,55.6Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝10.82min,τR(minor)＝9.76min.HRMS Calcd.for[C14H14F2O3+Na]+requires m/z 291.0809,found m/z 291.0814。
IIIb-4：[α]D 25 76.3(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.7Hz,1H),7.66(td,J＝7.5,1.2Hz,1H),7.55(d,J＝7.7Hz,1H),7.46–7.25(m,6H),6.63(t,J＝55.2Hz,1H),5.33–5.08(m,2H),3.73(d,J＝17.4Hz,1H),3.56(d,J＝17.6Hz,1H).13C NMR(101MHz,CDCl3)δ195.64(d,J＝6.8Hz),165.82(d,J＝12.1Hz),153.88,136.20,134.83,134.03(d,J＝3.6Hz),128.66,128.51,128.14,127.87,126.53,125.35,117.87,115.45(d,J＝6.1Hz),113.02,68.07,64.81(dd,J＝24.2,20.8Hz),31.35–28.68(m).19F NMR(376MHz,CDCl3)δ-125.84(dd,J＝287.6,55.0Hz,1F),-129.06(dd,J＝287.6,55.0Hz,1F).HPLCconditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝41.58min,τR(minor)＝27.07 min.HRMS Calcd.for[C18H14F2O3+Na]+requires m/z 339.0809,found m/z 339.0803。
IIIb-5：[α]D 2577.5(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.7Hz,1H),7.67(td,J＝7.5,1.2Hz,1H),7.58(d,J＝7.7Hz,1H),7.42(t,J＝7.4Hz,1H),6.66(t,J＝55.3Hz,1H),5.00(t,J＝3.5Hz,1H),3.74(d,J＝17.5Hz,1H),3.56(d,J＝17.5Hz,1H),2.05–1.48(m,14H).13C NMR(101MHz,CDCl3)δ196.10(d,J＝6.9Hz),165.09(d,J＝11.9Hz),153.95,136.02,134.19(d,J＝3.6Hz),153.95,136.02,115.60(d,J＝5.8Hz),113.17,79.68,65.13(dd,J＝23.7,21.1Hz),37.18,36.13,31.66(d,J＝2.9Hz),26.99,26.78.19FNMR(376MHz,CDCl3)δ-126.29(dd,J＝287.2,55.0Hz,1F),-128.91(dd,J＝287.2,55.0Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝14.81min,τR(minor)＝10.54min.HRMS Calcd.for[C21H22F2O3+Na]+requires m/z 383.1435,found m/z 383.1438。
IIIb-6：[α]D 2556.3(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.84–7.64(m,2H),7.57(d,J＝7.7Hz,1H),7.43(t,J＝7.5Hz,1H),6.60(t,J＝55.2Hz,1H),3.89–3.64(m,4H),3.56(d,J＝17.6Hz,1H).13C NMR(101MHz,CDCl3)δ195.75(d,J＝7.1Hz),166.43(d,J＝12.1Hz),153.88,136.19,134.01(d,J＝3.6Hz),128.12,126.52,125.33,117.84,115.42(d,J＝6.2Hz),112.99,64.61(dd,J＝24.3,20.8Hz),53.47,29.91,29.89,29.86,29.71.19FNMR(376MHz,CDCl3)δ-126.01(dd,J＝287.6,55.1Hz,1F),-129.29(dd,J＝287.5,55.2Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝14.21min,τR(minor)＝13.07min.HRMS Calcd.for[C12H10F2O3+Na]+requires m/z 263.0496,found m/z 263.0493。
IIIb-7：[α]D 2562.1(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.2Hz,1H),7.55(d,J＝1.6Hz,1H),7.39(dd,J＝8.4,1.6Hz,1H),6.52(t,J＝55.3Hz,1H),3.64(d,J＝14.6Hz,1H),3.47(d,J＝14.6Hz,1H),2.21–2.05(m,9H),1.64(d,J＝3.0Hz,6H).13C NMR(101MHz,CDCl3)δ194.91(d,J＝7.6Hz),163.99(d,J＝11.5Hz),155.35,142.67,132.66(d,J＝3.6Hz),117.90,115.48(d,J＝6.0Hz),113.05,66.31–65.13(m)40.97,35.92,30.86.19FNMR(376 MHz,CDCl3)δ-126.61(dd,J＝287.0,55.7Hz,1F),-128.64(dd,J＝287.0,55.7Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.6mL/min,254nm,τR(major)＝18.60min,τR(minor)＝13.85min.HRMS Calcd.for[C21H21ClF2O3+Na]+requires m/z 417.1045,found m/z 417.1047。
IIIb-8：[α]D 2569.7(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.78(dd,J＝8.5,5.2Hz,1H),7.25–7.05(m,2H),6.52(t,J＝55.4Hz,1H),3.66(d,J＝17.7Hz,1H),3.47(d,J＝17.7Hz,1H),2.27–1.99(m,9H),1.78–1.53(m,6H).13C NMR(101MHz,CDCl3)δ194.43(d,J＝7.0Hz),169.08,166.50,164.09(d,J＝11.4Hz),156.99(d,J＝10.6Hz),130.58,127.53(d,J＝10.8Hz),117.95,116.46(d,J＝24.1Hz),115.53(d,J＝10.1Hz),113.25(d,J＝22.8Hz),65.89(dd,J＝22.6,21.5Hz),84.19,40.98,35.93,30.86.19F NMR(376MHz,Chloroform-d)δ-99.44–100.44(m,1F),-126.72(dd,J＝287.0,54.9Hz,1F),-128.72(dd,J＝287.0,54.9Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.6mL/min,254nm,τR(major)＝12.87min,τR(minor)＝11.41min.HRMSCalcd.for[C21H21F3O3+Na]+requires m/z 401.1340,found m/z 401.1334。
IIIb-9：[α]D 25 46.2(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.78(dd,J＝8.5,5.2Hz,1H),7.25–7.02(m,2H),6.52(t,J＝55.3Hz,1H),3.75–3.59(m,1H),3.48(d,J＝17.7Hz,1H),1.46(s,9H).13C NMR(101MHz,CDCl3)δ194.35(d,J＝7.2Hz),169.11,166.53,164.46(d,J＝11.3Hz),156.98(d,J＝10.6Hz),130.53(dd,J＝3.7,1.8Hz),127.55(d,J＝10.9Hz),117.94,116.49(d,J＝24.0Hz),115.52(d,J＝5.7Hz),113.27(d,J＝22.9Hz),84.15,65.83(dd,J＝22.8,21.3Hz),29.72,27.76.19F NMR(376MHz,CDCl3)δ-100.12(td,J＝8.4,5.1Hz,1F),-126.75(dd,J＝287.1,54.9Hz,1F),-128.65(dd,J＝287.3,55.9Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝9.85min,τR(minor)＝8.84min.HRMS Calcd.for[C15H15F3O3+Na]+requires m/z 323.0871,found m/z 323.0869。
IIIb-10：[α]D 25 42.8(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.78(dd,J＝8.5,5.2Hz,1H),7.25–7.04(m,2H),6.53(t,J＝55.4Hz,1H),3.66(d,J＝17.7Hz,1H),3.49(d,J＝17.6Hz,1H),1.76(q,J＝7.5Hz,2H),1.43(s,6H),0.85(t,J＝7.5Hz,3H).13C NMR(101MHz,CDCl3)δ194.39(d,J＝7.2Hz),169.10,166.52,164.35(d,J＝11.4Hz),156.96(d,J＝10.6Hz),130.57,127.53(d,J＝10.9Hz),117.93,116.50(d,J＝24.2Hz),115.50(d,J＝5.7Hz),113.26(d,J＝22.9Hz),86.66,69.64–62.48(m),33.50,30.97–27.80(m),25.26,25.19,7.96.19F NMR(376 MHz,CDCl3)δ-99.23–-100.92(m,1F),-126.67(dd,J＝287.2,55.7Hz,1F),-128.66(dd,J＝287.2,55.7Hz,1F).HPLC conditions:Chiralcel AD-Hcolumn(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝8.95min,τR(minor)＝8.07min.HRMS Calcd.for[C16H17F3O3+Na]+requires m/z 337.1027,found m/z337.1031。
IIIb-11：[α]D 2573.2(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.74(d,J＝1.4Hz,1H),7.66–7.50(m,2H),6.52(t,J＝55.3Hz,1H),3.72–3.59(m,1H),3.47(d,J＝17.7Hz,1H),2.25–2.04(m,10H),1.64(t,J＝3.1Hz,6H).13C NMR(101MHz,CDCl3)δ195.16(d,J＝7.3Hz),163.95(d,J＝11.4Hz),155.44,131.68,131.61,129.80,126.22,117.90,115.50,113.05,84.27,69.02–60.29(m),40.98,35.94,30.88.19F NMR(376MHz,CDCl3)δ-126.57(dd,J＝287.1,54.9Hz,1F),-128.60(dd,J＝287.0,55.8Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝12.25min,τR(minor)＝10.99 min.HRMS Calcd.for[C21H21BrF2O3+Na]+requiresm/z 461.0540,found m/z 461.0545。
IIIb-12：1H NMR(400MHz,CDCl3)δ7.77(dd,J＝41.9,7.7Hz,2H),7.32(t,J＝7.7Hz,1H),6.53(t,J＝55.3Hz,1H),3.61(d,J＝17.9Hz,1H),3.42(d,J＝18.0Hz,1H),2.20-2.09(m,J,9H),1.71-1.62(m,6H).13C NMR(101MHz,CDCl3)δ195.69(d,J＝6.8Hz),163.85(d,J＝11.3Hz),153.62,138.66,136.08(d,J＝3.5Hz),129.66,123.92,121.83,115.42(dd,J＝247.3,241.0Hz),84.34,68.40–63.36(dd,J＝21.2,19.5Hz),40.96,35.92,30.87.19F NMR(376MHz,CDCl3)δ-126.40(dd,J＝287.5,54.9Hz,1F),-128.50(dd,J＝287.5,55.7Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝9.77min,τR(minor)＝8.75min.HRMSCalcd.for[C21H21BrF2O3+Na]+requires m/z 461.0540,found m/z 461.0543。
IIIb-13：[α]D 2554.8(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.51–7.38(m,2H),6.53(t,J＝55.5Hz,1H),3.60(d,J＝17.2Hz,1H),3.44(d,J＝17.3Hz,1H),2.40(s,3H),2.12(dd,J＝28.6,3.1Hz,9H),1.67–1.55(m,6H).13C NMR(101MHz,CDCl3)δ196.40(d,J＝7.2Hz),164.52(d,J＝11.6Hz),151.52,137.94,137.22,134.38(d,J＝3.6Hz),126.05,124.97,118.17,115.75(d,J＝5.9Hz),113.33,83.80,65.86(dd,J＝23.1,21.1Hz),40.96,35.95,30.85,29.94–28.85(m),21.03.19F NMR(376MHz,CDCl3)δ-126.66(dd,J＝286.5,55.2Hz,1F),-128.93(dd,J＝286.5,55.2Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝14.93min,τR(minor)＝11.19min.HRMS Calcd.for[C22H24F2O3+Na]+requires m/z397.1591,found m/z 397.1594。
IIIb-14：[α]D 2555.6(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.43(d,J＝8.4Hz,1H),7.31–7.22(m,2H),7.17(d,J＝2.5Hz,1H),6.53(t,J＝55.5Hz,1H),3.83(s,3H),3.64–3.32(m,2H),2.25–2.07(m,9H),1.73–1.56(m,6H).13C NMR(101MHz,CDCl3)δ196.33(d,J＝7.2Hz),164.47(d,J＝11.5Hz),159.68,147.13,135.38(d,J＝3.6Hz),125.50,118.12,115.70(d,J＝5.8Hz),105.92,83.86,66.28(dd,J＝23.1,21.1Hz),55.62,40.97,35.95,30.86,29.25.19F NMR(376MHz,CDCl3)δ-126.65(dd,J＝286.5,55.1Hz,1F),-129.01(dd,J＝286.5,55.8Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.6mL/min,254nm,τR(major)＝19.06min,τR(minor)＝14.77min.HRMSCalcd.for[C22H24F2O4+Na]+requires m/z 413.1540,found m/z 413.1544。
IIIb-15：[α]D 2554.3(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.5Hz,1H),7.04–6.85(m,2H),6.52(t,J＝55.5Hz,1H),3.91(s,3H),3.61(d,J＝17.4Hz,1H),3.42(d,J＝17.5Hz,1H),2.23–2.03(m,9H),1.63–1.47(m,6H).13C NMR(101MHz,CDCl3)δ194.25,166.25,164.71(d,J＝11.5Hz),157.19,127.29(d,J＝3.7Hz),126.84,118.23,116.27,115.81(d,J＝5.3Hz),113.39,109.37,83.75,65.81(dd,J＝23.0,20.8Hz),55.79,40.99,35.97,30.86,30.23–29.22(m).19F NMR(376MHz,CDCl3)δ-126.89(dd,J＝286.0,55.8Hz,1F),-128.97(dd,J＝286.0,55.8Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.6mL/min,254nm,τR(major)＝20.86min,τR(minor)＝17.40min.HRMS Calcd.for[C22H24F2O4+Na]+requires m/z 413.1540,found m/z413.1543。
IIIb-16：[α]D 2546.2(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ7.15(s,1H),6.96(s,1H),6.53(t,J＝55.5Hz,1H),4.00(s,3H),3.91(s,3H),3.56(d,J＝17.2Hz,1H),3.38(d,J＝17.2Hz,1H),2.20–2.05(m,9H),1.72–1.61(m,6H).13C NMR(101MHz,CDCl3)δ194.67(d,J＝7.3Hz),164.78(d,J＝11.7Hz),156.48,149.89(d,J＝13.3Hz),126.83,126.79,118.22,115.80(d,J＝5.5Hz),113.38,107.18,105.07,83.75,65.89(dd,J＝23.1,20.9Hz),56.40,56.11,45.33,41.00,35.98,30.86,29.57.19F NMR(376MHz,CDCl3)δ-126.79(dd,J＝285.6,55.1Hz,1F),-129.19(dd,J＝285.6,55.1Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,0.8mL/min,254nm,τR(major)＝29.10min,τR(minor)＝37.61min.HRMS Calcd.for[C23H26F2O5+Na]+requires m/z443.1646,found m/z 443.1643。
IIIb-17：[α]D 2510.5(c 0.20,CHCl3)；1H NMR(400MHz,CDCl3)δ8.03(dd,J＝7.9,1.4Hz,1H),7.51(td,J＝7.5,1.5Hz,1H),7.32(t,J＝7.6Hz,1H),7.26–7.21(m,1H),6.53(t,J＝55.4Hz,1H),3.33(ddd,J＝17.0,11.8,5.1Hz,1H),3.11–2.95(m,1H),2.60(ddd,J＝13.9,5.1,3.6Hz,1H),2.43–2.34(m,1H),2.15–2.01(dd,J＝46.0,3.1Hz,9H),1.65–1.58(m,7H).13C NMR(101MHz,CDCl3)δ190.57(d,J＝5.7Hz),164.98(d,J＝8.3Hz),143.31,134.19,128.82,128.00,126.86,118.48,116.03,113.58,83.90,61.40(t,J＝20.9Hz),55.44,40.97,35.93,30.82.19F NMR(376MHz,CDCl3)δ-127.40(dd,J＝282.9,55.3Hz,1F),-132.05(dd,J＝282.9,55.3Hz,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.8mL/min,254nm,τR(major)＝8.1`min,τR(minor)＝9.05min.HRMS Calcd.for[C22H24F2O3+Na]+requires m/z 397.1591,found m/z 397.1588。
实施例84
制备(S)-2-苯甲酰基-1-茚酮-2-甲酸甲酯IIIb-1(克级放大反应)
Figure GDA0003366917370000221
称取5mmol 1-茚酮-2-甲酸金刚酯IIIa-1，加入2.5mol％相转移催化剂Ia-8，5.0mmol TMSCF2Br，放入250mL反应瓶，加入30wt％K2CO3水溶液10mL，100mL甲苯，-20℃下搅拌反应。反应12小时后混合液分层，收集有机层，并旋干有机溶剂，柱层析分离(石油醚：乙酸乙酯＝25:1，v/v)得到不对称二氟甲基化产物IIIb-1 1.49g，收率83％，测得对映选择性为80％ee。
以上显示和描述了本发明的基本原理，主要特征和优点，在不脱离本发明精神和范围的前提下，本发明还有各种变化和改进，这些变化和改进都落入要求保护的本发明的范围。

Claims (9)

1.相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于具体过程为：将β-酮酸酯类化合物IIIa、相转移催化剂、TMSCF2Br和碱在溶剂中于-78～60℃搅拌反应，薄层色谱跟踪反应直至反应结束后混合液分层，收集有机层并旋干溶剂，柱层析分离得到手性α-二氟甲基-β-酮酸酯类化合物IIIb；制备过程中的反应方程式为：
Figure FDA0003366917360000011
其中R7为烷基、环烷基、芳环或苄基，n为1或2，R8、R9、R10为氢原子、卤素、烷基、烷氧基或环烷基；
所述相转移催化剂为金鸡纳碱辛可宁衍生物催化剂Ia，其化学式如下：
Figure FDA0003366917360000012
其中R1为氢、苯基、4-三氟甲基苯基、3-三氟甲基苯基或1-萘基；R2、R3、R4、R5、R6为氢原子、卤素、烷基、烷氧基或芳基。
2.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于所述金鸡纳碱辛可宁衍生物催化剂Ia的合成路线为：
Figure FDA0003366917360000013
该金鸡纳碱辛可宁衍生物催化剂Ia的具体合成过程为：使用正丁基锂与R1Br发生锂卤素交换反应后，与辛可宁发生反应得到C-2`位取代的辛可宁，之后再与取代苄溴在氯仿/甲醇混合溶液中反应得到金鸡纳碱辛可宁衍生物催化剂Ia。
3.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述碱为有机碱水溶液或无机碱水溶液；所述溶剂为卤代烃、芳香烃、烷烃或醚。
4.根据权利要求3所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述无机碱水溶液为碳酸钠、磷酸氢二钾、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、甲醇钠或乙醇钠中一种或多种水溶液组合。
5.根据权利要求3所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述无机碱水溶液为质量浓度为30％的碳酸钾水溶液、质量浓度为50％的氢氧化钠水溶液、质量浓度为50％的氢氧化钾水溶液、质量浓度为30％的碳酸铯水溶液、质量浓度为50％的磷酸氢二钾水溶液或质量浓度为50％的乙醇钠水溶液。
6.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述溶剂为甲苯、三氟甲苯、氯仿、乙醚、乙酸乙酯、对二甲苯、均三甲苯、正己烷或体积比为1:1的甲苯与氯仿的混合溶液。
7.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述相转移催化剂与β-酮酸酯类化合物的投料摩尔比为0.0001～0.5:1，TMSCF2Br与β-酮酸酯类化合物的投料摩尔比为1～3:1。
8.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：所述相转移催化剂与β-酮酸酯类化合物的投料摩尔比为0.01～0.05:1。
9.根据权利要求1所述的相转移催化β-酮酸酯不对称α-二氟甲基化的方法，其特征在于：反应温度为-40～0℃。
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