Journal of Radioanalytical and Nuclear Chemistry

Journal of Radioanalytical and Nuclear Chemistry

Supplementary information

List of Supporting Information

No / Content / Page
Synthesis section / 2-13
Table S1 / 1HNMR，13CNMR and MS analysis data of compounds / 13-23
Figure S1 / HPLC elution profiles of [18F] 1b and [19F] 1b / 24
Figure S2 / HPLC elution profiles of [18F]1c and [19F] 1c / 24
Figure S3 / HPLC elution profiles of [18F]2a and [19F] 2a / 25
Figure S4 / HPLC elution profiles of [18F]2b and [19F] 2b / 25
Figure S5 / HPLC elution profiles of [18F]2c and [19F] 2c / 26
Figure S6 / HPLC elution profiles of [18F]3a and [19F] 3a / 26
Figure S7 / HPLC elution profiles of [18F]3b and [19F] 3b / 27
Figure S8 / HPLC elution profiles of [18F]3c and [19F] 3c / 27
Figure S9 / HPLC elution profiles of [18F]3d and [19F] 3d / 28

Synthesis section

2-(prop-2-ynyloxy)ethanol(6a)

Under the protection of inert gas, a solution of compound 4 (5.0mL,45.0mmol), compound 5a (54mmol) and NaOH (2.160g, 54mmol) were stirred rapidly at 0℃ for 15min, then the mixture was heated to 45℃ for 3h. After filtration, the solid was washed with ethyl acetate, the filtrate was collected and washed with water as well as saturated salt water. The organic layer was dried with anhydrous sodium sulfate (Na2SO4) and filtered. The filtration was concentrated and the residual was purified by flash chromatography (EtOAc/hexanes: 1/3) to give compound 6a (2.35g, yield: 52.3%) as a yellow oil.

2-(2-(prop-2-ynyloxy)ethoxy)ethanol (6b)

Compound 6b was prepared from compound 4 (5.0mL, 45.0mmol), compound 5b (54mmol) and NaOH (2.160g, 54mmol), with the same procedure described for compound 6a. Compound 6b: 4.41g (yield: 68%).

2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethanol (6c)

Compound 6c was prepared from compound 4 (5.0mL, 45.0mmol), compound 5c (54mmol) and NaOH (2.160g, 54mmol), with the same procedure described for compound 6a. Compound 6b: 4.06g (yield: 48%).

2-(prop-2-ynyloxy)ethyl 4-methylbenzenesulfonate (7a)

A solution of 4-toluene sulfonyl chloride (3.840g, 20.0mmol) and compound 6a (10mmol) dissolved in 10 mL dichloromethane (DCM) and 6.9mL triethylamine (Et3N) was stirred at room temperature. After 1h, the mixture was cooled to 0℃ and 0.06g 4-dimethylaminopyridine (DMAP) was added. The reaction mixture was stirred at room temperature for 2h. The solution was then diluted with 20mL water as well as CH2Cl2 (20mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (Petroleum ether/EtOAc: 6/1) yielded compound 7a (2.21g, yield: 87%) as a yellow oil.

2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (7b)

Compound 7b was prepared from DCM (10.0mL), 4-toluene sulfonyl chloride (3.840g, 20.0mmol) Et3N (6.9 mL, 50mmol) and compound 6b (10mmol), with the same procedure described for compound 7a. Compound 7b: 2.32g (yield: 78%).

2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (7c)

Compound 7c was prepared from DCM (10.0mL), 4-toluene sulfonyl chloride (3.840g, 20.0mmol) Et3N (6.9 mL, 50mmol) and compound 6c (10mmol), with the same procedure described for compound 7a. Compound 7c: 3.08g (yield: 90%).

2-(2-methyl-4-nitro-3H-pyrrol-3-yl)ethyl 4-methylbenzenesulfonate (9)

A solution of 4-toluene sulfonyl chloride (3.840g, 20.0mmol) and compound 8 (1.700g, 10.0mmol) dissolved in 10 mL dichloromethane (DCM) and 6.9mL triethylamine (Et3N) was stirred at room temperature. After 1h, the mixture was cooled to 0℃ and 0.06g DMAP was added. The reaction mixture was stirred at room temperature for 80min. The solution was then diluted with 30mL water as well as EtOAc (30mL×3). The combined organic layers were washed with hydrochloric acid (5%), saturated NaHCO3 aqueous solution and saturated saline successively, and then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (EtOAc/hexanes: 50/50, V/V) yielded compound 9 (3.20g, yield: 98%) as a yellow oil.

1-(2-azidoethyl)-2-methyl-5-nitro-1H-imidazole (10)

To a solution of compound 9 (0.651g, 2.0mmol) in 10mL N,N-Dimethylformamide (DMF) was added 0.195 g sodium azide (3.0mmol) at room temperature, and the reaction was stirred at 75℃ for 2h. The solution was cooled to room temperature, and ethyl acetate (40mL) was added. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (EtOAc/hexanes: 50/50, V/V) yielded compound 10 (0.383g, 97%) as white solid.

2-((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (11a)

Compound 10 (0.196g, 1.0mmol) and compound 7a (1.2mmol) were dissolved in water (5mL) and t-BuOH (5mL) at room temperature, then CuSO4 (100μL, 0.1mol) and sodium ascorbate (200μL, 0.5mol) was added to the solution. The mixture was stirred at room temperature for 48h, The solution was then diluted with 10mL water as well as CH2Cl2 (30mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (CH2Cl2/CH3OH: 60/1) yielded compound 11a (0.24mg, yield: 54%) as a yellow oil.

2-(2-((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethyl 4-methylbenzenesulfonate（11b）

Compound 11b was prepared from compound 10 (0.196g, 1.0mmol) and compound 7b (1.2mmol), with the same procedure described for compound 11a. Compound 11b: 0.47g (yield: 95%).

2-(2-(2-((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate（11c）

Compound 11c was prepared from compound 10 (0.196g, 1.0mmol) and compound 7c (1.2mmol), with the same procedure described for compound 11a. Compound 11c: 0.47g (yield: 82%).

4-((2-iodoethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole (12a)

Compound 11a (0.4mmol) was dissolved in anhydrous acetone (5 mL) and NaI (0.197g, 1.3mmol) was added under the protection of inert gas. After stirring 3 h, the mixture was cooled to room temperature. Then 2M CH2Cl2 was added, the reaction mixture was condensed, and the crude product was purified by flash column (CH2Cl2/CH3OH: 60/1) to afford compound 12a as a yellow oil (14.45g, 89%).

4-((2-(2-iodoethoxy)ethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole（12b）

Compound 12b was prepared from compound 11b (0.4mmol) and NaI (0.197g, 1.3mmol), with the same procedure described for compound 12a. Compound 12b: 0.17g (yield: 95%).

4-((2-(2-(2-iodoethoxy)ethoxy)ethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole (12c)

Compound 12c was prepared from compound 11c (0.4mmol) and NaI (0.197g, 1.3mmol), with the same procedure described for compound 12a. Compound 12c: 0.15g (yield: 76%).

4-((2-fluoroethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole ([19F]1a)

Compound 12a (0.4mmol) was dissolved in anhydrous acetonitrile (5 mL) and AgF (0.254g, 2.0mmol) was added under light shielded condition. The mixture was stirred at room temperature for two days. The reaction was carefully quenched with saturated salt water (2mL) and filtered. The solid was washed with methylene chloride. The filtrate was concentrated under reduced pressure and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (CH2Cl2/CH3OH: 60/1) yielded compound 1a (0.12g, yield: 71%) as a yellow oil.

4-((2-(2-fluoroethoxy)ethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole ([19F]1b)

Compound 1b was prepared from compound 12b (0.4mmol) and AgF (0.254g, 2.0mmol), with the same procedure described for compound 1a. Compound 1b: 0.1g (yield: 76%).

4-((2-(2-(2-fluoroethoxy)ethoxy)ethoxy)methyl)-1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-1,2,3-triazole ([19F]1c)

Compound 1c was prepared from compound 12c (0.4mmol) and AgF (0.254g, 2.0mmol), with the same procedure described for compound 1a. Compound 1c: 0.1g (yield: 67%).

2-azidoethyl 4-methylbenzenesulfonate（14a）

Compound 13a (15.0mmol) was dissolved in 20mL DMF and 0.195g sodium azide (3.0mmol) was added to the solution. After stirring overnight, the mixture was diluted with 125mL ethyl acetate, the organic layer was washed with water (25.0mL×3) as well as saturated salt water and then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (EtOAc/hexanes: 1/1) yielded compound 14a (2.31g, yield: 64%) as a yellow oil.

2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate（14b）

Compound 14b was prepared from compound 13b (15.0mmol) and sodium azide (0.195g, 3.0mmol), with the same procedure described for compound 14a. Compound 14b: 3.33g (yield: 78%).

2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate（14c）

Compound 14c was prepared from compound 13c (15.0mmol) and sodium azide (0.195g, 3.0mmol), with the same procedure described for compound 14a. Compound 14c: 4.31g (yield: 87%).

2-methyl-5-nitro-1-(2-(prop-2-ynyloxy)ethyl)-1H-imidazole(15)

To a solution of metronidazole (0.857 g, 5.0mmol) in 0.80 mL 3-bromo-1-propyne (0.892 g, 7.5mmol) was added 0.240g NaOH (6.0mmol). The reaction mixture was stirred at room temperature for 12h. The solution was filtered, the filtrate was collected and extracted with methylene chloride (100mL), the organic layer was washed with water (10.0mL×3) as well as saturated salt water, and then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (EtOAc/hexanes: 8/2) yielded compound 15 (0.896g, 86%) as a red solid.

2-(2-(4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl 4-methylbenzenesulfonate(16b)

Compound 15 (0.430g, 2.1mmol) and compound 14b (2.3mmol) were dissolved in water (7mL), t-BuOH (7.0mL) and acetonitrile (1.5mL) at room temperature, then CuSO4 (100μL, 0.1mol) and sodium ascorbate (200μL, 0.5mol) was added to the solution. The mixture was stirred at room temperature for 48h, The solution was then diluted with 5mL water as well as CH2Cl2 (20mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (EtOAc/hexanes: 50/50, V/V) yielded compound 16b (1.08g, yield: 95%) as a yellow oil.

2-(2-(2-(4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate （16c）

Compound 16c was prepared from compound 15 (0.430g, 2.1mmol) and compound 14c (2.3mmol), with the same procedure described for compound 16b. Compound 16c: 1.1g (yield: 89%).

4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1-(2-(2-iodoethoxy)ethyl)-1H-1,2,3-triazole(17b)

Compound 17b was prepared from compound 16b (0.1mmol) and NaI (0.448g, 3.0mmol), with the same procedure described for compound 12a. Compound 17b: 38.25mg (yield: 85%).

1-(2-(2-(2-iodoethoxy)ethoxy)ethyl)-4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1H-1,2,3-triazole (17c)

Compound 17c was prepared from compound 16c (0.1mmol) and NaI (0.448g, 3.0mmol), with the same procedure described for compound 12a. Compound 17c: 27.17mg (yield: 55%).

4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1-(2-fluoroethyl)-1H-1,2,3-triazole( [19F]2a)

Compound 15 (0.162g, 1.0mmol) and compound 19 (1.2mmol) were dissolved in water (5mL) and t-BuOH (5mL) at room temperature, then CuSO4 (100μL, 0.1mol) and sodium ascorbate (200μL, 0.5mol) was added to the solution. The mixture was stirred at room temperature for 30h, The solution was then diluted with 10mL water as well as CH2Cl2 (30mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (CH2Cl2/CH3OH: 60/1) yielded compound [19F]2a (0.203g, yield: 72%) as a yellow oil.

4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1-(2-(2-fluoroethoxy)ethyl)-1H-1,2,3-triazole（[19F]2b）

Compound [19F]2b was prepared from compound 17b (0.5mmol) and NaF (0.254g, 2.0mmol), with the same procedure described for compound [19F]1a. Compound [19F]2b: 0.12g (yield: 71%).

1-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)-4-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)methyl)-1H-1,2,3-triazole ([19F]2c)

Compound [19F]2c was prepared from compound 17c (0.5mmol) and NaF (0.254g, 2.0mmol), with the same procedure described for compound [19F]1a. Compound [19F]2c: 0.15g (yield: 77%).

ethane-1,2-diyl bis(4-methylbenzenesulfonate) (21a)

Compound 21a was prepared from compound 20a (0.1mol) and TsCl (0.22mol), with the same procedure described for compound 9. Compound 21a: 22.35g (yield: 60.4%).

oxybis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) (21b)

Compound 21b was prepared from compound 20b (0.1mol) and TsCl (0.22mol), with the same procedure described for compound 9. Compound 21b: 29.93g (yield: 72.3%).

(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) ( 21c)

Compound 21c was prepared from compound 20c (0.1mol) and TsCl (0.22mol), with the same procedure described for compound 9. Compound 21c: 34.9g (yield: 76.2%).

((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (21d)

Compound 21d was prepared from compound 20d (0.1mol) and TsCl (0.22mol), with the same procedure described for compound 9. Compound 21d: 31.22g (yield: 62.1%).

2-(2-nitro-1H-imidazol-1-yl)ethyl 4-methylbenzenesulfonate (23a)

To a solution of compound 21a (11mmol) in anhydrous DMF (15 mL) was added 2-nitroimidazole (10mmol) in anhydrous DMF (25 mL) and triethylamine (15mmol) at room temperature. After the reaction mixture was stirred for four days, the solution was diluted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. Purification by FC (CH2Cl2/CH3OH: 100/1, V/V) yielded compound 23a (1.49g, yield: 43.6%) as a yellow solid.

2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl 4-methylbenzenesulfonate (23b)

Compound 23b was prepared from compound 21b (11mmol) and 2-nitroimidazole (10mmol), with the same procedure described for compound 23a. Compound 23b: 1.58g (yield: 40.2%).

2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (23c)

Compound 23c was prepared from compound 21c (11mmol) and 2-nitroimidazole (10mmol), with the same procedure described for compound 23a. Compound 23c: 2.18g (yield: 49.5%).

2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate (23d)

Compound 23d was prepared from compound 21d (11mmol) and 2-nitroimidazole (10mmol), with the same procedure described for compound 23a. Compound 23d: 2.0g (yield: 41.1%).

1-(2-azidoethyl)-2-nitro-1H-imidazole (24a)

Compound 24a was prepared from compound 23a (2.89mmol) and NaN3(5.78mmol), with the same procedure described for compound 10. Compound 24a: 0.41g (yield: 77.1%).

1-(2-(2-azidoethoxy)ethyl)-2-nitro-1H-imidazole (24b)

Compound 24b was prepared from compound 23b (2.89mmol) and NaN3(5.78mmol), with the same procedure described for compound 10. compound 24b: 0.52g (yield:80.1%).

1-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2-nitro-1H-imidazole (24c)

Compound 24c was prepared from compound 23c (2.89mmol) and NaN3(5.78mmol), with the same procedure described for compound 10.compound 24c: 0.58g (yield:75.0%).

1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-nitro-1H-imidazole (24d)

Compound 24d was prepared from compound 23d (2.89mmol) and NaN3(5.78mmol), with the same procedure described for compound 10.compound 24d: 0.65g (yield:71.8%).

2-((1-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (25a)

Compound 25a was prepared from compound 24a (1.98mmol) and 7a (2.37mmol), with the same procedure described for compound 11a. Compound 25a: 0.69g (yield: 80%).

2-((1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (25b)

Compound 25b was prepared from compound 24b (1.98mmol) and 7a (2.37mmol), with the same procedure described for compound 11a. Compound 25b: 0.8g (yield: 84.2%).

2-((1-(2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (25c)

Compound 25c was prepared from compound 24c (1.98mmol) and 7a (2.37mmol), with the same procedure described for compound 11a. Compound 25c: 0.76g (yield: 73.6%).

2-((1-(2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate (25d)

Compound 25d was prepared from compound 24d (1.98mmol) and 7a (2.37mmol), with the same procedure described for compound 11a. Compound 25d: 0.7g (yield: 62.2%).

1-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-iodoethoxy)methyl)-1H-1,2,3-triazole ( 26a)

Compound 26a was prepared from compound 25a (1.44mmol) and NaI (0.65g, 4.33mmol), with the same procedure described for compound 12a. Compound 26a: 0.38g (yield: 68.1%).

1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-iodoethoxy)methyl)-1H-1,2,3-triazole ( 26b)

Compound 26b was prepared from compound 25b (1.44mmol) and NaI (0.65g, 4.33mmol), with the same procedure described for compound 12a. Compound 26b: 0.38g (yield: 84.7%).

1-(2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-4-((2-iodoethoxy)methyl)-1H-1,2,3-triazole ( 26c)

Compound 26c was prepared from compound 25c (1.44mmol) and NaI (0.65g, 4.33mmol), with the same procedure described for compound 12a. Compound 26c: 0.53g (yield: 76.5%).

1-(2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-4-((2-iodoethoxy)methyl)-1H-1,2,3-triazole (26d)

Compound 26d was prepared from compound 25d (1.44mmol) and NaI (0.65g, 4.33mmol), with the same procedure described for compound 12a. Compound 26d: 0.53g (yield: 70.3%).

1-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-4-((2-fluoroethoxy)methyl)-1H-1,2,3-triazole ([19F]3a)

Compound [19F]3a was prepared from compound 26a (0.89mmol) and AgF (2.67mmol), with the same procedure described for compound [19F]1a. Compound [19F]3a: 0.11g (yield: 43.4%).

1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-4-((2-fluoroethoxy)methyl)-1H-1,2,3-triazole ([19F]3b)