Research group of Shen Qilong, Shanghai Institute of organic chemistry, Chinese Academy of Sciences: development of fluoroalkylthio reagents and their application in 18F chemistry

Positron emission computed tomography (PET) combined with CT is PET-CT imaging PET-CT is one of the most advanced functional molecular imaging techniques This technology has a wide range of applications in the field of pharmaceutical chemistry It can provide information about pharmacokinetics of drugs and guide the synthesis of lead compounds The core of this technology is how to develop appropriate radioactive tracers At present, the existing tracers include 18 F-FDG, 18 f-alftide-rgd, 11 c-acetic acid, 11 C-choline, etc Among these tracers, 18 F labeled molecules are widely used, mainly because 18 F has a more suitable half-life (T 1 / 2 = 109.7 min) Therefore, the development of 18 f-labeled fluoro group methodology is of great significance to promote the development of PET technology Recently, Shen Qilong, a researcher of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has successfully synthesized a series of 18 f-labeled aromatic rings and heterocycles by introducing bromodifluoromethylthiol into fluoroalkylthio reagents Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201813708) Brief introduction to Shen Qilong, researcher of "Hundred Talents Program" of Shanghai Institute of organic chemistry, Chinese Academy of Sciences In July 1996, he graduated from the Department of environmental science and engineering of Nanjing University; in July 1999, he graduated from the Shanghai Institute of organic chemistry; in July 2002, he graduated from the University of Massachusetts at Dartmouth with a master's degree in science; from September 2002 to September 2007, he studied at Yale University with a doctor's degree From October 2007 to March 2010, he was engaged in postdoctoral research in the Department of chemistry, University of Illinois at Urbana Champaign; after returning to China in April 2010, he worked in Shanghai Institute of organic chemistry, Chinese Academy of Sciences In 2016, he won the National Science Fund for Distinguished Young Scholars Several original electrophilic fluoroalkyl reagents have been developed, most of which have been commercialized More than 20 articles have been published in Chem Rev., acc.chem Res., J am Chem SOC., angel Chem Int.ed., and other magazines, with more than 2500 citations Frontier research achievements: the development and application of fluoroalkylthio reagents in 18F chemistry Shen Qilong research group of Shanghai organic Institute has made a series of pioneering work in the development of electrophilic fluoroalkylthio reagents The research group has successively developed several highly active electrophilic trifluoromethylthiolation reagents (angelw.chem.int.ed 2013, 52, 3457; angelw.chem.int.ed 2013, 53, 9316; J.Org Chem 2016, 81, 7486); meanwhile, it has developed the first electrophilic, nucleophilic and free radical type difluoromethylthiolation reagents (j.am.chem.soc 2015, 137, 10547; angelw Chem Int Ed 2015, 54, 7648; angelw Chem Int.ed 2016, 55, 15807); in addition, the first electrophilic difluoromethylsulfide reagent (angelw Chem Int ed 2017, 129, 11733) was also synthesized With these fluoroalkylthio reagents, it is very convenient to introduce fluoroalkylthio group into molecules On the basis of previous work, they assumed that the system would be extended to haloalkylthio group, because haloalkylthio group is an excellent 18 f-scf 3 precursor group Based on this, they pioneered the development of the first electrophilic bromodifluoromethylsulfonate The synthesis of 18 f-labelled trifluoromethylthio arenes has been reported in two cases In 2015, the Gouverneur research group (angel W chem Int ed 2015, 54, 9991) first synthesized bromodifluoromethylthio aromatic hydrocarbons using thiophene as the substrate, and then obtained 18 f-labeled target compounds through the fluorine halogen exchange strategy In 2017, the jubault research group (chem Commun 2017, 53, 5706) successfully obtained the target compound by the reaction of 18 f-labeled fluoroform (hcf218f) and aryl disulfide Looking at these two synthesis methods, we need to synthesize sulfur-containing substrates first They are suitable for simple small molecular compounds, but they are not suitable for complex compounds Therefore, the strategy of this study is to use the electrophilic bromodifluoromethylthiolation reagent developed by the research group to react with the readily available aryl boron reagent to obtain bromodifluoromethylthio modified aromatics, and then to obtain 18 f-labeled trifluoromethylthio aromatic rings through the fluorine halogen exchange strategy Fig 1.18 synthesis of f-labelled trifluoromethylthio aromatic ring (source: angelw Chem Int ed.) Firstly, the author synthesized bromodifluoromethylthiosulphonate The synthesis route is as follows: after extracting hydrogen from sodium hydride, benzylthiol reacts with difluorodibromo at low temperature for 24 hours, and the yield of the reaction is 34% Then, it reacts with chlorine and lithium alcohol in two steps, that is, the yield of the reagent is 73% It is a colorless oily liquid, stable at room temperature Fig 2 Synthesis route of bromodifluoromethiosulfonate (source: angelw Chem Int ed.) then, the coupling reaction between bromodifluoromethiosulfonate and arylboron reagent was investigated At first, the reaction of the reagent with arylboric acid was investigated Under the condition of Cu (MeCN) 4pf6 as catalyst, only a small amount of product (yield < 5%) was observed Then, the author found that the coupling product could be obtained in almost equivalent yield under the condition of (DPPE) CuCl as catalyst and sodium TERT butanol as base Subsequently, the author extended the substrate under the optimal reaction conditions (Fig 3) The results show that the bromodifluoromethylthio aryl ring can be obtained with high yield from the substrate with electron donor and electron deficient substituent (2A - V) For some heterocyclic compounds, such as benzofuran (2x), benzothiophene (2Z), pyridine (2C), quinoline (2e), pyrimidine (2AF), pyrazole (2ah AI), etc., the target compounds can be obtained in high yield All in all, this method has the advantages of mild conditions and wide substrate compatibility Figure 3 Substrate development (source: angelw Chem Int ed.) in order to investigate the practicability of the methodology, the author selected a series of natural products and drug molecules to be modified by bromodifluoromethylthiolation It was found that OLED material molecule (3b-c), natural product derivative (3j-k), natural product coumarin (3D), sandalwood Qi (3e) and vitamin E (3H) could get the product with medium to excellent yield The yield of clobete (3f) and fenofibrate (3G) was 92% and 96% Mecrolazine (3L), an allergic drug, can also be modified with bromodifluoromethione in 81% yield These applications also provide powerful means for drug development in the future Figure 4 Study on the practicability of the reaction (source: angelw Chem Int ed.) after successfully synthesizing a series of bromodifluoromethylthio modified aromatic rings, the author cooperated with Gouverneur group of Oxford University in the United Kingdom to carry out 18 F labeling research on the products by using the fluorine halogen exchange reaction developed by the group Under this condition, the author successfully realized the 18 F labeling of brominated difluoromethylsulfide modified aromatics with complex structure, and successfully obtained a series of 18 f-scf 3 aromatics and heterocyclic aromatics (Fig 5) For the common neutral and electron donating aromatics (9D, 9F, 9g-h, 9j), the radiochemical conversion of the reaction is higher (RCC: 47-86%); for the electron deficient aromatics (9i, 9K), the reaction conversion is slightly reduced; for the nitrogen heterocyclic aromatics (9a, 9C, 9e), the reaction conversion is significantly reduced The 18 F labeling of these complex compounds also provides the possibility for the application of this methodology in pet Fig 5.18 preparation of f-scf3 aromatics and heterocyclic aromatics (source: angelw Chem Int ed.) in order to further investigate the practicability of the brominated difluoromethylthiolation / 18 f-fluorination methodology, the author then tried to label the existing trifluoromethylthio drug molecules with 18 F The author selected a kind of amphetamine drug tiflorex for the treatment of obesity Before that, the 18 F labeling experiments of the drug were not successful Through this method, the author successfully achieved the 18 F labeling experiment of the drug The main experimental process is as follows: starting from the commercially available raw material 10, we obtained the molecule 12 modified by bromodifluoromethylsulfide in high yield through four steps of reaction; 12 and then obtained [18 F] tiflorex with 84% conversion through the experiments of halogen exchange and reductive amination The total conversion was 41% It also provides an important means for further study of pharmacokinetics of these drugs Figure 6 [18 F] the synthesis route of tiforex (source: angel Chem Int ed.) was published on angel Chem Int ed (DOI: 10.1002 / anie 201813708) The first authors of this paper are Wu Jiang and Zhao qunchao, Ph.D students of Shanghai organic Research Institute, Shen Qilong, researcher of Shanghai organic Research Institute, and V é ronique Gouverneur, Professor of Oxford University, UK Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.