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(E) Fluorination US 20090061471 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0061471 A1 Fasan et al. (43) Pub. Date: Mar. 5, 2009 (54) METHODS AND SYSTEMS FOR SELECTIVE Publication Classification FLUORINATION OF ORGANIC MOLECULES (51) Int. Cl. (76) Inventors: Rudi Fasan, Brea, CA (US); CI2O I/26 (2006.01) Frances H. Arnold, La Canada, CA CI2P 7/62 (2006.01) (US) CI2P 7/38 (2006.01) CI2P I 7/04 (2006.01) Correspondence Address: CI2P I 7/14 (2006.01) Joseph R. Baker, APC CI2P 9/44 (2006.01) Gavrilovich, Dodd & Lindsey LLP 4660 La Jolla Village Drive, Suite 750 (52) U.S. Cl. ........... 435/25; 435/135; 435/149; 435/126; San Diego, CA 92122 (US) 435/120: 435/74 (21) Appl. No.: 11/890,218 (22) Filed: Aug. 4, 2007 (57) ABSTRACT A method and system for selectively fluorinating organic Related U.S. Application Data molecules on a target site wherein the target site is activated (60) Provisional application No. 60/835,613, filed on Aug. and then fluorinated are shown together with a method and 4, 2006. system for identifying a molecule having a biological activity. OH DeOXO- F Oxygenase 1 fluorination HO F Oxygenase 2 DeOXO Sea-intries fluOrination Oxygenase 3 HO H F O F DeOXO (e) ---->fluorination Patent Application Publication Mar. 5, 2009 Sheet 1 of 8 US 2009/0061471 A1 OH DeOXO- F ov fluorination HO F Oxygenase 2 DeOXO - - -m-m-e- fluorination on N HO OH F DeOXO fluorination FI G. 1 Chemo-enzymatic strategy F Oxygenase OH DeOXO fluorination High regio- and stereoselectivity Highly enantiopure fluoro derivative in good yields Chemical Strategy F F FIUOrination (OE FChiral -m-ap reSOIUtion (o) Enantiopurein poor fluoro-derivative yields Poor Stereoselectivity With Current methods FIG. 2 Patent Application Publication Mar. 5, 2009 Sheet 2 of 8 US 2009/0061471 A1 D helix L helix FIG. 3 Patent Application Publication Mar. 5, 2009 Sheet 3 of 8 US 2009/0061471 A1 S (). S N S S -a-a-b- L l l l ()l S N S lS S S s SS gs S N. N O () Patent Application Publication Mar. 5, 2009 Sheet 4 of 8 US 2009/0061471 A1 2/BA co 9-9/8A aayaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa |||-8JPM aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa. 6-9/BM EFH 2222222222a2/2ZYZZ22a2/24%a22 Z1-8JPM- |JPA [JEM NISI: G-9UBA |-(}) 61-8.JPM S LIOS/a1103 fello I0IGLISO 31001 Patent Application Publication Mar. 5, 2009 Sheet 5 of 8 US 2009/0061471 A1 N scs S. a. N vs. seasyxxx seawaxxx Q SSIs S. l Lie as a t slala 2 2 S. axxas 2%Llls S. s ITTLs2 2. LLL's % 2. Zaayaay a S st UOS/8MU00 fe01 lOlillSlp lonpold Patent Application Publication Mar. 5, 2009 Sheet 7 of 8 US 2009/0061471 A1 B Regioselectivity in MIMP0 activity (GC analysis) 120.0% S 100.0% 2, 2 2 2 S 80.0% 3 É % S. 60.0%. aging S 40.0% 3 3- a MMPCH S on no % % ... WAO War3-19 War3-18 Var3-8 War2 Var3-5 var3-16 War3-6 War3-11 C 70% S 60% 3 50% S 40% S 30% is N is 20% is g: E. H. H. H. H. H. H. War3-19 War3-18 var3-8 War2 War3-5 War3-16 War3-6 Var3-11 FIG. 7 (Cont'd) Patent Application Publication Mar. 5, 2009 Sheet 8 of 8 US 2009/0061471 A1 Whole-cell activation of dihydrolasnone (DH) 35.0 300 25.0 200 15.0 OXDH 10.0 O 5 10 15 20 25 30 35 40 time (hrs) FIG. 8 US 2009/0061471 A1 Mar. 5, 2009 METHODS AND SYSTEMIS FOR SELECTIVE fluorine-containing Substance selected for research, pharma FLUORINATION OF ORGANIC MOLECULES ceutical, or agrochemical application has to be man-made. 0009. Despite a few reports on the application of molecu CROSS REFERENCE TO RELATED lar fluorine (F) for direct fluorination of organic compounds APPLICATIONS (Chambers, Skinner et al. 1996; Chambers, Hutchinson et al. 0001. This application claims priority to U.S. Provisional 2000), this method typically suffers from poor selectivity and Application Ser. No. 60/835,613 filed on Aug. 4, 2006, the requires handling of a highly toxic and gaseous reagent. Sev disclosure of which is incorporated herein by reference it its eral chemical strategies have been developed over the past entirety. decades to afford selective fluorination of organic compounds under friendlier conditions. These have been recently TECHNICAL FIELD reviewed by Togni (Togni, Mezzetti et al. 2001), Cahard (Ma 0002 The present disclosure generally relates to the fields and Cahard 2004), Sodeoka (Hamashima and Sodeoka 2006), of synthetic organic chemistry and pharmaceutical chemistry. and Gouverneur (Bobbio and Gouverneur 2006). These strat In particular, the present disclosure relates to methods and egies involve catalytic as well as non-catalytic methods. The latter comprise substrate-controlled fluorination methods, systems for the selective fluorination of organic molecules. which generally make use of a chiral auxiliary, and reagent controlled fluorination methods, which generally make use of BACKGROUND chiral electrophilic N F or nucleophilic fluorinating 0003. The importance of fluorine in altering the physico reagents. chemical properties of organic molecules and its exploitation 0010. These fluorination methods, however, need several in medicinal chemistry has been highlighted in recent reviews chemical steps to prepare the chiral Substrates (Davis and Han (Bohm, Banneretal. 2004). Although similar in size to hydro 1992: Enders, Potthoff et al. 1997) or the chiral reagents gen, H->F substitutions can cause dramatic effects on several (Davis, Zhou et al. 1998; Taylor, Kotoris et al. 1999; Nyffeler, properties of organic molecules, including the lipophilicity, Duron et al. 2005) and have an applicability restricted to dipole moment, and pKa thereof. In addition, fluorine substi reactive C–H bonds (Cahard, Audouard et al. 2000; Shibata, tutions can dramatically alter the reactivity of the fluorinated Suzuki et al. 2000; Kim and Park 2002; Beeson and Mac site as well as that of neighboring functional groups. Millan 2005; Marigo, Fielenbach et al. 2005) in specific 0004. In particular, in medicinal chemistry, there is a classes of compounds Such as aldehydes (Beeson and Mac growing interest towards incorporating fluorine atoms in Millan 2005; Marigo, Fielenbach et al. 2005) or di-carbonyls building blocks, lead compounds and drugs in that this may (Hintermann and Togni 2000; Ma and Cahard 2004; Shibata, increase by many-fold the chances of turning these molecules lshimaru et al. 2004; Hamashima and Sodeoka 2006). into marketable drugs. Several studies have shown that potent 0011. Despite much progress in the field of organofluorine drugs can be obtained through fluorination of much less chemistry, the number of available methods for direct or active precursors. Some representative examples include indirect asymmetric synthesis of organofluorine compounds anticholesterolemic EZetimib (Clader 2004), anticancer CF3 taxanes (Ojima 2004), fluoro-steroids, and antibacterial fluo remains limited and additional tools are desirable. In particu roquinolones. lar, a general method to afford mono- or poly-fluorination of 0005. The improved pharmacological properties of organic compounds at reactive and unreactive sites of their fluoro-containing drugs are often due to their improved phar molecular scaffold is desirable. macokinetic properties (biodistribution, clearance) and enhanced metabolic stability (Park, Kitteringham et al. 2001). SUMMARY Primary metabolism of drugs in humans generally occurs through P450-dependent systems, and the introduction of 0012 Provided herein are methods and systems for the fluorine atoms at or near the sites of metabolic attack has often selective fluorination of a target site of an organic molecule, proven Successful in increasing the half-life of a compound which include the activation and subsequent fluorination of (Bohm, Banner et al. 2004). A comprehensive review cover the target site. In the methods and systems herein disclosed, ing the influence of fluorination on drug metabolism (espe the target site is an oxidizable carbon atom of the organic cially P450-dependent) is presented. (Park, Kitteringham et molecule, the activation is performed by introducing an oxy al. 2001). gen-containing functional group on the target site, and the 0006. In other cases, the introduction of fluorine substitu fluorination of the activated site is performed by replacing the ents leads to improvements in the pharmacological properties functional group introduced on the target site with fluorine as a result of enhanced binding affinity of the molecule to The introduction of the oxygen-containing functional group biological receptors. Examples of the effect of fluorine on and the replacement of the functional group with a fluorine binding affinity are provided by recent results in the prepara can be performed by Suitable agents tion of NK1 antagonists (Swain and Rupniak 1999), 5HT1D 0013. According to a first aspect, a method for fluorinating agonists (van Niel, Collins et al. 1999), and PTB1B antago an organic molecule is disclosed, the method comprising nists (Burke, Ye et al. 1996). providing an organic molecule comprising a target site; pro 0007 Over the past years, fluorination has been covering viding an oxydizing agent that oxidizes the organic molecule an increasingly important role in drug discovery, as exempli by introducing an oxygen containing functional group on the fied by the development of fluorinated derivatives of the anti target site, contacting the oxydizing agent with the organic cancer drugs paclitaxel and docetaxel (Ojima 2004). molecule for a time and under condition to allow introduction 0008. However, only a handful of organofluorine com of the oxygen-containing functional group on the target site pounds occur in nature and even those only in very small thus providing an oxygenated organic molecule, providing a amounts (Harper and O'Hagan 1994). Consequentely, any fluorinating agent and contacting the fluorinating agent with US 2009/0061471 A1 Mar.
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