2-Bromoethyl trifluoromethanesulphonate

Under N2 protection, a solution of pyridine (1.74 Kg, 22.01 mol, 1.10 equiv) in dichloromethane (20 L) was cooled to -20 °C, trifluoromethanesulfonic anhydride (5.87 Kg, 20.81 mol, 1.04 eq.) was slowly added dropwise.The reaction system was stirred at -20°C for 0.5 hour and 2-bromoethanol (2.50 Kg, 20.01 mol, 1.0 equiv) was slowly added dropwise.The reaction temperature was maintained below 0° C. and stirred for 1.0 hour. TLC (petroleum ether:ethyl acetate=5:1) showed that the reaction was complete. After the reaction was completed, the reaction system was filtered, the filtrate was concentrated, petroleum ether (15 L) was added, the precipitated solid was filtered, and the filtrate was concentrated to give compound b. (4.80 Kg, yield 93.33percent) was a dark yellow oilINTERMEDIATE 732-Bromoethyl trifluoromethanesulfonateAnhydrous pyridine (8.5 mL, 105 mmol) and dry DCM (100 mL) were added to a 3-necked round-bottomed flask under a nitrogen atmosphere. The reaction flask was then cooled to about -2OTo a stirred solution of pyridine (0.712 mL, 8.80 mrnoi) in 80 mL at -20°C in an ethylene glycol-dry ice bath was added trifluorornethanesulfonicanhydride (1344 mU 8.00 mmoi) dropwise. The reaction was stirred for 10 mm, followed by slow addition 2-bromoethanol (0567 ml, 800 rnrnoi), and the reaction was again left to stir, warming to RT for 10 minutes. The resulting suspension was filtered, concentrated (using a rotary evaporator, keeping the water bath temp he/ow 20 °C) and petroleum ether (3 mL) was added Themixture was filtered and concentrated again under reduced pressure to give the title product 2-brornoethyl trifluoromethanesulfonate (1.6 g, 6.23 mrnol, 78percent) as a clear colorless oil, which was stored cold in a freezer to prevent decomposition.Synthesis of 2-bromoethyl triflate: To a solution of 2-bromoethanol (0.878, 7.026 mmol) in dry DCM (dichloromethane) (10 mL) was added pyridine (0.625 mL, 1.1 eq.) at RT. The solution was cooled to −78° C. and TfA solution of triflic anhydride (1.81 mL, 11 mmol) in CH2Cl2(5 mL) was added to a solution of pyridine (0.88 mL, 11 mmol) in CH2Cl2(5 mL) at −20°C. After stirring for 10 min, 2-bromoethanol (15) (0.71 mL, 10 mmol) was added to the mixture and the reaction mixture was stirred at −20°C for 15 min. The precipitate was removed by filtration and washed with Et2O (10 mL). The combined filtrates were concentrated in vacuo, and the residue was diluted with hexane (30 mL). The precipitate was removed by filtration and washed with Et2O (5 mL). The combined filtrates were concentrated in vacuoto provide crude product 16(2.38 g), which was used in the next step without further purification.Diphenyl sulfide (6.90 g, 18.5 mmol) was added to a solution of crude product 16in toluene (9 mL) at r.t. The reaction mixture was then heated at 100°C and stirred for 7 h. The solution was allowed to cool to r.t. and Et2O (20 mL) was added, resulting in the formation of a white precipitate. The mixture was stirred at r.t. overnight and the precipitate was collected by suction, washed with Et2O (3 mL) and dried in vacuoto provide 13(3.10 g, 70percent) as a white solid: mp 85.0–86.0°C (lit., 17)mp 86.5–88.0°C); IR (KBr, cm−1) ν3065, 2986, 1448, 1274, 1149, 1032, 755, 638; 1H-NMR (400 MHz, CDCl3) δ: 8.13–8.09 (m, 4H), 7.81–7.70 (m, 6H), 4.93–4.87 (m, 2H), 3.71–3.67 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ: 135.3, 131.9, 131.1, 122.7, 48.5, 24.0.C 18F-is obtained via the nuclear [REACTION 180] (p, [N) L8F.] This is achieved by bombarding a silver target containing [180] enriched water with accelerated protons [(17MEV).] The [18F-IS] loaded onto a resin and transported to the laboratory. The resin is eluted with 1.5 [ML] of an 80: 20 acetonitrile: aqueous potassium oxalate solution which is made by adding 0.05 mL of a solution of 200 mg of potassium oxalate/3 mg of potassium carbonate/5 [ML] of H20 to 0.25 mL of H20 and diluting with 12 [ML] of acetonitrile. To this is added 0.2 [ML] of a Kryptofix222 solution (36mg/mL acetonitrile) and the acetonitrile : H2O is removed at [120C] under an argon flow and vacuum. An additional 3 x 0.7 [ML] aliquots of acetonitrile are used to dry the [18F-.] The oil bath is lowered and [AFTER-30] seconds a solution of 0.02 [ML] of bromoethyl triflate (Dae Yoon Chi, Michael R [KILBOURN, ] John A Katzenellenbogen, Michael J Welch, J. [ORG.] Chem. , 1987, 52 (4), 658-664) in 0.7 mL of o-dichlorobenzene is added, the oil bath is raised and an argon flow is used to distill the [[8F] FCH2CH2BR] that forms into a vial at [0C] that contains 0.3 mg of (2S, 3S)-l-t-butoxycarbonyl-2-phenyl-3- [2-hydroxy-5- (5'-trifluoro-methyltetrazo-l- yl) phenylmethylene-amino] -piperidine) in 0.2 [ML] [OFDMF AND-L-2MG] of cesium carbonate. After the amount of radioactivity in the reaction vial peaks, the distillation is stopped and the reaction vial is heated at [110C] for 10 minutes. The DMF is removed over five minutes using an argon flow at [110C] and 0.1 mL of TFA is then added and allowed to sit at [110C] for 30 seconds. The reaction mixture is diluted with 0.2 mL of ethanol and 0.6 [ML] of [H20] and purified by preparative HPLC [Waters C18 [GBONDAPAK, ] 7.8 x 300 mm, 3 mL/minute, 20 minute linear gradient 20: 80 to 90: 10 acetonitrile: H20 (95: 5: 0.1 [H20] : MeCN: TFA) ]. The product elutes at- 12 minutes.EXAMPLE 19; [18F]3-(2-Fluoroethoxy)-5-[(2-methyl-d3-1, 3-thiazol-4-yl)ethynyl]pyridine; [18F]F- was produced by 11 MeV proton bombardment of [18O]H2O and passing the target contents through an anion exchange resin to recover the [18O]H2O. The [18F]F- was transported to the radiochemistry laboratory on the anion exchange resin which was eluted with 1.5 mL of a mixture of 80% MeCN:20% oxalate* (aq.) solution [*0.05 mL of (200 mg K2C2O4/3 mg K2CO3/5 ML H2O)+0.25 mL H2O+1.2 mL MeCN]. To the aqueous fluoride solution was added 0.2 mL of Kryptofix222 (36 mg/mL MeCN) and the fluoride was dried at 115 C. (oil bath) under vacuum and argon flow (10 mL/min). Additional aliquots of MeCN (3×0.7 mL) were added for azeotropic drying at 115 C. The oil bath was lowered, and after 1 minute, a solution of bromoethyltriflate (0.005 mL, Chi et al, JOC, 1987, 52, 658-664) in 1, 2-dichlorobenzene (0.7 mL) was added and the oil bath was raised. An argon stream was used to distill the [18F]FCH2CH2Br into a vial at RT containing 3-hydroxy-5-[(2-methyl-d3-1, 3-thiazol-4-yl)ethynyl]pyridine (0.3 mg) in DMF (0.2 mL) containing a small amount (1-2 mg) of Cs2CO3. When the amount of radioactivity trapped reached a peak, the mixture was transferred to a 2 mL vial at 100 C. containing a small amount of cesium carbonate. The reaction mixture was heated for five minutes at 100 C., diluted with H2O (0.8 mL) and purified by HPLC (Waters C18 Xterra, 7.8×150 mm, 15 minute linear gradient, 20% MeCN:(95:5:0.1 H2O:MeCN:TFA) to 90% MeCN, 3 mL/min). The peak corresponding to [18F]3-(2-fluoroethoxy)-5-[(2-methyl-d3-1, 3-thiazol-4-yl)ethynyl]pyridine was collected (7 minute retention time) in a 50 mL round bottom flask on a rotary evaporator, most of the solvent was removed in vacuo, and was transferred to a capped vial using physiologic saline as a rinse to give 28 mCi of the product.[18F]BFE was produced according to Zuhayra et al.44 Briefly, to the dried [18F]fluoride-aminopolyether a mixture of 30 muL BETfO and 500 muL 1, 2-dichlorobenzene (o-DCB) was added. After heating at 100 C for 10 min, [18F]BFE was distilled at 130 C under helium flow into the respective solvent (DMF, DMSO and 2-butanone). The precursor SNAP-acid (4 mg/mL) was activated by adding an equimolar amount of tetrabutylammonium hydroxide (TBAH) and dissolved in the respective solvent. The [18F]BFE solution was added to the precursor solution (1:1) and the reaction mixture was heated at 75-140 C for 10-20 min.[18F]Fluoride, obtained on a QMA cartridge, was eluted into a conical reaction vial with a Kryptofix (37.2mg/mL) and K2CO3 (3.3mg/mL) solution in acetonitrile/ water (0.75mL, 95/5, v/v). Removal of solvents and further drying of the activity was achieved by heating the reaction vial at 100C and by azeotropic distillation with acetonitrile (3×0.75mL) under a stream of N2. The dried activity was allowed to cool to RT, and a solution of [ F]F was obtained via the nuclear reaction Omicron(rho, eta) F. This was achieved by bombarding 2-3 mL of oxygen-18 enriched water (90-99% enrichment) contained in a closed niobium target with 18-MeV protons accelerated in an IBA Cyclone 18/9 cyclotron for 30 min to 1 hour. (0464) [00146] The irradiated target water was transferred to a remote controlled synthesis module where the [18F]fluoride was displaced from the column with a solution of potassium carbonate (K2C03) and Kryptofix 222 which was collected in a conical reactor vessel. (0465) [00147] The [18F]F7K2C03/kryptofix mixture was evaporated under a stream of helium by applying thermal heating to evaporate water and acetonitrile (CH3CN) and the residue was further dried by azeotropic distillation using anhydrous CH3CN. About 0.33 mL of CH3CN was added, the mixture was heated under helium flow to dryness, and the operation repeated 3 times. (0466) [00148] A solution of (1) Continuous bombardment of H218O with a cyclotron proton beam to produce 18F-, using a helium gas to pass 18F- from the target to the target water recovery bottle of the synthesis module.(2) 18F is pressed out of the target water recovery bottle - through the QMA column, 18F- is captured on the QMA column.(3) 18F- adsorbed on the QMA column was rinsed into the reaction tube with 0.9 ml of K2.2.2 / K2CO3 solution, and then heating of the reaction tube was started to remove the water and acetonitrile in the system.After evaporating, continue to add 0.5ml of anhydrous acetonitrile to the reaction flask, reheat and evaporate.(4) adding orthodichlorobenzene-dissolved BrC2H4OTf (15 mul of BrC2H4OTf dissolved in 1.0 ml of o-dichlorobenzene) to the reaction flask to carry out the substitution reaction to generate the intermediate BrC2H418F.An automated multi-purpose synthesizer developed in ourinstitute was used for the present radiosynthesis [41, 42]. As shownin Scheme 1, radiosynthesis was performed using the precursor, which was produced via the method described in SupplementalData. 18F was produced by the cyclotron using the 18O (p, n) 18Freaction on > 98% enriched H218O (ROTEM Industries, Arava, Israel)and 18 MeV protons (14.2 MeV on the target). After dryness of [18F]F, a solution of bromoethyl triflate (BrCH2CH2OTf, 10 mL) in odichlorobenzene(150 mL) was added to the reaction vial containingdry [18F]F at 130 C. The resulting [18F]FEtBr was distilled undernitrogen, and bubbled into another reaction vial containing phenolprecursor (1.5 mg) and NaOH (8 mL, 0.5 M) in anhydrous N, Ndimethylformamide(250 mL) at 15 C. After trapping the radioactivityfor 2 min, the reaction mixture was heated at 85 C for10 min. Subsequently, [18F]VUIIS1018A was purified using semipreparativeHPLC according to the following conditions: CAPCELLPAK C18 column (inner diameter: 10 mm, length: 250 mm; Shiseido, Tokyo, Japan), CH3CN/H2O/Et3N (6.5/3.5/0.01, v/v/v) as the mobilephase, 5.0 mL/min flow rate, and UV detection at 254 nm. Theretention time (tR) of [18F]VUIIS1018A was approximately 11.3 min.The desired radioactive fractions were collected in a sterile flask, evaporated to dryness in vacuo, re-dissolved in 5mL of sterilenormal saline, passed through a Millex-GV filter (Millipore; Billerica, MA, USA), and transferred into a sterile vial to obtain thedesired [18F]VUIIS1018A product.[ F]FEB was synthesized in a first hot cell (e.g., hot cell 'A' as illustrated in FIG. 6A) by reacting 2-bromoethyl trifluoromethanesulfonate ('2' in FIG. 6A) with freshly dried [18F]F' (as 18FK[2.2.2]) at 80 C in 1 , 2-dichlorobenzene. The alkylation agent was then distilled under a stream of helium to a separate hot cell (e.g., hot cell 'B' as illustrated in FIG. 6B) containing 1 mg of precursor N-(2, 6-dimethylphenyl)-2- (ethylamino)acetamide and 12 mg Nal in 200 uL DMSO (FIG. 2A). After heating at 120C for 20 min, the reactor was cooled to room temperature and removed from the hot cell. The total radioactivity of the vessel was 20 mCi. A 10 mu. aliquot (1 mCi) was removed, diluted with 90 muL· water and analysed by analytical HPLC, as shown in FIG. 6B, which demonstrated 30% conversion to N-(2, 6-dimethylphenyl)-2-(ethyl(2-(fluoro- 18F)ethyl)amino)acetamide. (0578) OTHER EMBODIMENTS

Molecular Weight:257.03
XLogP3:1.6
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:255.90166
Monoisotopic Mass:255.90166
Topological Polar Surface Area:51.8
Heavy Atom Count:11
Complexity:203
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes