Pan-JAK激酶抑制剂作为一种高度靶向性的化合物，在药化研究当中占据着举足轻重的地位。包括辉瑞公司生产的托法替尼在内，JAK激酶抑制剂类药物有数十种已经进入或接近进入临床的各个阶段。PF- 06263276化合物作为一种被设计出来的全新Pan-JAK激酶抑制剂分子，在应用缓释策略进行靶向治疗慢性阻塞性肺疾病的研究中表现出了十分优异的活性。因此如何高效大规模合成该类化合物，是一项亟待解决的问题。本文仅就此进行探讨。
药化研究当中的原初合成方案
我们首先通过对该药物的逆合成分析(Scheme 1)可知，针对该类化合物的合成，该化合物由A、B、C三模块组成。其中A模块可由D和E经由一步碳-氮偶联得到，B模块可以由G和F闭环形成咪唑环制得。C模块则可以通过制成金属类化合物，选择性对B苯环上的溴代位点进行偶联。在该合成策略中，应适当采用保护基对活泼基团进行保护，避免其他副反应的发生。
应用该组装策略，曾经有人报道过具体的合成路线。该路线选用SEM保护的溴代苯酚化合物作为起始原料，首先经历一步钯催化的硼化反应，将溴转化为频哪醇硼酸酯，得到化合物3，在与THP保护的苯并吡咯4进行Suzuki偶联反应，得到化合物5.之后用醇钠水解氰基，得到亚胺酸酯类化合物6。之后在酸性条件下和Boc保护的哌啶类化合物7反应，生成咪唑类前体化合物8。随后加浓盐酸对缩酮去保护，发生串联闭环反应，合成关键的咪唑环，得到化合物9.最后将化合物9与哌嗪模块通过接酰胺的方式组合，即得到Pan-JAK激酶抑制剂1。
据文献的报道，该路线的合成适用于毫克级制备抑制剂1,。其中Suzuki偶联步和咪唑闭环步骤当中对于保护基的需求是无法避免的。因此如何采取更好的策略提高该化合物的合成效率是亟待解决的一大问题。
化合物9的合成与保护及策略改进
在研究当中，作者指出在初始路线的化合物4中，1位氮采用THP保护存在以下问题：THP保护基容易在外加甲醇钠的条件下脱保护，同时在后续咪唑环关环时，THP也采用一步法脱保护，但在脱去保护以后，保护基会产生杂质化合物，在反应体系中难以去除。
在经过多次试验检测后，作者在文中提出了应用N,N-二甲基磺酰胺作为保护基的改进方案，该保护基可由廉价的磺酰氯前体组装。同时对于氰基水解的产率有着很高的促进作用，在反应中醇钠的装载量也可以降至一当量。该保护基在强酸加热条件下可以高效脱保护。整个路线优化后，合成化合物9的路线展示如下：
硼化反应以及后续的Suzuki偶联
采用钯催化的硼化反应对于大当量制备Suzuki偶联前体硼酸酯来说过于昂贵，且反应性效率过低，因此作者在这里提出了使用格式试剂进攻硼烷的策略来生成反应性更好的硼酸化合物。反应中会存在一定的硼酸酐类杂质，为了提高后续偶联反应的产率，这里作者采取硼化反应后不经提纯直接进行下一步反应的策略提高产率。该部分路线优化后如下:
Scheme 6 前提化合物13的优化合成路线
酰胺缩合相关研究
使用HATU作为缩合脱水剂对于大规模制备而言太过于昂贵，在经过筛选后，作者发现使用价低的CDI在50℃条件下反应也可以获得比较高的缩合产率。同时产物的提纯可以通过低温结晶的方式达到，为整个反应的规模流程做了简化。
抑制剂1的晶型提纯
由于PJK激酶抑制剂在使用当中对于其固体晶型有着严格眼球，因此对于提纯结晶部分的研究也是必不可少的。在经过一系列的筛选和研究后，作者发现在甲基乙基酮(含3%水)当中对化合物1进行加热重结晶提纯可以以很高效的得到高度结晶的纯品化合物。同时，还可以有效的减少NMP杂质的含量。详细的操作方法为：在甲基乙基酮(含3%水)中加入粗品化合物1，75-80℃下加热24h，冷却结晶，过滤干燥提纯即可。
路线概括为，选用化合物2作为起始原料，引发格式试剂后原位反应生成硼酸和硼酸酐混合物，不经提纯直接加入化合物24完成偶联反应的到化合物13，随后经过加入醇钠水解氰基，哌啶化合物乙酸去Boc保护后生成二氨基化合物以及强酸去缩酮保护引发闭环脱水，得到关键中间体16，随后和硫酸共热去N,N-二甲基磺酰基保护基得到化合物19。最后在使用脱水剂CDI缩合生成酰胺得到粗品产物1。应用上文提到的在MEK当中加热24h的方法，提纯化合物1，得到高纯度高度结晶的纯品。
实验操作
6-Bromo-3-cyano-N,N-dimethyl-1H-indazole-1-sulfonamide (24). A 20-L jacketed reactor was charged with N-methyl-pyrrolidinone (NMP, 4.1 L), 6-bromo-1H-indazole-3-carbonitrile (23, 0.854 kg, 3.85 mol), and K2CO3 (1.03 kg, 7.45 mol, 1.94 equiv). The batch was warmed to 30 °C, and dimethylsulfamoyl chloride (0.608 kg, 4.23 mol, 1.10 equiv) was added to the reactor at such a rate to maintain the batch temperature in the 25 to 35 °C range (the addition took place over 40 min). Upon reaction completion (∼30 min), the reaction was cooled to 20 °C and water (8.5 L) was added to precipitate 24 while maintaining the internal temperature below 35 °C. The resulting slurry was stirred for 30 min and filtered. The filter cake was washed with water until the pH of the filtrates was below 8. The solid was dried on the filter
under a stream of nitrogen at ambient temperature to afford 1.20 kg of 24 (95% yield). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 8.6, 1.4 Hz, 1H), 3.09 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 141.3, 129.3, 125.2, 123.5, 123.4, 120.6, 116.6, 111.6, 39.1. HRMS (ESI) calcd for C10H8BrO2N4S [M - H]−: 326.9557; found 326.9558.
(2-Ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)- methoxy)phenyl)boronic Acid (20). A 200-L glass lined reactor was charged with 2-MeTHF (9.9 L) and magnesium turnings (1.18 kg, 48.6 mol, 2.0 equiv). 1,2-Dibromoethane (0.11 L, 0.23 kg, 1.2 mol, 0.050 equiv) was added to the reactor. The batch temperature was closely monitored during this addition to ensure the spike in batch temperature indicative of the exothermic reaction between magnesium and dibromoethane was observed (11 °C spike was recorded). The batch was heated to 60 °C, and a solution of aryl bromide 2 (8.50 kg, 24.3 mol, 1.0 equiv) in 2-MeTHF (25 L) was added according to the following protocol: about 10% of the total amount was added initially, and the start of the reaction was confirmed by the batch temperature rise (10 °C exotherm was observed). The remaining solution of 2 was then added at such a rate as to maintain the batch temperature within a 10 °C range above the reactor’s jacket temperature (60 to 70 °C for a 60 °C jacket; the addition took place over approximately 2 h). The mixture was then held at 60 °C for an additional hour and analyzed by HPLC to confirm the full consumption of aryl bromide 2. After cooling to 0 °C, tri-isopropyl borate (6.68 kg, 35.5 mol, 1.46 equiv) was added while the internal temperature was held between 0 and 10 °C. The reaction mixture was warmed to 20 °C and stirred for 3 h. The mixture was filtered through a glass wool-packed cartridge to remove unreacted magnesium (magnesium caught in the filter and left in the reactor was wetted with water before being exposed to air), and the filtrate was transferred to a clean reactor and cooled to 10 °C. One molar aqueous HCl (27 kg, 27 mol, 1.1 equiv) was added to the reactor while maintaining the batch temperature below 20 °C. After stirring at 20 °C for 1 h, the layers were separated and the organic phase was washed with 15% brine (15 L). The resulting 2-MeTHF solution (46.7 kg) was analyzed by HPLC and determined to contain 78.8% of boronic acid 20, 9.6% of borinic acid 21, and 9.1% of the desbromoaryl side product 22 (by area count at 215 nm). This solution was used in the next step without any additional processing.26 A sample of the pure boronic acid 20 was prepared from an aliquot of the final solution via concentration to dryness and crystallization though the addition of heptane. 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J = 12.30 Hz, 1H), 7.15 (d, J = 7.78 Hz, 1H), 5.37 (s, 2H), 3.77−3.92 (m, 2H),
3.16 (q, J = 7.49 Hz, 2H), 1.35 (t, J = 7.53 Hz, 3H), 0.92−1.09 (m, 2H), 0.03 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 150.64 (d, JC−F = 2.9 Hz), 150.73 (d, JC−F = 243.6 Hz), 148.44 (d, JC−F = 10.3 Hz), 124.38 (d, JC−F = 16.9 Hz), 121.6, 118.03, 93.62, 66.92, 28.62, 18.08, 17.69, −1.36. 19F NMR: (376 MHz, CDCl3) δ −139.44 ppm. HRMS (ESI) calcd for C16H24BF4SiO6 [M + TFA]−: 427.1377; found 427.1380.
3-Cyano-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)- ethoxy)methoxy)phenyl)-N,N-dimethyl-1H-indazole-1-sulfonamide (13). A 200-L glass-lined reactor was charged
with the solution of boronic acid 20 and borinic acid 21 in 2-MeTHF obtained in the previous step (46.7 kg, with an estimated 19.4 mol of 20, 1.1 equiv), 24 (5.80 kg, 17.6 mol), anhydrous K3PO4 (7.48 kg, 35.2 mol, 2.0 equiv), 1,1′-bis(ditert- butylphosphino)ferrocene (167 g, 0.352 mol, 0.020 equiv), and water (5.8 L). The reactor and its contents were inerted and degassed via three vacuum-nitrogen purge cycles. Pd(OAc)2 (79.1 g, 0.351 mol, 0.020 equiv) was added to the reactor, and the batch was heated to 50 °C, held at that temperature for 30 min, and then heated further to 65 °C. After 2 h at 65 °C, HPLC analysis showed complete consumption of aryl bromide 24. The mixture was cooled to 15 °C, and water (12 L) was added. After stirring for 20 min, the mixture was filtered through a pad of Celite to remove insoluble material and the phases were separated. The organic solution was washed with 16% aqueous solution of NaCl (15.3 kg), filtered through a pad of magnesium sulfate (8.7 kg), and concentrated at reduced pressure to 15 L (jacket temperature
50 °C) to further azeotropically dry it. To the residue was added 2-MeTHF to a final volume of approximately 50 L, and the solution was treated with Si-thiol resin (4.8 kg). After stirring at 40 °C for 12 h, the suspension was cooled to 20 °C, the scavenger resin was filtered off, the filtrates were concentrated to a minimum volume, and the residue was diluted with methanol (50 L). The resulting solution (50.6 kg) was assayed by HPLC to contain 15.6 wt % of 13, which corresponded to 7.89 kg of the product in solution (86% yield based on the amount of 24). An isolated sample of compound 13 was characterized as follows: 1H NMR (400 MHz, DMSOd6) δ 8.09 (dd, J = 8.4, 0.8 Hz, 1H), 7.90 (t, J = 1.1 Hz, 1H), 7.53 (dd, J = 8.4, 1.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 11.8 Hz, 1H), 5.35 (s, 2H), 3.82−3.74 (m, 2H), 2.98 (s, 6H), 2.48 (q, J = 8.2, 7.5 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H), 0.96−0.83 (m, 2H), −0.01 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 150.2 (d, JC−F = 243.4 Hz), 144.2 (d, JC−F = 10.6 Hz), 142.3, 140.2, 137.6 (d, JC−F = 3.5 Hz), 133.3 (d, JC−F =6.4 Hz), 127.4, 123.1, 122.9, 119.7, 118.2 (d, JC−F = 1.8 Hz), 117.3 (d, JC−F = 18.9 Hz), 112.8, 112.1, 93.4, 65.9, 38.4, 25.2, 17.4, 15.6, −1.4. 19F NMR: (376 MHz, CDCl3) δ −137.64 ppm. HRMS (ESI) calcd for C24H32FN4SSiO4 [M + H]+: 519.1882; found 519.1894.
6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-N,N-dimethyl-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)- 1H-indazole-1-sulfonamide Dihydrochloride (16·2HCl).
The solution of 13 in methanol obtained in the previous step (50.6 kg, assayed to contain 15.6 wt %, 7.89 kg, 15.2 mol of 13) was charged into a 200-L jacketed reactor. Sodium methoxide solution in methanol (25 wt %, 3.31 kg, 15.3 mol, 1.01 equiv) was added to the reactor (the batch temperature was maintained at 20−25 °C), and the resulting solution was stirred at this temperature for 1 h. Upon complete conversion of nitrile 13 to imidate 14, acetic acid (1.01 kg, 16.8 mol, 1.10 equiv) was added, and the mixture was concentrated in vacuum to approximately 17 L. Isopropanol (34 L) was added to the reactor and the concentration was repeated. Another portion of isopropanol (56 L) was added, and the residual level of methanol in the resulting solution was determined by headspace GC to be 0.3%. A sample of the intermediate methyl 1-(dimethylsulfamoy l ) -6-(2-ethyl-5-fluoro-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)-1H-indazole-3-carboximidate (14) was isolated and characterized. 1H NMR (400 MHz, CDCl3) δ 8.64 (br s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 11.6 Hz, 1H), 5.32 (s, 2H), 4.11 (s, 3H), 3.79−3.91 (m, 2H), 3.03 (s, 6H), 2.53 (q, J = 7.4 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H), 0.96−1.04 (m, 2H), 0.04 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 163.31, 151.02 (d, JC−F = 244.3 Hz), 144.84 (d, JC−F = 11.0 Hz), 142.74, 142.25 (d, JC−F = 1.5 Hz), 141.36, 138.13 (d, JC−F = 3.7 Hz), 134.77 (d, JC−F = 5.9 Hz), 126.58, 122.50, 120.28, 118.47 (d, JC−F = 1.5 Hz), 117.79 (d, JC−F = 19.1 Hz), 113.36, 94.41, 66.84, 53.78, 39.14, 26.08, 18.21, 15.93, −1.25 (s). LC−MS (ESI) calcd for C25H35FN4O5SSi: 551.2 [M + H]+; found 551.0.
To the isopropanol solution of imidate 14 obtained above was added tert-butyl 3-amino-4,4-diethoxypiperidine-1-carboxylate oxalate5 (7·(CO2H)2; 6.38 kg, 16.9 mol, 1.11 equiv), and the mixture was heated to 50 °C and held at this temperature for 10 h. HPLC analysis showed complete conversion of the imidate ester to amidine 15. The mixture was cooled to 0 °C, and concentrated aqueous HCl solution (37%, 17 L, 204 mol, 13 equiv) was added (the ensuing exotherm warmed the batch to 14 °C). The contents of the reactor were then heated at 50 °C for 4 h to fully convert amidine 15 to imidazole 16. The resulting suspension was cooled to 20 °C and filtered, and the solid was washed with isopropanol (37 L) and dried on the filter under a stream of nitrogen to afford 8.97 kg of 16·2HCl (81%, adjusted for 76.5% free base potency, based on the amount of 13). 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 2H), 8.58 (d, J = 8.6 Hz, 1H), 7.85 (br s, 1H), 7.46 (dd, J = 8.2, 1.2 Hz, 1H), 7.09 (d, J = 12.1 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.31 (br s, 2H), 3.40−3.56 (m, 2H), 3.02−3.13 (m, 2H), 2.99 (s, 6H), 2.42−2.50 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 149.00 (d, JC−F = 240.6 Hz), 144.68 (d, JC−F = 11.7 Hz), 142.04, 141.61, 138.89, 137.50 (d, JC−F = 2.9 Hz), 137.44, 130.99 (d, JC−F = 5.9 Hz), 126.44, 122.34, 120.20, 118.04 (d, JC−F = 3.7 Hz), 117.23 (d, JC−F = 18.3 Hz), 112.50, 40.83, 38.62, 25.50, 25.16, 19.07, 15.75. 19F NMR (376 MHz, DMSO-d6) δ −140.26 ppm. HRMS (ESI) calcd for C23H26N6FO3S [M + H]+: 485.1766; found
485.1766.
5-Ethyl-2-fluoro-4-(3-(4,5,6,7-tetrahydro-1H-imidazo- [4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol Sulfate (19·H2SO4). A 200-L glass-lined reactor was charged with 16·2HCl (8.96 kg, 12.3 mol) and water (60 L). Concentrated sulfuric acid (31.4 kg) was added slowly to keep the batch temperature below 50 °C. The resulting mixture was heated at 105 °C until complete removal of the dimethylsulfamoyl protecting group (at least 16 h; as the reaction neared completion, the slurry
turned into a clear solution). The mixture was cooled to 70 °C to induce product crystallization, then reheated to 90 °C, held at that temperature for 30 min, and finally cooled to 20 °C over 2 h. After an additional 30 min hold at 20 °C, the solids were filtered and the cake was washed with water until the pH of the filtrates was neutral (about 40 L) followed by a MeOH wash (10 L). The solid was dried under vacuum at 50−65 °C to afford 5.40 kg of 19·H2SO4 (87.3% adjusted for 95.9% sulfate potency; water content in the solid after 4 days of drying was 3.3%). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br s, 1H), 9.88 (br s, 1H), 9.13 (br s, 2H), 8.31 (d, J = 8.2 Hz,
1H), 7.44 (s, 1H), 7.15 (dd, J = 8.4, 1.0 Hz, 1H), 7.03 (d, J = 11.7 Hz, 1 H), 6.94 (d, J = 9.4 Hz, 1H), 4.20−4.31 (m, 2H), 3.41−3.55 (m, 2H), 2.87−3.01 (m, 2H), 2.42−2.50 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 148.88 (d, JC−F = 239.9 Hz), 144.13 (d, JC−F = 12.5 Hz), 141.30, 141.24, 139.00, 137.52 (d, JC−F = 2.9 Hz), 135.72, 132.14 (d, JC−F = 5.9 Hz), 123.48, 121.30, 118.88, 117.77 (d, JC−F = 2.9 Hz), 117.24 (d, JC−F = 17.6 Hz), 110.38, 25.18, 15.71. 19F NMR (376 MHz, DMSO-d6) δ −140.59 ppm. HRMS (ESI) calcd for C21H21FN5O [M + H]+: 378.1725; found 378.1726.
(2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol- 3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (1). A 100-L glass-lined jacketed reactor was charged with N-methylpyrrolidinone (NMP, 22 L) and 5-(piperidin-1-yl)pyrazine-2- carboxylic acid (10; 2.73 kg, 13.2 mol, 1.35 equiv). To the resulting solution was added CDI (2.13 kg, 13.1 mol, 1.34 equiv) in portions (a weak exotherm and slow gas evolution was observed). The mixture was stirred for 2 h and then analyzed by HPLC to confirm conversion of the acid to the activated acyl imidazole (for HPLC analysis, a sample from the reaction was quenched into a solution of pyrrolidine in MeCN; conversion of 10 to the acyl imidazole was inferred from integration of the peaks corresponding to the unreacted 10 and its pyrrolidine amide derivative assuming complete conversion of the activated acid to the amide). In a separate reactor, 19·H2SO4 (4.65 kg, 9.78 mol, limiting reagent) was combined with NMP (18 L) and the mixture was heated to 50 °C. To this mixture was added the activated acid from the first reactor over approximately 20 min while maintaining the receiving batch temperature at 50−55 °C. The mixture was stirred for 4 h at this same temperature, cooled to 20 °C, and filtered to remove the solids (mostly imidazole sulfate salts). The filtrate was slowly added to a solution of sodium bicarbonate (1.58 kg, 18.8 mol, 1.9 equiv) in water (130 L) with fast stirring while maintaining the batch temperature below 30 °C (the addition was mildly exothermic). The resulting fine slurry was filtered and the filter cake was washed with water until the pH of the
filtrates was below 8 (approximately 50 L).
Removal of Bis-acylated Impurities. The deliquored wet cake of 1 was mixed on the filter with MeOH (44 L), and the slurry was transferred from the filter into a 200-L reactor by pulling vacuum. An aqueous solution of NaOH (50 wt %, 1.20 kg, 15.0 mol, 1.53 equiv) was added to the MeOH slurry, and the mixture was heated to 45 °C, held at this temperature for 1−2 h, and then analyzed to confirm disappearance of the bisacylated side products. Acetic acid (1.2 L, 21 mol, 2.2 equiv) was added, and the batch was held at 45 °C for 1−2 h and then cooled to 20 °C over 2 h. The mixture was filtered, and the filter cake was washed first with a mixture of methanol (2.7 kg) and water (2.7 kg) followed by a methanol wash (7.0 L). The solid was dried on the filter under a stream of nitrogen to afford 4.91 kg (81% adjusted for 91.8% potency) of crude 1 as the free base. The isolated material had an acceptable HPLC purity; however, the residual solvent content was high: NMP: 0.2%; MeOH: 5.9%; and AcOH: 0.4% (all weight% determined by quantitative NMR using maleic acid as internal standard).
Recrystallization from MEK/Water. A mixture of crude 1 (4.90 kg, 7.71 mol), 2-butanone (MEK, 49 L), and water (0.75 L) was heated to 50 °C and seeded with Form 1 (50 g). The batch temperature was increased to 70 °C and stirred at this temperature until complete polymorph conversion to Form 1 was observed as determined by PXRD analysis (24−30 h). The mixture was cooled to 10 °C over 2 h, held at this temperature for 5 h, and then filtered. The filter cake was washed with MEK (10 L) and dried under vacuum at 50 °C for 20 h to afford 4.52 kg of 1 (100% based on the amount of crude 1, strengthadjusted). 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 12.40 (s, 1H), 9.69 (s, 1H), 8.40 (d, J = 1.3 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 7.38 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (d, JH−F = 11.9 Hz, 1H), 6.93 (d, J JH−F = 9.1 Hz, 1H), 4.74 (s, 2H), 3.96 (t, J = 5.7 Hz, 2H), 3.69 (t, J = 5.4 Hz, 4H), 2.80 (d, J = 5.8 Hz, 2H), 2.54−2.44 (m, 2H), 1.74−1.50 (m, 6H), 1.03 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO-d6, 50 °C) δ 166.3, 154.0, 148.9 (d, JC−F = 239.5 Hz), 144.0 (d, JC−F = 11.9 Hz), 143.2, 141.1, 140.5, 138.8, 137.4 (d, JC−F = 3.2 Hz), 136.6, 135.5, 132.3 (d, JC−F = 5.9 Hz), 127.9, 123.0, 121.6, 119.0, 117.7 (d, JC−F = 3.1 Hz), 117.1 (d, JC−F = 18.1 Hz), 110.0 (2C), 44.8, 25.1, 24.9 (2C), 23.9, 15.5. (Five 13C resonances not observed in 13C NMR spectrum
due to imidazole tautomerization). 19F NMR (376 MHz, DMSO-d6) δ −141.1. HRMS (ESI) calcd for C31H32N8FO
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