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Supporting Information

Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system

Young-Do Kwona , Jeongmin Sonb , Mijin Yuna,b and Joong-Hyun Chuna [footnoteRef:1] [1: Corresponding author. Joong-Hyun Chun, Tel.: +82-2-2228-2348; fax: +82-2-312-0578; e-mail: [email protected]]

a Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

b Department of Nuclear Medicine, Severance Hospital, Yonsei University Health System, Seoul 03722, Republic of Korea

Table of contents

1. General informationp2

2. Optimization study for [18F]fluoride ion elutionp3

3. Chemical syntheses for compounds 2–5ap4–8

4. Radiochemistryp9–11

5. Effect of water content on radiofluorinationp12

6. Selected radio-TLC & radio-HPLC chromatogramsp13–19

7. NMR spectra for compounds 2–5ap20–28

1. General information

(1-Phenyl-1H-1,2,3-triazol-4-yl)methanol was purchased from Enamine (Monmouth Jct., NJ, USA). Methanesulfonyl chloride was purchased from Wako (Osaka, Japan). 2-(3-Methanesulfonyloxypropoxy)naphthalene (1), 2-(3-fluoropropoxy)naphthalene (1a), 2-O-tetrahyyranyl-1,3-ditosylpropanetriol, 2-fluoroethanol tosylate and precursors for [18F]fallypride, [18F]-(E)-PSS232, and [18F]FMISO and non-radioactive fluoro-standards were purchased from FutureChem (Seoul, Republic of Korea). Oxygen-18 enriched water was purchased from Rotem (Beer Sheva, Israel). All other chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA), ACROS organics (Waltham, MA, USA), and Alfa Aesar (Ward Hill, MA, USA) and used without further purification. Sep-Pak® Light QMA cartridge (carbonate form, part no. 186004540) was purchased from Waters (Milford, MA, USA). Reaction progress was monitored by thin-layer chromatography (TLC). TLC analysis was performed using an aluminum-backed plate with silica gel 60 F254, and TLC spots were visualized under 254 nm UV light. Crude products were purified on a column chromatography using silica gel (0.060–0.020 mm, 60 A). Melting points were recorded using a Stuart SMP10 Melting Point Apparatus and uncorrected. 1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance III HD 300 spectrometer (300 MHz) installed at Yonsei Center for Research Facilities (YCRF at Yonsei University, Seoul, Republic of Korea). For 1H and 13C NMR spectra, the chemical shifts were reported in δ units (ppm) relative to the residual protonated solvent resonance, and the coupling constants (J) were given in Hz. 19F NMR spectra were referenced to external CFCl3 (δ = 0.0 ppm) in the indicated solvent. Electrospray ionization (ESI) high resolution mass spectrometry (HRMS) was performed at Korea Basic Science Institute (KBSI), Ochang, Republic of Korea. HPLC was carried out on an Ultimate 3000 spectra system (Thermo Scientific, Waltham, MA, USA).

2. Optimization study for [18F]fluoride ion elution

The cyclotron-produced 18F- in H218O (18–44 MBq) was initially trapped on a QMA cartridge. Radioactivity of the trapped [18F]fluoride ion (radioactivity A) was measured. The trapped [18F]fluoride was eluted from QMA with 200–1000 μL volume of a phase transfer agent (PTA) solution of K 2.2.2. (12 mg, 32 μmol) and K2CO3 (2.2 mg, 16 μmol) in acetonitrile (MeCN)-H2O (49:1 v/v, total 1000 μL) and collected in an empty vial. Radioactivity of the eluted [18F]fluoride was measured (radioactivity B). The measurements for radioactivity A and B were determined with a CRC®-712M dose calibrator (Capintec, Ramsey, NJ, USA). The value of the elution efficiency was an average of two runs.

Figure S1. A curve of the elution efficiency vs. the volume of PTA solution

3. Chemical Syntheses for compounds 2–5a

(1-Phenyl-1H-1,2,3-triazol-4-yl)methyl 4-methylbenzenesulfonate (2)

(1-Phenyl-1H-1,2,3-triazol-4-yl)methanol (0.37 g, 2.0 mmol) was added at 0 oC to a mixture of potassium hydroxide (0.64 g, 5.0 mmol) and p-toluenesulfonyl chloride (0.45 g, 2.2 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at room temperature for 3 h. The mixture was then diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The organic layer was dried over with MgSO4, concentrated in vacuo and the obtained crude product was purified by column chromatography (ethyl acetate/hexanes, 3:7) on a silica gel to give compound 2 (0.33 g, 50%) as a white solid; m.p. 104–106 oC. 1H NMR (300 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2 H), 7.69–7.65 (m, 2 H), 7.56–7.43 (m, 3 H), 7.34 (d, J = 8.0 Hz, 2 H), 5.30 (d, J = 0.3 Hz, 2 H), 2.43 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 145.3, 141.8, 136.8, 133.1, 130.1, 130.0, 129.3, 128.1, 122.3, 120.7, 63.2, 21.7. HRMS (ESI): calcd. for C16H16N3O3S [M + H]+ 330.0912; found 330.0913.

4-(Fluoromethyl)-1-phenyl-1H-1,2,3-triazole (2a)

Compound 2 (0.15 g, 0.46 mmol) and 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (0.92 mL, 0.92 mmol) were mixed in tert-amyl alcohol (6 mL) and stirred at 80 oC for 17 h. The organics was evaporated, and the resulting oil was taken up with dichloromethane (20 mL). The organic layer was washed with water (20 mL), dried over with MgSO4, and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (ethyl acetate/hexanes, 1:4 (v/v)) on a silica gel to give 2a (51 mg, 63%) as a white solid; m.p. 108–110 oC. 1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 2.5 Hz, 1 H), 7.76–7.71 (m, 2 H), 7.58–7.45 (m, 3 H), 5.60 (dd, J = 0.4, 48.2 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 143.9 (d, J = 21 Hz), 136.9, 130.0, 129.2, 121.9 (d, J = 3 Hz), 120.8, 75.9 (d, J = 163 Hz). 19F NMR (282 MHz, CDCl3, 1H-decoupled): δ = –208.5. HRMS (ESI): calcd. for C9H9FN3 [M + H]+ 178.0781; found 178.0789.

(1-Phenyl-1H-1,2,3-triazol-4-yl)methyl methanesulfonate (3)

Methanesulfonyl chloride (0.30 g, 2.6 mmol) was added at 0 oC to a solution of (1-phenyl-1H-1,2,3-triazol-4-yl)methanol (0.16 g, 0.87 mmol) and trimethylamine (0.38 mL, 2.6 mmol) in dichloromethane (10 mL). The mixture was stirred at 0 oC for 45 min. The mixture was washed with water (20 mL). The organic layer was dried over with MgSO4, evaporated and purified by column chromatography (ethyl acetate/hexane, 1:1.2) on silica gel to yield compound 3 (0.15 g, 70%) as a white solid; m.p. 110–112 oC. 1H NMR (300 MHz, CDCl3): δ = 8.15 (s, 1 H), 7.76–7.72 (m, 2 H), 7.58–7.45 (m, 3 H), 5.47 (s, 2 H), 3.09 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 141.9, 136.8, 130.0, 129.4, 122.7, 120.8, 62.4, 38.5. HRMS (ESI): calcd. for C10H12N3O3S [M + H]+ 254.0599; found 254.0599.

2-(1H-benzo[d][1,2,3]triazol-1-yl)ethyl 4-methylbenzenesulfonate (4)

A mixture of benzotriazole (0.18 g, 1.5 mmol), ethylene di(p-toluenesulfonate) (1.1 g, 3.0 mmol), and potassium carbonate (0.55 g, 6.0 mmol) in MeCN (6 mL) and N,N-dimethylformamide (2 mL) was stirred at 60 oC for 22 h. The mixture was diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The organic layer was dried over with MgSO4, evaporated and purified by column chromatography (ethyl acetate/hexane, 1:1.8) on silica gel to yield compound 4 (0.17 g, 36%) as a white solid; m.p. 126–128 oC. 1H NMR (300 MHz, CDCl3): δ = 8.03–7.99 (m, 1 H), 7.57–7.47 (m, 2 H), 7.43 (d, J = 8.3 Hz, 2 H), 7.41–7.35 (m, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 4.90 (t, J = 5.2 Hz, 2 H), 4.52 (t, J = 5.1 Hz, 2 H), 2.37 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 145.9, 145.3, 133.5, 131.8, 129.9, 127.9, 127.6, 124.2, 120.0, 109.6, 68.1, 47.1, 21.7. HRMS (ESI): calcd. for C15H16N3O3S [M + H]+ 318.0912; found 318.0912.

1-(2-Fluoroethyl)-1H-benzo[d][1,2,3]triazole (4a)

A mixture of benzotriazole (0.20 g, 1.7 mmol), 2-fluoroethanol tosylate (0.73 g, 3.4 mmol), and potassium carbonate (0.55 g, 6.7 mmol) in MeCN (5 mL) was stirred at 80 oC for 15 h. The mixture was diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The organic layer was dried over with MgSO4, evaporated and purified by column chromatography (ethyl acetate/hexane, 1:2.5) on silica gel to yield compound 4a (0.15 g, 53%) as a white solid; m.p. 55–57 oC. 1H NMR (300 MHz, CDCl3): δ = 8.07–8.04 (m, 1 H), 7.60–7.56 (m, 1 H), 7.52–7.47 (m, 1 H), 7.40–7.34 (m, 1 H), 4.98 (s, 2 H), 4.91–4.80 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 146.1, 133.8, 127.8, 124.2, 120.0, 109.7 (d, J = 3 Hz), 82.2 (d, J = 172 Hz), 48.7 (d, J = 21 Hz). 19F NMR (282 MHz, CDCl3, 1H-decoupled): δ = –219.6. HRMS (ESI): calcd. for C8H9FN3 [M + H]+ 166.0781; found 166.0786.

3-(Naphthalen-2-yloxy)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzene-sulfonate (5)

A mixture of 2-O-tetrahyyranyl-1,3-ditosylpropanetriol (1.1 g, 2.2 mmol), 2-naphthol (0.21 g, 1.5 mmol), and potassium carbonate (0.61 g, 4.4 mmol) in MeCN (8 mL) was stirred at 70 oC for 15 h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (2 x 30 mL). The organic layer was dried over with MgSO4, evaporated and purified by column chromatography (ethyl acetate/hexane, 1:5) on silica gel to yield compound 5 (0.46 g, 70%; a mixture of isomers) as a colorless oil; 1H NMR (300 MHz, CDCl3): δ = 7.80–7.74 (m, 3 H), 7.71 (d, J = 8.6 Hz, 2 H), 7.48–7.42 (m, 1 H), 7.38–7.32 (m, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.08–6.99 (m, 2 H), 4.85–4.73 (m, 1 H), 4.40–4.05 (m, 5 H), 3.93–3.80 (m, 1 H), 3.53–3.45 (m, 1 H), 2.33 (s, 1 H), 2.32 (s, 2 H), 1.83–1.66 (m, 2 H), 1.63–1.49 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 156.3, 156.2, 145.0, 144.9, 134.53, 134.51, 132.9, 132.8, 129.93, 129.89, 129.4, 129.23, 129.21, 128.1, 128.0, 127.7, 126.9, 126.61, 126.58, 124.0, 123.9, 118.8, 106.94, 106.91, 99.2, 98.5, 72.7, 72.3, 69.4, 69.1, 66.9, 66.2, 63.0, 62.4, 30.66, 30.58, 25.42, 25.37, 21.7, 19.6, 19.1. HRMS (ESI): calcd. For C25H29O6S [M + H]+ 457.1685; found 457.1679.

2-(1-Fluoro-3-(naphthalen-2-yloxy)propan-2-yloxy)-tetrahydro-2H-pyran (5a)

A solution of compound 5 (0.29 g, 0.64 mmol) and 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran (1.3 mL, 1.3 mmol) in tert-amyl alcohol (6 mL) was stirred at 80 oC for 14 h. The reaction mixture was concentrated, and the residue was taken up with ethyl acetate (20 mL). The organic layer was washed with water (20 mL), dried over with MgSO4, and evaporated. The residual product thus obtained was purified by column chromatography (ethyl acetate/hexane, 1:13) on silica gel to yield compound 5a (0.13 g, 68%; a mixture of isomers) as a colorless oil; 1H NMR (300 MHz, CDCl3): δ = 7.79–7.72 (m, 3 H), 7.47–7.42 (m, 1 H), 7.37–7.32 (m, 1 H), 7.20–7.15 (m, 2 H), 4.94–4.53 (m, 3 H), 4.38–4.17 (m, 3 H), 4.05–3.94 (m, 1 H), 3.60–3.53 (m, 1 H), 1.92–1.54 (m, 6 H). 13C NMR (75 MHz, CDCl3): δ = 156.6, 156.5, 134.61, 134.59, 129.61, 129.57, 129.3, 129.2, 127.8, 126.9, 126.58, 126.56, 123.94, 123.91, 118.9, 107.04, 107.00, 99.2, 98.7, 83.2 (d, J = 170 Hz), 83.1 (d, J = 170 Hz), 73.8 (d, J = 21 Hz), 73.5 (d, J = 22 Hz), 66.9 (d, J = 8 Hz), 66.6 (d, J = 7 Hz), 62.9, 62.6, 30.83, 30.78, 25.5, 19.6, 19.5. 19F NMR (282 MHz, CDCl3, 1H-decoupled): δ = –231.1, –231.9. HRMS (ESI): calcd. For C18H22FO3 [M + H]+ 305.1553; found 305.1562.

4. Radiochemistry

4.1. The radiofluorination procedures for screening experiments in Table 1

The cyclotron-produced 18F- in H218O (ca. 0.5 GBq) was trapped on a QMA cartridge, and then the QMA was manually air-purged using 10 mL syringe to minimize residual water. The trapped [18F]fluoride was released with a PTA solution of K 2.2.2. (12 mg, 32 μmol) and K2CO3 (2.2 mg, 16 μmol) in MeCN-H2O (49:1 v/v; total 1000 μL). 200 μL of the 18F-/K 2.2.2./K2CO3 eluate was added to a solution of compound 1 (ca. 2.0 mg) in different set of solvents (MeCN, N-methyl-2-pyrolidone, 1,4-dioxane, DMSO, DMF, or DMA). The overall volume including 200 μL 18F- eluate was adjusted to 2 mL with other organic solvents. The total volume percent of MeCN including 18F- eluate in MeCN was varied (10–70%). The radiofluorination was performed in a conductively heated reaction vessel (Monowave 50, Anton Paar GmbH, Austria) at 100 oC for 10 min. After the reaction mixture was cooled to 60 oC, an aliquot (ca. 200 μL) was diluted with MeCN-H2O (40:60 v/v, 3 mL). Radio-TLC to monitor RCYs of [18F]1a was developed with the eluent (ethyl acetate-hexane, 1:9 v/v). The RCYs were determined with AR-2000 radio-TLC imaging scanner (Eckert & Ziegler Radiopharma Inc., Hopkinton, MA, USA).

4.2. General procedures for radiofluorination in Tables 2–4

The cyclotron-produced 18F- in H218O (0.19–0.37 GBq) was trapped on a QMA cartridge. The residual water was removed by manual air-purging with 10 mL syringe. The trapped [18F]fluoride ion was eluted with a PTA solution containing K 2.2.2. (7.2 mg, 19 μmol) and K2CO3 (1.3 mg, 9.6 μmol) in MeCN-H2O (49:1 v/v; 600 μL). The 18F-/K 2.2.2./K2CO3 eluate was added to a solution of a precursor (ca. 1.0–2.7 mg) in corresponding solvent (1.4 mL DMSO or DMA). Each mixture was heated to 100–140 oC for 10–20 min. The reaction mixture was then cooled to 60 oC, and an aliquot (ca. 200 μL) was taken and diluted with MeCN-H2O (40:60 v/v, 3 mL). RCYs of labeled products were determined, based on either reverse phase radio-HPLC using a Luna® 5 um C18(2) 100 Å, 4.6 × 250 mm analytical column or radio-TLC analysis of the crude product. For radio-HPLC analysis, the identity of [18F]fluorinated products were further confirmed by coinjection with the corresponding fluoro-standards. Radio-TLC and radio-HPLC conditions are as follows:

Radio-TLC eluent

ethyl acetate:hexanes = 1:2 (v/v) for compound [18F]2a



Radio-HPLC condition

65% MeCN/H2O, 1.2 mL/min (isocratic), λ = 254 nm for [18F]-(E)-PSS232

55% MeCN/H2O, 1.0 mL/min (isocratic), λ = 254 nm for [18F]-protected FMISO

65% MeCN/H2O with 0.1% Et3N, 1.2 mL/min (isocratic), λ = 254 nm for [18F]fallypride

4.3. Automated radiosynthesis on a commercial module

The radiosynthesis of [18F]fallypride was carried out using a GE TRACERlab™ FXFN Pro (GE Healthcare, Madison, WI, USA). The cyclotron-produced 18F- in H218O (ca. 1.4 GBq) was trapped on a QMA cartridge, and then the QMA was vacuumed for 1.0 min to remove residual water. The trapped [18F]fluoride was released with a PTA solution containing K 2.2.2. (7.2 mg, 19 μmol) and K2CO3 (1.3 mg, 9.6 μmol) in MeCN-H2O (49:1 v/v; 600 μL). A pre-dissolved tosyl-fallypride precursor (ca. 3.0 mg) in DMA (1.4 mL) was added to the 18F-/K 2.2.2./K2CO3 eluate. The mixture was heated to 140 oC for 10 min. The reaction mixture was cooled to 60 oC and transferred into an empty vial. An aliquot (ca. 200 μL) was taken and diluted with MeCN-H2O (40:60 v/v, 3 mL). RCYs of [18F]fallypride were determined, based on the analysis of radio-HPLC of the crude product. The identity of [18F]fallypride was confirmed with coinjection of fluoro-fallypride standard with the HPLC method described above.

4.4. Automated radiosynthesis and HPLC purification on a commercial module

The radiosynthesis of [18F]fallypride was carried out using a GE TRACERlab™ FXFN (GE Healthcare, Madison, WI, USA). The cyclotron-produced 18F- in H218O (ca. 3.9 GBq) was trapped on a QMA cartridge, and then the QMA was vacuumed for 1.0 min to remove residual water. The trapped [18F]fluoride was released with a PTA solution containing K 2.2.2. (7.2 mg, 19 μmol) and K2CO3 (1.3 mg, 9.6 μmol) in MeCN-H2O (49:1 v/v; 600 μL). A pre-dissolved tosyl-fallypride precursor (ca. 3.0 mg) in DMA (1.4 mL) was added to the 18F-/K 2.2.2./K2CO3 eluate (ca. 3.4 GBq). The mixture was heated to 140 oC for 10 min. The reaction mixture was diluted with 2.0 mL HPLC eluent (55% MeCN/H2O with 0.1% Et3N (v/v)) and purified by reverse phase HPLC (eluent: 55% MeCN/H2O with 0.1% Et3N (v/v); 3.0 mL/min (isocratic); and λ = 254 nm) using a Luna® 5 um C18(2) 100 Å, 10 × 250 mm semi-preparative column. The purified [18F]fallypride (decay-corrected 0.83 GBq; RCY 25% from the activity determined in reactor) was collected from 25 min to 27.5 min. The radiochemical purity and identity of [18F]fallypride was confirmed, based on the analytical radio-HPLC using a Luna® 5 um C18(2) 100 Å, 4.6 × 250 mm analytical column with the HPLC method described in ‘General procedures for radiofluorination in Tables 2–4’. The identity of [18F]fallypride was further confirmed with coinjection of fluoro-fallypride standard.

5. Effect of water content on radiofluorination (water tolerance experiment)

A 18F-/K 2.2.2./K2CO3 eluate was prepared by the same procedure in ‘General procedures for radiofluorination in Tables 2–4’. The eluate and additional water (10, 20, 50, 100 or 200 μL) was added to a solution of compound 1 (ca. 2.0 mg) in corresponding solvent (1.4 mL DMSO or DMA). Each mixture was heated to 140 oC for 10 min. The reaction mixture was then cooled to 60 oC, and an aliquot (ca. 200 μL) was taken and diluted with MeCN-H2O (40:60 v/v, 3 mL). Radio-TLC to monitor RCYs of [18F]1a was developed with the eluent (ethyl acetate-hexane, 1:9 v/v).

Figure S2. Effect of additional/external water on radiofluorination in a mixed organic solvent

6. Selected radio-TLC & radio-HPLC chromatograms

a) Table 1, entry 2

Reaction conditions: Precursor 1, 30% DMSO/MeCN (v/v), 100 oC, 10 min

Radio-TLC eluent, ethyl acetate:hexanes = 1:9 (v/v)

b) Table 1, entry 4



c) Table 2, entry 5

Reaction conditions: Precursor 1, 70% DMA/MeCN (v/v), 140 oC, 10 min


d) Table 2, entry 5



e) Table 3, entry 6, [18F]2a



f) Table 3, entry 6, [18F]4a



g) Table 4, [18F]-(E)-PSS232

Reaction conditions: Mesyl-PSS232 (2.0 mg), 70% DMSO/MeCN (v/v), 140 oC, 10 min

HPLC conditions: 65% MeCN/H2O (v/v), 1.2 mL/min, λ = 254 nm

Luna® 5 um C18(2) 100 Å, 4.6 × 250 mm analytical column

h) Table 4, [18F]-protected FMISO

Reaction conditions: Tosyl-FMISO (2.5 mg), 70% DMA/MeCN (v/v), 140 oC, 10 min

HPLC conditions: 55% MeCN/H2O (v/v), 1.0 mL/min, λ = 254 nm


i) Table 4, [18F]fallypride

Reaction conditions: Tosyl-fallypride (2.7 mg), 70% DMA/MeCN (v/v), 140 oC, 10 min

HPLC conditions: 65% MeCN/H2O with 0.1% Et3N (v/v), 1.2 mL/min, λ = 254 nm


j) Table 4, [18F]Fallypride production on GE TRACERlab™ FXFN Pro


HPLC conditions: 65% MeCN/H2O with 0.1% Et3N (v/v), 1.2 mL/min, λ = 254 nm


k) Table 4, [18F]Fallypride production and HPLC isolation on GE TRACERlab™ FXFN


Semi-preparative HPLC conditions:

55% MeCN/H2O with 0.1% Et3N (v/v), 3.0 mL/min, λ = 254 nm

Luna® 5 um C18(2) 100 Å, 10 × 250 mm semi-preparative column

Analytical HPLC conditions:

65% MeCN/H2O with 0.1% Et3N (v/v), 1.2 mL/min, λ = 254 nm

a Luna® 5 um C18(2) 100 Å, 4.6 × 250 mm analytical column

7. NMR spectra for compounds 2–5a

Compound 2 1H NMR

Compound 2 13C NMR

Compound 2a 1H NMR

Compound 2a 13C NMR

Compound 2a 19F NMR (proton-decoupled)

Compound 3 1H NMR

Compound 3 13C NMR

Compound 4 1H NMR

Compound 4 13C NMR

Compound 4a 1H NMR

Compound 4a 13C NMR


Compound 5 1H NMR

Compound 5 13C NMR

Compound 5a 1H NMR

Compound 5a 13C NMR


N

N

N

OTs

N

N

N

F

2

1 M TBAF in THF

tert-Amyl alcohol

2a

(63%)

80

o

C, 17 h

N

N

N

OH

N

N

N

OMs

MsCl, Et

3

N

DCM

0

o

C, 45 min

3

(70%)

N

NH

N

K

2

CO

3

MeCN, DMF

TsO

OTs

N

N

N

OTs

4 (36%)

60

o

C, 22 h

K

2

CO

3

MeCN

TsO

F

N

NH

N

N

N

N

F

4a (53%)

80

o

C, 15 h

TsOOTs

OO

O

OTs

OO

5 (70%)

2-Naphthol, K

2

CO

3

MeCN

70

o

C, 15 h

OOTs

OO

5

OF

OO

5a (68%)

1 M TBAF in THF

tert-Amyl alcohol

80

o

C, 14 h

020406080

0

1000

2000

3000

4000

Position (mm)

Counts

F-18 - 180323_T_11.R001

020406080

0

1000

2000

3000

4000

Position (mm)

Counts

F-18 - 180323_T_13.R001

020406080

0

2000

4000

6000

8000

10000

12000

Position (mm)

Counts

F-18 - 180116_T_5.R001

020406080

0

2000

4000

6000

8000

10000

12000

Position (mm)

Counts

F-18 - 171110_T_3.R001

020406080

0

2000

4000

6000

8000

Position (mm)

Counts

F-18 - 171206_T_5.R001

020406080

0

1000

2000

3000

4000

5000

Position (mm)

Counts

F-18 - 171205_T_5.R001

N

N

N

OTs

2

N

N

N

F

2a

N

N

N

OMs

3

N

N

N

OTs

4

N

N

N

F

4a

OOTs

OO

5

OF

OO

5a

N

N

N

OH

N

N

N

OTs

TsCl, KOH

THF

2

(50%)

rt, 3 h

Documents

ars.els-cdn.com · Web viewAll other chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA), ACROS organics (Waltham, MA, USA), and Alfa Aesar (Ward Hill, MA, USA) and used