一种高效相转移催化的4-取代吡唑酮类化合物不对称氟化方法

1.本发明属于相转移催化及有机合成技术领域，具体涉及一种高效相转移催化的4
‑ꢀ
取代吡唑酮类化合物不对称氟化方法。


背景技术：

2.吡唑酮是含两个氮原子的五元杂环化合物，是很多天然产物以及具有生物活性化合物的核心结构。特别是吡唑-5-酮类化合物，具有杀虫、抗菌、镇痛、抗炎、抗肿瘤等作用，目前已经发现对cd80有抑制作用，对蛋白酶抗性朊蛋白积累有较强的抑制作用，也可以作为细胞因子、p38激酶抑制剂、神经保护剂、hiv-1整合酶抑制剂和退烧药等 (progress in chemistry,2020,32,1710)。另一方面，含氟化合物在医药、农药、生命科学和材料科学中发挥着日益重要的作用，目前上市的小分子药物中，有25％以上的药物分子中含有氟原子(org.process res.dev.2020,24,470)。但是氟原子不能从天然产物中获得，含氟手性化合物的制备一直是有机氟化学家们关注和研究的重点。通过不对称催化方法引入手性氟原子是获取含氟手性化合物最直接、最有效的一种方法(chem. rev.,2015,115,826)。其中，络合金属催化(j.am.chem.soc.2002,124,14530)和有机催化(science 2011,334,1681)是最具代表性的两种不对称氟化方案。但是，针对于吡唑酮这一重要结构单元，通过不对称催化引入手性氟原子的方法非常少。马军安等人在2012年首次发展了吡唑酮的不对称迈克尔加成/氟化两步串联反应在吡唑酮4-位引入手性氟原子(chem.eur.j.2012,18,14255)，随后，王保民等人发展了不对称的f-c 加成/氟化两步串联反应在吡唑酮4-位引入手性氟原子(org.lett.2015,17,5168)。但是，这些工作都是在反应的第一步引入了手性中心，而实际发生氟化的步骤是一个非对映选择性的氟化过程。2016年，王保民等人又报道了4-取代吡唑酮的直接不对称氟化反应，使用金鸡纳碱奎宁作为催化剂(10mol％)，碳酸铯作为碱，但是反应的对映选择性不高(35-81％ee)，需要3-5天的反应时间，以及-60℃的超低温。显然，高的催化剂用量、苛刻的反应条件以及较低的对映选择性限制了该方法在实际生产中的应用。


技术实现要素：

3.本发明解决的技术问题是提供了一种高效相转移催化的4-取代吡唑酮类化合物不对称氟化方法，该方法使用相转移催化策略，利用金鸡纳碱衍生相转移催化剂成功实现了广泛且高效、高对映选择性的4-取代吡唑酮类化合物不对称氟化反应。
4.本发明为解决上述技术问题采用如下技术方案：一种高效相转移催化的4-取代吡唑酮类化合物不对称氟化方法，其特征在于具体过程为：将4-取代吡唑酮类化合物ia、相转移催化剂和亲电氟化试剂在溶剂中搅拌混合均匀，再加入碱，于-78～60℃搅拌反应制得手性α-氟代吡唑酮类化合物ib，制备过程中的反应方程式为：
[0005][0006]
其中r1为苯基或取代苯基，该取代苯基苯环上的取代基为f、cl、br、i、甲氧基、 c
1-4
烷基、硝基、乙腈基或三氟甲基，r2为甲基、乙基或取代乙基，该取代乙基上的取代基为苯基、取代苯基、萘基或炔基，取代苯基苯环上的取代基为f、cl、br、i、甲氧基、c
1-4
烷基、硝基、乙腈基或三氟甲基，r3为c
1-4
烷基、苯基、取代苯基或萘基，该取代苯基苯环上的取代基为f、cl、br、i、甲氧基、c
1-4
烷基、硝基、乙腈基、o-ch
2-o (亚甲基二氧基)或三氟甲基；
[0007]
所述相转移催化剂为金鸡纳碱辛可宁衍生物iia或iib，其对应的结构式为：
[0008][0009]
其中r3为h或甲氧基，r4为叔丁基、金刚基、异丙基、苄基或取代芳基；
[0010]
所述亲电氟化试剂的结构式为：
[0011][0012]
其中r6为h、甲氧基、甲基、氯、溴或碘。
[0013]
进一步限定，所述相转移催化剂金鸡纳碱辛可宁衍生物iia或iib的具体合成过程为：使用伯胺与溴乙酰溴反应生成溴代酰胺，随后进一步与金鸡纳碱在四氢呋喃中反应得到相转移催化剂金鸡纳碱辛可宁衍生物iia或iib；对应的合成路线为：
[0014][0015]
进一步限定，所述溶剂为卤代烃、芳香烃、烷烃或醚；优选为甲苯、三氟甲苯、氯仿、对二甲苯、均三甲苯或正己烷中一种或多种。
[0016]
进一步限定，所述碱为有机碱或无机碱水溶液；优选为无机碱水溶液，该无机碱水溶液为碳酸钠、磷酸氢二钾、磷酸钾、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、氟化钾或乙酸钾中的一种或多种水溶液组合。
[0017]
进一步限定，反应温度为-20～25℃。
[0018]
进一步限定，所述相转移催化剂用量为4-取代吡唑酮类化合物ia用量的0.01-10 mol％；优选为0.5-1mol％。
[0019]
进一步限定，所述亲电氟化试剂与4-取代吡唑酮类化合物ia的投料摩尔比为1～2:1。
[0020]
进一步限定，反应时间为10min～1h。
[0021]
本发明与现有技术相比具有以下优点和有益效果：本发明的有效性体现在使用廉价易得的手性相转移催化剂，成功实现了4-取代吡唑酮类合物的不对称亲电氟化反应，具有极高的收率和高对映选择性(最高98％ee)，而且反应在10min至1h内即可完成。该方法为制备光学活性的α-氟代吡唑酮类化合物提供了高效的合成途径。本发明的氟化方法中反应产物在反应体系中极易分离，放大至克级仍能保持较高的氟化效率，同时相转移催化剂可以循环使用多次并保持较好的催化效果。本发明反应条件温和，操作简单，具有良好的底物适用性以及环境友好性，成本低，适合规模化工业生产。
具体实施方式
[0022]
下面结合技术方案详细叙述本发明的具体实施例，使本领域的技术人员更好的理解本发明。
[0023]
实施例1
[0024]
溴代酰胺的合成
[0025][0026]
在含有苯胺(10mmol)的二氯甲烷(15ml)中，加入碳酸钾(2.1g,15mmol)的水溶液(20ml)。随后将混合物冷却至0℃，将溴乙酰溴(1.3ml，15mmol)加入3 ml二氯甲烷中混合，进行滴加，继续反应1h。反应结束后两相分离，水相用二氯甲烷萃取三次(3x15 ml)；有机相用水洗两次、饱和食盐水洗一次，无水硫酸钠干燥，旋干得到产品s1，收率95％。使用同样的方法也合成了结构各异的溴代酰胺s2～s16，反应收率以及化合物结构如下所示：
[0027][0028]
实施例2
[0029]
iia-1的制备
[0030]
将辛可宁(1.0g，3.4mmol)和相应的溴代酰胺(3.4mmol)混合，加入thf 30ml，进行加热回流2h，薄层色谱法控制反应，反应结束后降温，旋干溶剂。取二氯甲烷(2 ml)将旋干后的固体全部溶解,再向该溶液中滴加乙醚(25ml)，使固体全部析出。将沉淀物进行抽滤，用乙醚洗涤，最后进行干燥、称重得到产品。
[0031][0032]
白色固体，mp：196-201℃；[α]
d25 42.0(c 0.20,chcl3)；1h nmr(400mhz,dmso-d6) δ11.04(d,j＝5.5hz,1h),8.98(d,j＝4.5hz,1h),8.25
–
8.02(m,2h),7.87
–
7.70(m, 4h),7.60(ddd,j＝8.4,6.8,1.4hz,1h),7.50
–
7.38(m,2h),7.21(td,j＝7.4,1.2hz,1h), 6.79(dd,j＝15.5,3.4hz,1h),6.21
–
5.91(m,2h),5.37
–
5.13(m,2h),4.80(dd,j＝16.1, 12.1hz,1h),4.66(d,j＝15.9hz,1h),4.34(dt,j＝39.0,10.2hz,3h),3.96
–
3.83(m,1h), 3.76
–
3.59(m,1h),2.87(q,j＝8.7hz,1h),2.23(t,j＝11.9hz,1h),2.02
–
1.85(m,3h), 1.20
–
0.98(m,1h).
13
c nmr(101mhz,dmso-d6)δ163.22,150.65,148.05,145.14, 138.24,137.06,130.39,129.89,129.62,127.51,125.14,124.83,123.60,120.63,120.10, 117.68,66.01,65.19,59.70,59.59,57.60,37.58,26.62,23.39,20.59,11.76。
[0033]
实施例3～16的实施过程与实施例2相同，但使用下表中所列的相转移催化剂结构 iia-2～iia-15代替iia-1，结果见表1。
[0034]
表1所合成相转移催化剂的实验结果
[0035]
[0036][0037]
相转移催化剂的相关熔点、旋光及核磁数据：
[0038]
iia-2：白色固体，mp：88-92℃；[α]
d25 92.5(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.95(d,j＝5.5hz,1h),8.99(d,j＝4.5hz,1h),8.32
–
8.13(m,2h),8.10
–ꢀ
7.69(m,6h),7.68
–
7.49(m,3h),7.41(ddd,j＝8.4,6.8,1.4hz,1h),6.90(d,j＝3.5hz, 1h),6.20(q,j＝6.5,4.8hz,1h),6.05(ddd,j＝17.2,10.2,6.7hz,1h),5.38
–
5.21(m,2h), 5.06(d,j＝15.9hz,1h),4.84(dd,j＝16.1,12.1hz,1h),4.58
–
4.21(m,3h),3.98(t,j＝ 11.4hz,1h),3.87
–
3.70(m,1h),3.65
–
3.52(m,2h),2.98
–
2.82(m,1h),2.24(t,j＝11.9 hz,1h),1.96(d,j＝8.5hz,3h),1.75(td,j＝5.9,5.2,2.6hz,2h),1.06(d,j＝8.8hz,1h). 13
c nmr(101mhz,dmso-d6)δ164.26,150.65,148.06,145.24,137.11,134.24,132.29, 130.32,129.86,128.77,128.28,127.43,127.05,126.84,126.77,126.05,124.87,123.70, 123.13,122.91,120.62,117.67,67.48,66.11,65.42,59.57,57.56,37.60,26.64,25.60,23.43, 20.68,11.77。
[0039]
iia-3：淡黄色固体，mp：213-215℃；[α]
d25 74.5(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.38(q,j＝4.8,3.6hz,1h),8.99(d,j＝4.5hz,1h),8.27(d,j＝8.5hz,1h), 8.08(d,j＝8.4hz,1h),7.93
–
7.66(m,2h),7.52(t,j＝7.7hz,1h),7.30(t,j＝7.6hz, 1h),7.19(d,j＝7.6hz,2h),6.95(dd,j＝16.5,3.9hz,1h),6.20
–
5.95(m,2h),5.29(dd, j＝14.1,3.3hz,2h),5.04(s,1h),4.76(d,j＝15.6hz,1h),4.52
–
4.31(m,2h),4.16(t,j ＝11.5hz,1h),3.97(t,j＝11.7hz,1h),3.78(q,j＝15.5,12.4hz,1h),2.86(q,j＝8.9hz, 1h),2.66
–
2.44(m,6h),2.13(q,j＝11.8hz,1h),1.92(dd,j＝20.2,6.8hz,4h),1.31
–ꢀ
0.81
20.68,14.57,11.75。
[0044]
iia-8：乳白色固体，mp：129-134℃；[α]
d25 66.4(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ11.09(d,j＝3.6hz,1h),8.98(d,j＝4.5hz,1h),8.24(dt,j＝8.8,2.2hz,1h), 8.09(dd,j＝8.5,1.2hz,1h),7.81(ddd,j＝9.5,5.7,1.7hz,2h),7.57(ddd,j＝8.4,6.8,1.4 hz,1h),7.05(d,j＝2.2hz,2h),6.80(dd,j＝15.9,3.6hz,1h),6.37(t,j＝2.2hz,1h), 6.17
–
5.92(m,2h),5.77(s,1h),5.28(ddt,j＝14.9,3.1,1.4hz,2h),4.95
–
4.80(m,1h), 4.69(d,j＝15.9hz,1h),4.44
–
4.21(m,3h),4.00
–
3.87(m,1h),3.78(s,8h),3.38(s,2h), 2.86(q,j＝8.8hz,1h),2.51(p,j＝1.8hz,1h),2.22(t,j＝11.9hz,1h),2.04
–
1.87(m, 3h),1.16
–
0.96(m,1h).
13
c nmr(101mhz,dmso-d6)δ163.32,161.12,150.66,148.06, 145.17,139.90,137.05,130.38,129.90,127.40,124.83,123.72,120.63,117.65,98.43,96.92, 65.91,65.35,59.63,59.56,57.54,55.76,55.42,37.56,26.60,23.39,20.63,11.75。
[0045]
iia-9：白色固体，mp：172-177℃；[α]
d25 35.6(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.45(d,j＝6.3hz,1h),8.97(d,j＝4.5hz,1h),8.25
–
7.97(m,2h),7.88
–ꢀ
7.71(m,2h),7.65
–
7.35(m,9h),7.32
–
7.23(m,1h),6.74(dd,j＝15.0,3.2hz,1h),6.04
ꢀ–
5.70(m,2h),5.31
–
4.96(m,2h),4.68(d,j＝15.6hz,1h),4.44
–
4.07(m,3h),3.82(dt, j＝51.6,11.2hz,2h),3.54
–
3.40(m,1h),2.77(q,j＝8.8hz,1h),2.10(q,j＝12.1hz, 1h),1.97
–
1.71(m,3h),0.96
–
0.78(m,1h).
13
c nmr(101mhz,dmso-d6)δ163.59, 150.60,148.06,145.18,139.14,138.26,137.01,133.52,131.08,130.28,129.89,129.19, 128.99,128.61,127.93,127.80,127.77,127.54,124.87,123.90,120.48,117.63,66.18,65.42, 59.41,57.24,37.55,26.53,23.35,20.69,11.72。
[0046]
iia-10：白色固体，mp：145-150℃；[α]
d25 76.4(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ11.34(s,1h),8.98(d,j＝4.5hz,1h),8.31(dd,j＝8.6,3.3hz,1h),8.22(d,j ＝2.0hz,1h),8.08(dd,j＝8.5,1.2hz,1h),7.86
–
7.73(m,3h),7.71
–
7.64(m,2h),7.59
ꢀ–
7.48(m,5h),7.46
–
7.37(m,1h),6.81(dd,j＝15.9,3.7hz,1h),6.17(q,j＝5.8,4.4hz, 1h),6.02(ddd,j＝17.3,10.2,6.8hz,1h),5.33
–
5.20(m,2h),5.00(d,j＝15.8hz,1h), 4.78(d,j＝15.6hz,1h),4.54
–
4.19(m,3h),4.08
–
3.98(m,1h),3.83
–
3.65(m,1h),2.87 (d,j＝8.4hz,1h),2.29
–
2.14(m,1h),1.92(d,j＝12.0hz,3h),1.10
–
0.97(m,1h).
13
c nmr(101mhz,dmso-d6)δ170.79,163.37,150.67,148.07,145.22,141.47,140.27, 138.87,137.04,130.36,130.21,129.83,129.56,128.30,127.43,127.09,124.85,123.83, 123.43,120.64,119.15,118.50,117.65,65.88,65.54,60.24,59.71,59.43,57.55,37.57, 26.62,23.43,21.25,20.69,14.56,11.75。
[0047]
iia-11：白色固体，mp：216-222℃；[α]
d25 64.5(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.41(s,1h),8.99(d,j＝4.5hz,1h),8.27
–
8.03(m,2h),7.88
–
7.74(m,2h), 7.51(ddd,j＝8.4,6.8,1.3hz,1h),7.43(d,j＝7.9hz,2h),7.31(dtd,j＝21.0,7.4,1.6hz, 2h),6.88(d,j＝3.4hz,1h),6.15
–
5.95(m,2h),5.45
–
5.12(m,2h),5.00
–
4.61(m,2h), 4.48
–
4.21(m,3h),3.82(dt,j＝74.1,11.5hz,2h),3.31
–
3.13(m,1h),2.87(q,j＝8.8hz, 1h),2.17(q,j＝12.3hz,1h),1.93(d,j＝13.1hz,3h),1.16(dd,j＝21.0,6.8hz,6h), 1.04(dt,j＝15.4,9.0hz,1h).
13
c nmr(101mhz,dmso-d6)δ164.15,150.65,148.07, 145.23,
144.06,137.08,133.38,130.34,129.91,127.82,127.51,127.47,126.51,124.88, 123.76,120.57,117.67,66.21,65.21,59.67,59.26,57.42,37.59,27.74,26.64,23.97,23.84, 23.39,20.69,11.75。
[0048]
iia-12：白色固体，mp：179-184℃；[α]
d25 21.5(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.34(d,j＝6.3hz,1h),8.99(d,j＝4.5hz,1h),8.32
–
8.19(m,1h),8.09 (dd,j＝8.5,1.2hz,1h),7.86
–
7.73(m,2h),7.62
–
7.46(m,2h),7.30(dddd,j＝28.2,13.7, 7.4,1.8hz,3h),6.87(dd,j＝16.1,3.6hz,1h),6.19
–
5.93(m,2h),5.37
–
5.20(m,2h), 4.93(d,j＝16.2hz,1h),4.69(d,j＝16.3hz,1h),4.49
–
4.32(m,2h),4.22(d,j＝9.8hz, 1h),3.95(t,j＝11.4hz,1h),3.85
–
3.66(m,1h),2.86(q,j＝8.8hz,1h),2.23
–
2.09(m, 1h),1.97
–
1.82(m,3h),1.39(d,j＝1.5hz,10h),0.99(d,j＝12.1hz,1h).
13
c nmr(101 mhz,dmso-d6)δ164.81,150.65,148.09,147.17,145.30,137.05,134.52,131.91,130.31, 129.92,128.35,127.51,127.11,124.93,123.94,120.58,117.66,66.29,65.39,65.10,59.66, 59.28,57.22,37.61,35.28,31.45,31.40,26.68,23.38,20.76,15.65,11.74。
[0049]
iia-13：乳白色固体，mp：181-186℃；[α]
d25 46.3(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ11.05(d,j＝3.9hz,1h),8.98(d,j＝4.5hz,1h),8.26(d,j＝8.3hz,1h), 8.09(dd,j＝8.5,1.3hz,1h),7.88
–
7.69(m,4h),7.62(ddd,j＝8.3,6.8,1.4hz,1h),7.46 (dd,j＝8.7,1.8hz,2h),6.80(dd,j＝16.0,3.6hz,1h),6.18
–
5.90(m,2h),5.28(ddd,j＝ 14.6,3.1,1.4hz,2h),4.87(t,j＝14.3hz,1h),4.69(d,j＝15.8hz,1h),4.43
–
4.21(m, 3h),3.95(d,j＝11.1hz,1h),3.73(q,j＝9.3hz,1h),2.86(q,j＝8.8hz,1h),2.51(p,j＝ 1.8hz,1h),2.34
–
2.06(m,1h),1.94(t,j＝8.2hz,3h),1.29(s,9h),1.05(q,j＝8.0,6.4 hz,1h).
13
c nmr(101mhz,dmso-d6)δ170.79,162.91,150.63,148.05,147.51,145.24, 145.19,137.06,135.70,130.34,129.86,127.57,126.16,126.00,124.83,123.76,120.67, 120.60,119.90,117.65,65.91,65.39,60.23,59.63,59.47,57.51,37.57,34.64,31.62,26.61, 23.41,21.25,20.65,14.57,11.75。
[0050]
iia-14：淡黄色固体，mp：263-267℃；[α]
d25 26.5(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.32(s,1h),8.80(d,j＝4.5hz,1h),7.94(d,j＝9.2hz,1h),7.77(d,j＝4.6 hz,1h),7.54
–
7.18(m,6h),6.87(d,j＝3.3hz,1h),6.12
–
5.88(m,2h),5.36
–
5.18(m, 2h),4.84(d,j＝16.8hz,1h),4.72
–
4.39(m,3h),4.23(t,j＝11.0hz,1h),3.74(dt,j＝ 31.7,11.1hz,2h),3.42(s,3h),2.85(q,j＝8.7hz,1h),2.17
–
1.81(m,4h),1.37(s,9h), 0.91(d,j＝6.9hz,1h).
13
c nmr(101mhz,dmso-d6)δ165.16,158.36,147.72,146.80, 144.21,143.92,137.02,134.28,131.80,131.72,128.23,127.41,126.92,126.15,122.78, 120.82,117.66,101.91,66.59,64.05,60.79,59.52,57.31,56.13,37.73,35.28,31.44,26.83, 23.32,20.96,11.75。
[0051]
iib-1：白色固体，mp：215-220℃；[α]
d25-11.3(c 0.20,chcl3)；1h nmr(400mhz, dmso-d6)δ10.39(s,1h),8.98(d,j＝4.5hz,1h),8.21(dd,j＝8.6,1.3hz,1h),8.08(dd, j＝8.4,1.2hz,1h),7.84
–
7.68(m,2h),7.61
–
7.43(m,2h),7.30(dddd,j＝26.6,12.1,7.3, 1.9hz,3h),6.88(d,j＝4.1hz,1h),6.14(t,j＝3.5hz,1h),5.66(ddd,j＝17.4,10.7,5.6 hz,1h),5.34
–
4.98(m,2h),4.96
–
4.64(m,2h),4.47(q,j＝10.6,9.9hz,2h),4.30(dt,j ＝12.6,3.2hz,1h),4.00(dd,j＝12.6,10.2hz,1h),3.90
–
3.77(m,1h),2.88(s,1h),2.22
ꢀ–
1.89(m,4h),1.38(s,9h),1.15
–
0.96(m,1h).
13
c nmr(101mhz,dmso-d6)δ164.97, 150.64,148.05,147.19,145.38,138.58,134.53,131.89,130.35,129.96,128.33,127.48, 127.46,127.14,124.72,123.69,120.49,116.17,65.96,64.51,60.40,59.31,56.21,37.29, 35.27,31.40,25.76,25.26,21.55。
[0052]
实施例17
[0053]
4-取代吡唑酮不对称氟化产物ib-1的制备
[0054][0055]
取10ml单口反应瓶，分别加入0.0324g(0.1mmol)吡唑啉酮底物ia-1，nfsi 0.0346 g(0.11mmol)，以及0.0025g(0.005mmol)相转移催化剂iia-1。0℃下，加入2ml甲苯，随后，向体系中加入0.2ml 30wt％k2co3水溶液，强力搅拌反应10min后，tlc(薄层色谱)跟踪反应基本完全。使用体积比石油醚/乙酸乙酯＝10:1柱层析分离得到产物。白色固体,mp：58-63℃；[α]
d25 13.6(c 0.41,chcl3)；97％yield,37％ee.1h nmr(400mhz, chloroform-d)δ7.85
–
7.66(m,2h),7.61
–
7.46(m,2h),7.35(dq,j＝9.3,2.6,1.8hz,3h), 7.26
–
7.12(m,2h),7.08
–
6.87(m,4h),6.81
–
6.65(m,2h),3.61
–
3.21(m,2h).
13
c nmr (101mhz,chloroform-d)δ166.88(d,j＝21.5hz),152.99(d,j＝13.9hz),135.78,130.05, 128.82,128.72,128.29,128.27,128.01,127.74,127.29,126.84,125.54,125.53,124.80, 118.19,95.27,93.28,40.05(d,j＝26.0hz).
19
f nmr(376mhz,chloroform-d)δ-162.21 (s,1f).hplc conditions:chiralcel as-h column(250
×
4.6mm),hexane/i-proh＝90/10, 1ml/min,254nm,τr(major)＝5.83min,τr(minor)＝5.21min。
[0056]
实施例18～31的实施过程与实施例17相同，但使用相转移催化剂iia-2～iia-15代替iia-1，结果见表2。
[0057]
表2使用不同催化剂制备吡唑酮不对称氟化产物ib-1
[0058][0059]
实施例32～37的实施过程与实施例28相同，但使用下表中所列的温度代替0℃，结果见表3。
[0060]
表3在不同温度下制备吡唑酮氟化产物ib-1
[0061][0062]
实施例38～47的实施过程与实施例35相同，但使用下表中所列的碱代替30wt％ k2co3，结果见表4。
[0063]
表4使用不同碱制备吡唑酮氟化产物ib-1
[0064][0065]
实施例48～54的实施过程与实施例43相同，但使用下表中所列的溶剂代替甲苯，结果见表5。
[0066]
表5使用不同溶剂制备吡唑酮羟基化产物ib-1
[0067][0068]
实施例55～59的实施过程与实施例43相同，但使用下表中所列的4-取代吡唑酮浓度代替原有浓度，结果见表6。
[0069]
表6使用不同浓度制备羟基化产物ib-1
[0070][0071][0072]
实施例60～63的实施过程与实施例58相同，但使用下表中所列的催化剂用量代替原有催化剂用量，结果见表7。
[0073]
表7使用不同催化剂量制吡唑酮羟基化产物ib-1
[0074][0075]
实施例64～67的实施过程与实施例62相同，但使用下表中所列的亲电氟化试剂代替原有亲电氟化试剂，结果见表8。
[0076]
表8使用不同氟化试剂制吡唑酮羟基化产物ib-1
[0077][0078][0079]
实施例68～101的实施过程与实施例17相同，但使用下表中所列的4-取代吡唑酮 ia-2～ia-36代替原底物ia-1，结果见表9。
[0080]
表9使用不同4-取代吡唑酮制备其光学活性的氟化产物ib-2～ib-35
124.30,124.26,122.78(q,j＝272.3hz),94.85,92.85,39.81(d,j＝26.6hz).
19
f nmr(376 mhz,chloroform-d)δ-62.76(s,3f),-162.96(s,1f).hplc conditions:chiralcel oj-h column(250
×
4.6mm),hexane/i-proh＝95/5,1ml/min,254nm,τr(major)＝8.32min, τr(minor)＝7.76min。
[0086]
实施例70
[0087]
ib-4,淡黄色固体，mp：102-106℃；[α]
d25 55.6(c 0.54,chcl3)；98％yield,87％ee. 1
h nmr(400mhz,chloroform-d)δ7.93
–
7.83(m,2h),7.80
–
7.66(m,2h),7.61
–
7.48 (m,3h),7.45
–
7.33(m,2h),7.25
–
7.17(m,1h),6.61(tt,j＝8.8,2.3hz,1h),6.52
–
6.30 (m,2h),3.70
–
3.37(m,2h).
13
c nmr(101mhz,chloroform-d)δ167.41(d,j＝21.3hz), 163.86(d,j＝12.7hz),161.38(d,j＝12.8hz),153.87(d,j＝13.7hz),136.72,133.83, 131.46,129.26,128.99,126.60,126.58,126.15,119.18,113.02(d,j＝25.6hz),103.69(t,j ＝25.1hz),95.55,93.55,40.55(d,j＝27.5hz).
19
f nmr(376mhz,chloroform-d)δ
ꢀ‑
109.16(s,2f),-162.68(s,1f).hplc conditions:chiralcel oj-h column(250
×
4.6mm), hexane/i-proh＝95/5,1ml/min,254nm,τr(major)＝8.32min,τr(minor)＝7.76min。
[0088]
实施例71
[0089]
ib-5,淡黄色固体，mp：117-121℃；[α]
d25 27.6(c 0.51,chcl3)；97％yield,80％ee. 1
h nmr(400mhz,chloroform-d)δ8.02
–
7.82(m,4h),7.78
–
7.65(m,2h),7.62
–
7.46 (m,3h),7.43
–
7.31(m,2h),7.25
–
7.17(m,1h),7.14
–
6.94(m,2h),3.81
–
3.55(m,2h). 13
c nmr(101mhz,chloroform-d)δ167.24(d,j＝21.3hz),153.70(d,j＝13.8hz), 147.62,137.68,137.57,136.61,131.57,131.01,129.32,129.01,128.93,128.92,126.58, 126.56,126.22,123.52,118.98,95.55,93.55,40.73(d,j＝27.2hz).
19
f nmr(376mhz, chloroform-d)δ-162.65(s,1f).hplc conditions:chiralcel ad-h column(250
×
4.6mm), hexane/i-proh＝90/10,1ml/min,254nm,τr(major)＝10.02min,τr(minor)＝12.02 min。
[0090]
实施例72
[0091]
ib-6,淡黄色胶体；[α]
d25 110.7(c 0.58,chcl3)；95％yield,84％ee.1h nmr(400 mhz,chloroform-d)δ7.90
–
7.80(m,2h),7.71
–
7.60(m,2h),7.57
–
7.46(m,3h),7.44
–ꢀ
7.30(m,3h),7.21(ddt,j＝8.6,7.2,1.2hz,2h),7.15
–
7.04(m,2h),3.72
–
3.47(m,2h). 13
c nmr(101mhz,chloroform-d)δ167.58(d,j＝21.5hz),153.93(d,j＝13.7hz), 136.65,133.31,131.39,131.29
–
130.81(m),129.21,129.16,129.14,128.92,128.90,126.88 (q,j＝3.8hz),126.63,126.61,126.09,125.23
–
124.39(m),95.91,93.91,40.81(d,j＝26.8 hz).
19
f nmr(376mhz,chloroform-d)δ-62.90(s,3f),-163.34(s,1f).hplc conditions: chiralcel oj-h column(250
×
4.6mm),hexane/i-proh＝95/5,1ml/min,254nm,τr (major)＝10.40min,τr(minor)＝8.67min。
[0092]
实施例73
[0093]
ib-7,白色固体，mp：85-89℃；[α]
d25 46.5(c 0.42,chcl3)；96％yield,83％ee.1h nmr(400mhz,chloroform-d)δ7.81(dq,j＝6.9,1.2hz,2h),7.72
–
7.62(m,3h),7.59
–ꢀ
7.44(m,3h),7.43
–
7.29(m,4h),7.25
–
7.18(m,1h),3.82
–
3.52(m,2h).
13
c nmr(101 mhz,chloroform-d)δ167.19(d,j＝21.4hz),153.71(d,j＝13.5hz),136.46,132.86(d,j ＝
10.6hz),131.73(q,j＝33.6hz),131.65,130.33,129.33,128.98,126.60,126.58,126.28, 122.78(q,j＝272.8hz),122.04,122.00,121.96,95.41,93.40,40.61(d,j＝27.2hz).
19
f nmr(376mhz,chloroform-d)δ-63.10(s,6f),-164.38(s,1f).hplc conditions:chiralcelad-h column(250
×
4.6mm),hexane/i-proh＝98/2,1ml/min,254nm,τr(major)＝ 22.00min,τr(minor)＝18.38min。
[0094]
实施例74
[0095]
ib-8,淡黄色固体，mp：165-169℃；[α]
d25 56.7(c 0.72,chcl3)；96％yield,87％ee. 1
h nmr(400mhz,chloroform-d)δ7.88
–
7.73(m,4h),7.48
–
7.30(m,5h),7.23
–
7.17 (m,1h),3.57(tt,j＝15.2,1.8hz,1h),3.29(ddt,j＝26.9,15.1,1.6hz,1h).
13
c nmr(101 mhz,chloroform-d)δ165.72(d,j＝22.6hz),153.29(d,j＝13.7hz),153.22,146.02, 143.59,143.55,141.35,138.81,137.60,135.99,130.45,128.06,127.98,125.60,125.58, 125.10,117.98,104.31(t,j＝18.1hz),92.43,90.40,28.68,27.29(d,j＝26.7hz).
19
f nmr (376mhz,chloroform-d)δ-139.19
–‑
139.75(m,2f),-153.43(t,j＝20.8hz,1f),-161.83 (dd,j＝21.0,14.2hz,2f),-170.79(t,j＝10.5hz,1f).hplc conditions:chiralcel ad-h column(250
×
4.6mm),hexane/i-proh＝90/10,1ml/min,254nm,τr(major)＝5.04 min,τr(minor)＝5.54min。
[0096]
实施例75
[0097]
ib-9,淡黄色胶体；[α]
d25 48.2(c 0.41,chcl3)；99％yield,92％ee.1h nmr(400mhz, chloroform-d)δ7.95
–
7.86(m,2h),7.74
–
7.62(m,2h),7.57
–
7.46(m,3h),7.40
–
7.33 (m,2h),7.20(t,j＝7.4hz,1h),7.00(t,j＝7.9hz,1h),6.67(ddd,j＝8.3,2.6,0.9hz,1h), 6.49(dt,j＝7.5,1.2hz,1h),6.38(t,j＝2.1hz,1h),3.69
–
3.51(m,2h),3.49(s,3h).
13
c nmr(101mhz,chloroform-d)δ168.05(d,j＝21.5hz),159.39,154.19(d,j＝13.8hz), 136.93,131.32,131.20,131.14,129.53,129.52,129.42,129.10,128.88,126.69,126.68, 125.92,122.23,119.30,114.59,114.42,96.28,94.29,54.92,41.21(d,j＝26.3hz).
19
f nmr (376mhz,chloroform-d)δ-162.10(s,1f).hplc conditions:chiralcel oj-h column(250
ꢀ×
4.6mm),hexane/i-proh＝80/20,1ml/min,254nm,τr(major)＝8.86min,τr(minor) ＝13.25min。
[0098]
实施例76
[0099]
ib-10,白色固体，mp：86-89℃；[α]
d25 56.7(c 0.42,chcl3)；98％yield,92％ee.1h nmr(400mhz,chloroform-d)δ7.72(dq,j＝8.4,1.5hz,4h),7.40
–
7.24(m,5h),7.17
–ꢀ
7.06(m,1h),6.89
–
6.63(m,2h),6.38(dd,j＝9.0,4.4hz,1h),3.72
–
3.27(m,2h),3.09(s, 3h).
13
c nmr(101mhz,chloroform-d)δ167.19(d,j＝21.8hz),155.19
–
153.34(m), 152.72,152.70,136.12,128.70,128.68,127.88,127.44,125.45,125.43,124.73,119.58, 117.97,117.64(d,j＝23.6hz),114.14(d,j＝22.7hz),109.48(d,j＝8.4hz),94.88,92.89, 53.74,34.19(d,j＝27.1hz).
19
f nmr(376mhz,chloroform-d)δ-124.15(s,1f),
ꢀ‑
164.47(s,1f).hplc conditions:chiralcel oj-h column(250
×
4.6mm),hexane/i-proh＝ 95/5,1ml/min,254nm,τr(major)＝17.41min,τr(minor)＝16.05min。
[0100]
实施例77
[0101]
ib-11,无色胶体；[α]
d25 112.3(c 0.42,chcl3)；99％yield,90％ee.1h nmr
mhz,chloroform-d)δ8.03
–
7.82(m,4h),7.56
–
7.38(m,5h),7.24(d,j＝7.5hz,1h), 5.54
–
5.32(m,1h),5.22
–
4.92(m,2h),3.18
–
2.89(m,2h).
13
c nmr(101mhz, chloroform-d)δ167.90(d,j＝21.7hz),154.26(d,j＝13.9hz),137.23,131.23,129.06, 128.99,128.94,126.63,126.62,126.37,126.26,125.82,122.71,118.94,95.41,93.43,39.16 (d,j＝26.1hz).
19
f nmr(376mhz,chloroform-d)δ-164.30(s,1f).hplc conditions: chiralcel ad-h column(250
×
4.6mm),hexane/i-proh＝90/10,1ml/min,254nm,τr (major)＝5.54min,τr(minor)＝4.95min。
[0110]
实施例82
[0111]
ib-16,无色油状物；[α]
d25 57.3(c 0.25,chcl3)；94％yield,89％ee.1h nmr(400 mhz,chloroform-d)δ7.95(ddt,j＝15.4,7.9,1.2hz,4h),7.58
–
7.39(m,5h),7.30
–
7.26 (m,1h),3.27(ddd,j＝15.8,8.1,2.8hz,1h),3.12(ddd,j＝15.8,7.5,2.8hz,1h),1.93(t,j ＝2.7hz,1h).
13
c nmr(101mhz,chloroform-d)δ165.82(d,j＝21.0hz),152.35(d,j＝ 13.4hz),136.08,130.33,128.07,127.99,127.56,127.54,125.56,125.54,124.94,118.04, 92.99,91.00,72.12(d,j＝19.0hz),71.90(d,j＝2.6hz),24.30(d,j＝34.1hz).
19
f nmr (376mhz,chloroform-d)δ-164.40(s,1f).hplc conditions:chiralcel ad-h column(250
ꢀ×
4.6mm),hexane/i-proh＝80/20,1ml/min,254nm,τr(major)＝5.85min,τr(minor) ＝5.19min。
[0112]
实施例83
[0113]
ib-17,无色油状物；[α]
d25 29.6(c 0.21,chcl3)；95％yield,72％ee.1h nmr(400 mhz,chloroform-d)δ7.67
–
7.59(m,2h),7.40
–
7.30(m,2h),7.29
–
7.23(m,3h),7.21
–ꢀ
7.12(m,3h),3.65
–
3.10(m,2h),2.14(d,j＝1.6hz,3h).
13
c nmr(101mhz, chloroform-d)δ136.97,130.65,130.55,129.76,128.87,128.77,128.06,125.65,118.96, 95.52,93.56,13.83.
13
c nmr(101mhz,chloroform-d)δ167.79(d,j＝21.0hz),157.01(d, j＝16.4hz),39.41(d,j＝26.1hz).
19
f nmr(376mhz,chloroform-d)δ-167.08(s,1f). hplc conditions:chiralcel ad-h column(250
×
4.6mm),hexane/i-proh＝99/1,1ml/ min,254nm,τr(major)＝＝16.00min,τr(minor)＝13.90min。
[0114]
实施例84
[0115]
ib-18,白色固体，mp：131-135℃；[α]
d25 79.5(c 0.41,chcl3)；99％yield,92％ee.1h nmr(400mhz,chloroform-d)δ7.76
–
7.65(m,3h),7.59(dt,j＝9.6,2.1hz,1h),7.48 (td,j＝8.1,5.7hz,1h),7.39(dd,j＝8.6,7.4hz,2h),7.25
–
7.18(m,2h),6.23(t,j＝2.3 hz,1h),6.01(d,j＝2.3hz,2h),3.71
–
3.32(m,8h).
13
c nmr(101mhz,chloroform-d) δ167.96(d,j＝21.3hz),164.16,161.70,160.57,153.18(dd,j＝13.9,3.2hz),136.78, 131.72,131.60,131.56,131.47,130.82,130.74,128.92,126.07,122.50,122.48,122.45, 119.17,118.14(d,j＝21.3hz),114.50
–
112.27(m),107.43,100.77,95.88,93.89,55.06, 41.33(d,j＝26.1hz).
19
f nmr(376mhz,chloroform-d)δ-110.99(s,1f),-162.34(s,1f). hplc conditions:chiralcel ad-h column(250
×
4.6mm),hexane/i-proh＝90/10,1ml/ min,254nm,τr(major)＝＝6.84min,τr(minor)＝7.63min。
[0116]
实施例85
[0117]
ib-19,白色固体，mp：122-126℃；[α]
d25 64.3(c 0.40,chcl3)；97％yield,86％
ee.1h nmr(400mhz,chloroform-d)δ7.89
–
7.78(m,2h),7.77
–
7.62(m,2h),7.54
–
7.43(m, 2h),7.43
–
7.33(m,2h),7.25
–
7.15(m,1h),6.23(t,j＝2.3hz,1h),6.00(d,j＝2.3hz, 2h),3.65
–
3.33(m,8h).
13
c nmr(101mhz,chloroform-d)δ167.96(d,j＝21.4hz), 160.60,153.32(d,j＝14.0hz),137.26,136.85,131.80,131.69,129.40,128.94,128.04, 128.02,127.92,127.90,126.06,119.19,107.52,100.68,95.99,94.01,55.11,41.39(d,j＝ 26.2hz).
19
f nmr(376mhz,chloroform-d)δ-162.48(s,1f).hplc conditions:chiralcelad-h column(250
×
4.6mm),hexane/i-proh＝98/2,1ml/min,254nm,τr(major)＝＝21.46min,τr(minor)＝17.56min。
[0118]
实施例86
[0119]
ib-20,淡黄色固体，mp：131-135℃；[α]
d25 27.5(c 0.57,chcl3)；98％yield,86％ee. 1
h nmr(400mhz,chloroform-d)δ7.80
–
7.60(m,2h),7.43(ddd,j＝8.2,1.8,1.0hz, 1h),7.41
–
7.31(m,3h),7.24
–
7.13(m,1h),6.92(d,j＝8.1hz,1h),6.23(t,j＝2.3hz, 1h),6.11
–
5.94(m,4h),3.63
–
3.35(m,8h).
13
c nmr(101mhz,chloroform-d)δ167.90 (d,j＝21.6hz),160.49,153.86,153.72,150.13,148.43,136.96,132.02,131.90,128.83, 125.78,123.71,123.69,122.05,122.02,119.10,108.65,107.53,106.24,101.71,100.61, 96.25,94.27,55.09,41.61(d,j＝26.3hz).
19
f nmr(376mhz,chloroform-d)δ-161.64(s, 1f).hplc conditions:chiralcel as-h column(250
×
4.6mm),hexane/i-proh＝80/20,1 ml/min,254nm,τr(major)＝＝8.45min,τr(minor)＝10.87min。
[0120]
实施例87
[0121]
ib-21,淡黄色固体，mp：78-81℃；[α]
d25 43.2(c 0.40,chcl3)；93％yield,92％ee. 1
h nmr(400mhz,chloroform-d)δ7.98(d,j＝8.1hz,2h),7.73(dd,j＝8.4,6.9hz,4h), 7.46
–
7.35(m,2h),7.23(d,j＝7.5hz,1h),6.23(t,j＝2.3hz,1h),5.98(d,j＝2.3hz, 2h),3.57
–
3.32(m,8h).
13
c nmr(101mhz,chloroform-d)δ167.98(d,j＝21.1hz), 160.62,152.98(d,j＝14.1hz),136.73,132.47(q,j＝32.8hz),128.98,126.92,126.91, 126.22,125.97,125.93,123.67(q,j＝1651.3,817.3hz),119.22,107.53,100.64,95.78, 93.79,55.04,41.29(d,j＝26.0hz).
19
f nmr(376mhz,chloroform-d)δ-62.99(s,3f),
ꢀ‑
162.75(s,1f).hplc conditions:chiralcel ad-h column(250
×
4.6mm),hexane/i-proh ＝90/10,1ml/min,254nm,τr(major)＝＝7.44min,τr(minor)＝6.46min。
[0122]
实施例88
[0123]
ib-22,白色胶体；[α]
d25 52.5(c 0.42,chcl3)；97％yield,90％ee.1h nmr(400mhz, chloroform-d)δ7.82(d,j＝8.0hz,2h),7.78
–
7.66(m,2h),7.45
–
7.30(m,4h),7.24
–ꢀ
7.09(m,1h),6.22(t,j＝2.3hz,1h),6.01(d,j＝2.2hz,2h),3.46(s,8h),3.07
–
2.84(m, 1h),1.30(dd,j＝6.9,1.1hz,6h).
13
c nmr(101mhz,chloroform-d)δ168.05(d,j＝21.4 hz),160.44,154.31(d,j＝13.8hz),152.41,137.02,132.07,131.95,128.84,127.18,127.12, 126.79,126.78,125.78,119.16,107.39,100.93,96.21,94.23,55.00,41.43(d,j＝26.2hz), 34.21,23.75,23.74.
19
f nmr(376mhz,chloroform-d)δ-161.86(s,1f).hplc conditions: chiralcel ad-h column(250
×
4.6mm),hexane/i-proh＝80/20,1ml/min,254nm,τr (major)＝＝5.80min,τr(minor)＝4.77min。
[0124]
实施例89
chiralcel oj-h column(250
×
4.6mm),hexane/i-proh＝98/2,1ml/min,254nm,τr (major)＝16.66min,τr(minor)＝19.44min。
[0148]
实施例101
[0149]
ib-35,白色固体；mp：81-85℃；[α]
d25 31.2(c 0.40,chcl3)；96％yield,98％ee.1h nmr(400mhz,chloroform-d)δ7.85(dd,j＝6.7,3.0hz,2h),7.57
–
7.37(m,3h),7.24
–
7.03(m,3h),6.95
–
6.74(m,2h),3.84(ddd,j＝11.2,6.9,4.2hz,1h),3.61
–
3.31(m,2h), 1.86
–
1.72(m,1h),1.72
–
1.52(m,4h),1.31
–
0.98(m,6h).
13
c nmr(101mhz, chloroform-d)δ168.54(d,j＝20.8hz),152.91(d,j＝13.7hz),130.54,130.13,129.02, 128.25,127.71,126.30,126.29,96.54,94.56,52.84,40.76(d,j＝26.1hz),30.13,30.00, 25.22,25.08.
19
f nmr(376mhz,chloroform-d)δ-165.69(s,1f).hplc conditions: chiralcel oj-h column(250
×
4.6mm),hexane/i-proh＝99/1,0.5ml/min,254nm,τr (major)＝15.05min,τr(minor)＝12.07min。。
[0150]
实施例102
[0151]
制备(r)-吡唑酮手性氟化产物ib-27(催化剂循环使用)
[0152][0153]
称取1mmol 4-取代吡唑酮ia-27，加入0.5mol％相转移催化剂iia-12，放入100ml 反应瓶，加入38wt％k2hpo4水溶液5ml，50ml甲苯，20℃下搅拌下加入1.05mmol nfsi(第一次投料)。反应30min后，hplc测定反应的转化率及ee值，进一步向体系中加入1mmol 4-取代吡唑酮ia-27，1.05mmol nfsi(第二次投料)继续搅拌反应30 min，hplc测定反应的转化率及ee值后继续投料。反应一共投料十次，每次投料的反应时间、转化率以及ee值如表10所示。
[0154]
表10每次投料的反应时间、转化率以及ee值
[0155]
[0156]
反应在第十次投料30min后，加入30ml乙酸乙酯，合并有机层。有机层用水洗 2次，饱和食盐水洗一次，无水硫酸钠干燥后浓缩(》99％收率，95.5％ee)。粗品直接用无水乙醇结晶，得到3.75g产品，总收率81％，测得ee值为99.7％。
[0157]
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。