SUPPORTING INFORMATION. Titania-Catalyzed Radiofluorination of Tosylated Precursors in Highly Aqueous Medium

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1 SUPPRTING INFRMATIN Titania-Catalyzed Radiofluorination of Tosylated Precursors in Highly Aqueous Medium Maxim E. Sergeev, * Federica Morgia, Mark Lazari, Christopher Wang Jr., R. Michael van Dam * Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 4323 CNSI, 57 Westwood Plaza, Los Angeles, CA 995, USA. msergeev@mednet.ucla.edu mvandam@mednet.ucla.edu TABLE F CNTENTS 1. General information S2 2. Effect of water content in reaction medium. S3-S4 3. Effect of catalyst loading. S5-S6 4. Effect of temperature. S7-S8 5. Effect of reaction time. S9-S1 6. Effect of substrate-catalyst pre-incubation time. S11-S12 7. Effect of DMS in reaction mixture. S13-S14 8. Effect of reaction time for radiofluorination after pre-incubation. S15-S16 9. Effect of type of alcohol co-solvent addition. S17-S18 1. Exemplary HPLC-chromatograms and comparison with microchip S19-S2 preparation of Fallypride. 11. General procedure for the synthesis of tosylated precursors 1b-u. S21 S ptimized general procedure for titania-catalyzed 18Fradiosynthesis of compounds 2a-x. 14. [ 18 F]Fallypride production run and QC tests. S23-S NMR data for tosylated precursors S25-S NMR spectra of tosylated precursors S33-S64 17 References to NMR spectra of 19 F-labeled compounds S65-S66 S1

2 1. General information. All the solvents and reagents were purchased from Sigma-Aldrich Chemical Co. (St. Louis, M). Tosylated precursors and/or fluorinated cold standards were either commercially available from Sigma-Aldrich Chemical Co. (St. Louis, M) and Advanced Biochemical Compounds (ABX GMBH, Radeberg, Germany), or synthesized in-house according to common previously reported procedures. No-carrier-added [ 18 F]fluoride ion was obtained from the UCLA Biomedical Cyclotron by irradiation of 85% 18 -enriched water with an 11 MeV proton beam using an RDS-112 cyclotron (Siemens Medical Solution, Knoxville, TN). Radioactivity was determined using a calibrated ion chamber (Capintec CRC-15R). A radioactive thin layer chromatography scanner (MiniGITA star) (Raytest USA, Inc, Wilmington, NC) and an analytical-scale high performance liquid chromatography (HPLC) system (Knauer Smartline Analytical System, column: Phenomenex Luna C18 5 µm, 25 mm 4.6 mm; UV/vis detection at λ = 21 nm, Bioscan radiometric detector, Knauer, Germany) were used to analyze radiofluorination efficiency. The analyticalscale HPLC used for purification was equipped with a SecurityGuard C18 guard column (Phenomenex, Torrance, CA), a Phenomenex Luna reversed-phase C-18 column (25 x 4.6 mm), a variable wavelength UV detector at 21 nm and a gamma coincidence detector (Eckert&Ziegler, Washington DC, USA). TLC mobile phase: acetonitrile-water 5:5 v/v. HPLC mobile phase: acetonitrile-water 55:45 v/v. Gas chromatograpy mass spectra (GC-MS) were registered with Agilent 789A system with 5975C triple-axis detector; Inductively-coupled plasma mass spectroscopy (ICP-MS) was performed using an Agilent 75c quadrupole ICP- MS system with hydrogen/helium octopole collision cell. 1 H NMR spectra were recorded on Bruker AV4 spectrometer at 4 MHz and are reported in ppm with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm). 13 C NMR spectra were recorded on Bruker AV4 spectrometer at 1 MHz and are reported in ppm with the solvent resonance employed as the internal standard (CDCl 3 at 77. ppm). S2

3 2. Effect of water content in reaction medium. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (.14 mmol; crystalline composition: 45% rutile, 55% anatase; <2 nm size) and tosylated precursor 1a (2.3 µmol) solution in pre-determined amount (see Table 1) of 1:1 (v/v) mixture of acetonitrile (MeCN) and thexyl alcohol (thexh). The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. A pre-determined volume (see Table 1) of this solution (containing mci radioactivity) was then added into reaction vial, resulting into -62% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater. Reaction was performed at 11 C for 7 minutes. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S3

4 RCC, % Table 1. Effect of water content on RCC. Entry ACN- [ 18 F]/TBAB aq. Water content, Compound 2a purity in RCC, thexh volume, [µl] [vol %] extract, [%] [%] volume, [µl] 1 a ± 2 64 ± ± 2 65 ± ± 2 65 ± ± 3 65 ± ± 4 51 ± ± 5 29 ± ± 4 16 ± a [ 18 F]fluoride/TBAB complex was dried and reconstituted in anhydrous acetonitrile before addition Water content, vol % Figure 1. Effect of water content on RCC in Ti 2 -catalyzed radiofluorination of tosyl-fallypride 1a. S4

5 3. Effect of catalyst loading. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 ( mmol) and tosylated precursor 1a (2.3 µmol) solution in 3 µl of 1:1 (v/v) mixture of acetonitrile and thexyl alcohol. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater.. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 11 C for 7 minutes. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S5

6 RCC, % Radioactivity content, % Fluorination efficiency, % Table 2. Effect of catalyst loading on trapping and RCC. Entry Catalyst, [mmol] Compound 2a purity in extract, [%] Extraction efficiency, [%] [18F]-trapping, [%] RCC, [%] ± 1 97 ± 2 3 ± 1 2 ± ± 1 9 ± 3 1 ± 1 21 ± ± 2 86 ± 2 14 ± 2 31 ± ± 5 8 ± 2 2 ± 2 68 ± ± 3 56 ± 3 44 ± 2 22 ± ± 1 46 ± 4 54 ± 3 1 ± ± 1 21 ± 5 79 ± 3 2 ± Catalyst amount / mmol Catalyst amount, mmol Figure 2. (left) Radioactivity extraction and trapping at different catalyst loading amount. Blue for radioactivity counted in organic extract, red for radioactivity trapped in catalytic layer. (right) Radiochemical purity of 2a Catalyst amount, mmol Figure 3. Effect of catalyst loading amount on RCC. S6

7 4. Effect of temperature. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 ( mmol) and tosylated precursor 1a (2.3 µmol) solution in 3 µl of 1:1 (v/v) mixture of acetonitrile and thexyl alcohol. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater.. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at pre-determined temperature for 7 minutes. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S7

8 RCC, % Table 3. Effect of temperature on RCC. Reaction time was 7 min. Entry Temperature, [ C] Compound 2a purity in extract, [%] RCC, [%] ± 3 19 ± ± 2 52 ± ± 1 68 ± ± 1 69 ± ± 2 68 ± Temperature, C Figure 4. Effect of temperature on RCC in Ti 2 -catalyzed radiofluorination of tosyl-fallypride 1a. Reaction time was 7 min. S8

9 5. Effect of reaction time. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 ( mmol) and tosylated precursor 1a (2.3 µmol) solution in 3 µl of 1:1 (v/v) mixture of acetonitrile and thexyl alcohol. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater.. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for pre-determined time period. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S9

10 RCC, % Table 4. Effect of reaction time on RCC. Reaction was performed at 13 C. Compound 2a Entry Time, [min] purity in extract, RCC, [%] [%] ± 3 56 ± ± 1 61 ± ± 2 67 ± ± 1 68 ± ± 1 69 ± ± 3 78 ± ± 1 77 ± Reaction time, min Figure 5. Effect of reaction time on RCC of Ti 2 -catalyzed radiofluorination of tosyl-fallypride 1a. Reaction was performed at 13 C. S1

11 6. Effect of substrate-catalyst pre-incubation time. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (.14 mmol) and tosylated precursor 1a (2.3 µmol) solution in 1:1 (v/v) mixture of acetonitrile and thexyl alcohol (3 µl). Vial was capped and incubated at room temperature for a predetermined time period. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into pre-incubated reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater.. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for 1 minutes. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S11

12 RCC, % Table 5. Effect of substrate-catalyst incubation time on RCC. Compound 2a Entry Time, [min] purity in extract, RCC, [%] [%] 1 85 ± 3 68 ± ± 1 68 ± ± 1 68 ± ± 2 68 ± ± 1 71 ± ± 1 74 ± ± 3 78 ± ± 3 78 ± ± 1 78 ± Substrate-catalyst incubation time, min Figure 6. Effect of substrate-catalyst incubation time on RCC. S12

13 7. Effect of DMS in reaction mixture. N HN 1a S 18 F - / H 2 DMS MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (.14 mmol) and tosylated precursor 1a (2.3 µmol) solution in a mixture of acetonitrile and thexyl alcohol (3 µl), including varying amounts of DMS (Table 6). Vial was capped and incubated at room temperature for 1 hour. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into pre-incubated reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to pre-heated oil-bath.. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for 5 min. After the reaction is done, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S13

14 Radioactivity extraction, % RCC, % Table 6. Effect of DMS on extraction and RCC.# Precursor in ACN/tHexH, ul ACN/tHexH, ul DMS, ul DMS, vol % Compound 2a purity in extract, [%] Extraction efficiency, % RCC, % 1 a ± 1 79 ± 1 77 ± ± 3 59 ± 3 3 ± ± 2 34 ± 2 18 ± ± 1 23 ± 4 9 ± ± 4 13 ± ± 1 6 b ± 2 a Standard experiment, reference point; b precursor 1a was initially dissolved in DMS. 1 8 A 1 8 B DMS content, vol % DMS content, vol % Figure 7. Effect of DMS addition on radiofluorination of 1a. A) Radioactivity extraction efficiency; B) Radiochemical conversion. S14

15 8. Effect of reaction time for radiofluorination after pre-incubation. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (.14 mmol) and tosylated precursor 1a (2.3 µmol) solution in 1:1 (v/v) mixture of acetonitrile and thexyl alcohol (3 µl). Vial was capped and incubated at room temperature for 1 hour. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into pre-incubated reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for pre-determined time-period. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S15

16 RCC, % Table 7. Evaluation of reaction time on radiofluorination after 1 hr substrate-catalyst incubation. Entry Time, [min] Compound 2a purity in extract, [%] RCC, [%] ± 3 34 ± ± 1 49 ± ± 2 7 ± ± 1 73 ± ± 1 78 ± ± 2 77 ± ± 4 78 ± ± 2 79 ± ± 3 78 ± ± 2 78 ± Reaction time, min Figure 8. Evaluation of radiofluorination time profile after 1 hr substrate-catalyst incubation. S16

17 9. Effect of type of alcohol co-solvent addition. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (.14 mmol) and tosylated precursor 1a (2.3 µmol) solution in 1:1 (v/v) mixture of acetonitrile and alcohol (3 µl). Vial was capped and incubated at room temperature for 1 hour. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. An aliquot of this solution (1 µl, containing mci radioactivity) was then added into pre-incubated reaction vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to computer-controlled Peltier heater. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for pre-determine time-period. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. S17

18 Table 8. Effect of type of alcohol co-solvent. Entry Alcohol Fluorination efficiency, [%] REE, [%] RCC, [%] 1-39±2 1 31±2 2 MeH 76±3 8±3 61±3 3 EtH 85±4 8±2 68±3 4 n-prh 92±5 8±4 74±4 5 i-prh 83±3 8±2 66±3 6 t-buh 8±4 8±1 64±3 7 thexh 97±2 8±1 78±2 8 n-octanol 82±4 8±2 66±3 9 cyclohexanol 95±1 8±1 76±1 Extraction efficiency was virtually identical for alcohols tested (~8% REE), though in some cases (methanol, ethanol), the Ti 2 was observed to stick to the glass vial more, requiring a larger volume of MeH and longer time for extraction. However, relatively small differences in fluorination efficiency were observed, leading to small differences in RCC. S18

19 1. Exemplary HPLC-chromatograms and comparison with microchip preparation of Fallypride. Figure 9. a) Exemplary HPLC-chromatogram of micro-chip [ 18 F]Fallypride preparation (crude product, prior to final purification). 1 Inset shows enlarged UV-area of target compound 2a. Top is UV absorbance signal, bottom is gamma signal. b) Co-injection with cold standard, [ 19 F]Fallypride. 1. Javed, M. R.; Chen, S.; Lei, J.; Collins, J.; Sergeev, M.; Kim, H.-K.; Kim, C.-J.; Dam, R. M. van; Keng, P. Y. Chem. Commun. 214, 5, S19

20 Figure 1. a) Exemplary HPLC-chromatogram of non-optimized Ti 2 -catalyzed [ 18 F]Fallypride preparation (crude product, after extraction and before final purification). Top is UV absorbance signal; bottom is gamma signal. b) Co-injection with cold standard, [ 19 F]Fallypride. S2

21 11. General procedure for the synthesis of tosylated precursors 1b-u. R H TsCl Cs 2 C 3 ACN, 25 C R Ts 1b-u Tosylated precursors 1b-u were synthesized by general procedure of Pasha et al. 1 To a solution of corresponding starting alcohol (1.9 mmol) in MeCN (1 ml) p- toluenesulfonyl chloride (2.2 mmol), and Cs 2 C 3 (1 mol%), were added. The reaction mixture was stirred rapidly at 25 C for 1 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was diluted with water (2 ml) and product was extracted with diethyl ether (2 ml). The organic extract was then washed with saturated solution of NaHC 3 (2 1 ml), saline (2 1 ml) and water (1 ml). After drying over anhydrous Na 2 S 4, volatiles were evaporated under reduced pressure, residue was dissolved in a mixture of ethyl acetate:hexane 1:5 and purified via flash chromatography over silica gel. Structure identity was confirmed by 1 H and 13 C NMR spectroscopy, spectra were consistent with literature data. 1, 2 Purity was established by RP-HPLC with C18-column and a mixture of acetonitrile and water 55:45. Precursors 1a, 1v, 1w and 1x were purchased from Advanced Biochemical Compounds (ABX GMBH, Radeberg, Germany). 1. Reddy, M. B. M.; Pasha, M. A. Phosphorus, Sulfur, Silicon Relat. Elem. 211, 186, Kim, D.-Y.; Kim, H.-J.; Yu, K.-H.; Min, J.-J. Bioconjugate Chem. 212, 23, S21

22 12. ptimized general procedure for titania-catalyzed 18 F-radiosynthesis of compounds 2a-x. R S 1a-x 18 F - / H 2 MeCN/thexyl alcohol TBAB aq. Ti 2, heat R 18 F 2a-x Prior to use titanium dioxide was calcined at 55 ºC during 12 h. A screw-cap scintillation vial (Fisherbrand # A) was loaded with Ti 2 (11.5 mg,.14 mmol) and tosylated precursor 1a-x (2.3 µmol) solution in 1:1 v/v mixture of acetonitrile and thexyl alcohol (3 µl). Vial was capped and incubated at room temperature for 1 hour. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. The aqueous solution of [ 18 F]F - /TBAHC 3 (1.5-3 mci, 1 µl) was then added into pre-incubated vial, resulting into 25 vol% water content in reaction mixture. The vial was capped and transferred to pre-heated oil bath. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 ºC for 5 minutes. After the reaction, the product was extracted with methanol (2 2 µl). Combined extracts were thoroughly filtered through Whatman Anotop 1 Plus filter (.2 µm) and radiolabeled product content was analyzed by radio-tlc and HPLC. Radiolabeled compound identity was established by co-injection with standard 19 F-fluorinated compounds. S22

23 13. [ 18 F]Fallypride production run and QC tests. N HN 1a S 18 F - / H 2 MeCN-thexyl alcohol TBAB Ti 2, heat N HN 2a F 18 Procedure: Six screw-cap scintillation vials (Fisherbrand # A) were loaded with Ti 2 (.14 mmol) and tosylated precursor 1a (2.3 µmol) solution in 3 µl of 1:1 (v/v) mixture of acetonitrile and thexyl alcohol. The aqueous solution of [ 18 F]F - /TBAB was prepared by mixing equal volumes of [ 18 ]H 2 /[ 18 F] and 75 mm aqueous solution of TBAB. 1 µl of this solution (containing 2.6 mci radioactivity) was then added into each reaction vial, resulting into 25 vol% water content in reaction mixture. The vials were capped and transferred to pre-heated oil bath. The reaction mixture was mixed by refluxing solvent; no active magnetic stirring was used. Reaction was performed at 13 C for 5 minutes. After the reaction is done, the product from each vial was extracted with methanol (2 2 µl). For statistical purposes, pairs of organic extracts were combined, giving 3 portions, each containing 8 µl of organic extract. Purification/reformulation process: Each combined organic extract (8 µl) was evaporated under stream of nitrogen in plastic Eppendorf tube using oil bath. Residue was reconstituted in 9 µl of HPLC buffer (55:45 v/v MeCN / aq. ammonium formate + 1% triethylamine) and purified via HPLC (Phenomenex Luna reversed-phase C-18 column (25 x 4.6 mm)), collecting peak at 12 min. Collected fraction (~2 ml) was evaporated under stream of nitrogen in plastic Eppendorf tube using oil bath. Residue was reconstituted in DPBS buffer and sterile filtered into sterile vial using Whatman Anotop 1 Plus sterile filter (.2 µm). Resulting injectable solution underwent usual set of QC tests, 1 including determination of endotoxin level, sterility, GCMS determination of residual solvents and ICP-MS determination of titanium content. HPLC chromatogram of final injectable solution and results of QC tests are shown below. S23

24 Reg #1 5 mau UV min 8 CPS ChA min Figure 11. HPLC-chromatogram of injectable [ 18 F]Fallypride formulation Table 9. Quality control tests of injectable [ 18 F]Fallypride solution. Clinical QC test Clinical acceptance criteria Results of this study ptical clarity Clear and particle free Clear and particle free ph Radiochemical purity >95% >99% Radiochemical identity 18 F-radionuclide identity Matches retention time of the standard Half-life min Matches retention time of the standard Half-life 111 min Endotoxin level < 5 EU/mL < 1 EU/mL Filter integrity > 5 psig > 1 psig MeCN content < 41 ppm <2 ppm Thexyl alcohol content < 5 ppm <1 ppm Sterility No growth in 14 days No growth in 14 days Titanium content None specified 36±4 ng 1. Javed, M. R.; Chen, S.; Lei, J.; Collins, J.; Sergeev, M.; Kim, H.-K.; Kim, C.-J.; Dam, R. M. van; Keng, P. Y. Chem. Commun. 214, 5, 1192 S24

25 14. NMR data for tosylated precursors. S Phenyl p-toluenesulfonate (1b): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2 H), 7.4 (d, J=8.1 Hz, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), 2.5 (s, 3 H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 155.4, 146.8, 141.6, 13.2, 129.6, 127., 12.8, 115.3, S Benzyl p-toluenesulfonate (1c): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), 7.38 (d, J = 4.65 Hz, 4H), (m, 1H), 4.7 (s, 2H), 2.5 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 146.8, 141.7, 14.8, 13.2, 128.5, 127.6, 127., 126.9, 65.3, 21.8 S25

26 S 2-Phenylethyl p-toluenesulfonate (1d): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), (m, 2H), (m, 3H), 3.87 (t, J = 6.6 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.5 (s, 3H; 13 C NMR (1 MH, CDCl 3, ppm) δ 146.8, 141.7, 138.4, 13.2, 129., 128.5, 127., 126.4, 63.6, 39.2, S 3-Phenylpropyl p-toluenesulfonate (1e): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), (m, 2H), (m, 3H), 3.69 (t, J = 6.36 Hz, 2H), (m, 2H), 2.5 (s, 3H), (m, 2H; 13 C NMR (1 MHz, CDCl 3, ppm) δ 146.8, 141.8, 13.2, 128.4, 128.3, 127., 125.8, 62.2, 34.2, 32., S26

27 S 6-Phenylhexyl p-toluenesulfonate (1g): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), (m, 2H), (m, 3H), 3.64 (t, J = 6.6 Hz, 2H), (m, 2H), 2.5 (s, 3H), (m, 4H), (m, 4H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 146.8, 142.7, 141.7, 13.2, 128.3, 128.2, 127., 125.6, 62.9, 35.8, 32.6, 31.4, 29., 25.6, S Naphth-1-yl p-toluenesulfonate (1h): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 1H), (d, 2H), (m, 1H), (m, 2H), 7.46 (d, J = 8.31 Hz, 1H), (d, 2H), 7.33 (dd, J = 7.46, 8.19 Hz, 1H), 6.84 (dd, J =.98, 7.58 Hz, 1H), 2.49 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 151.3, 146.8, 141.6, 134.7, 13.2, 127.6, 127., 126.4, 125.8, 125.2, 124.3, 121.5, 12.6, 18.6, 21.8, 15.. S27

28 S Naphth-2-yl p-toluenesulfonate (1i): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (m, 2H), 7.69 (dd, J =.61, 8.19 Hz, 1H), 7.45 (ddd, J = 1.22, 6.91, 8.25 Hz, 1H), 7.41 (d, J =.61, 8.68 Hz, 2H), 7.35 (ddd, J = 1.22, 6.91, 8.25 Hz, 1H), (m, 2H), 2.49 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 153.3, 146.8, 141.6, 134.6, 13.2, 129.8, 128.9, 127.7, 127., 126.5, 126.3, 123.6, 117.7, 19.5, S 1-Phenylethyl p-toluenesulfonate (1j): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), (m, 4H), (m, 1H), 4.9 (q, J = 6.36 Hz, 1H), 2.5 (s, 3H), 1.5 (d, J = 6.6 Hz, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ S28

29 S ctyl p-toluenesulfonate (1k): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), (d, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2.5 (s, 3H), (m, 2H), (m, 1H), (m, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 146.8, 141.7, 13.2, 127., 63., 32.8, 31.8, 29.4, 29.2, 25.7, 22.6, 21.8, S Cyclohexyl p-toluenesulfonate (1l): 1 H NMR (4 MHz, CDCl 3, ppm) δ (d, 2H), 7.41 (d, J = 8.7 Hz, 2H), 3.6 (td, J = 4.68, 8.99 Hz, 1H), 2.49 (s, 3H), (m, 5H), (m, 5H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 146.8, 141.7, 13.2, 127., 114.9, 7.3, 35.5, 25.4, 24.1, 21. S29

30 S m-cresyl p-toluenesulfonate (1n): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 2H), 7.32 (d, J = 8.7 Hz, 2H), (m, 1H), 7.5 (d, J = 7.58 Hz, 1H), 6.87 (s, 1H), (m, 1H), 2.46 (s, 3H), 2.3 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 149.9, 145.5, 14.3, 132.9, 13., 129.5, 128.8, 128.1, 123.3, 119.4, 77.6, 77.3, 22., S p-ethylphenyl p-toluenesulfonate (1o): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 2H), (m, 2H), (m, 2H), (m, 2H), 2.61 (q, J = 7.58 Hz, 2H), 2.45 (s, 3H), 1.21 (t, J = 7.58 Hz, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 147.6, 145.2, 143.1, 132.6, 129.7, 128.8, 128.5, 122.1, 77.3, 76.7, 28.2, 21.7, S3

31 S p-ethoxycarbonylphenyl p-toluenesulfonate (1p): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 2H), (m, 2H), 7.32 (dd, J =.49, 8.56 Hz, 2H), (m, 2H), 4.36 (q, J = 7.9 Hz, 2H), 2.45 (s, 3H), 1.38 (t, J = 7.21 Hz, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 165.5, 152.9, 145.7, 132.1, 131.3, 129.9, 129.3, 128.5, 122.3, 115., 77.4, 77., 76.7, 61.3, 21.8, S N p-nitrophenyl p-toluenesulfonate (1q): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 2H), (m, 2H), 7.36 (d, J = 8.7 Hz, 2H), (m, 2H), 2.48 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 153.6, 145.9, 131.4, 129.8, 128.2, 125.1, 122.9, 76.7, 76.4, S31

32 S N p-cyanophenyl p-toluenesulfonate (1r): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 2H), (m, 2H), 7.35 (d, J = 8.7 Hz, 2H), (m, 2H), 2.47 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 152.6, 146.1, 133.9, 131.9, 13.1, 128.5, 123.5, 117.7, 115., 111.2, 77.4, 77., 76.7, S N pyridin-2-yl p-toluenesulfonate (1s): 1 H NMR (4 MHz, CDCl 3, ppm) δ (m, 1H), 8.15 (d, J = 1.71 Hz, 1H), (m, 2H), (m, 1H), 7.33 (d, J = 8.7 Hz, 2H), (m, 1H), 2.45 (s, 3H); 13 C NMR (1 MHz, CDCl 3, ppm) δ 148.5, 146.8, 146.3, 144.3, 132., 13.5, 13.3, 128.8, 124.5, 77.6, 77.3, 22.. S32

33 Normalized Intensity NMR spectra of tosylated precursors. Phenyl p-toluenesulfonate (1b) 1 H-NMR Tosylated precursors.48.esp M3(m) M4(m) M2(d) M5(m) CHLRFRM-d M1(m) M6(s) Current Data Parameters NAME PhTs-schanger EXPN 48 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W.2.1 F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S33

34 Normalized Intensity C-NMR Tosylated precursors.481.esp CHLRFRM-d Current Data Parameters NAME PhTs-schanger EXPN 481 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S34

35 Normalized Intensity Benzyl p-toluenesulfonate (1c) 1 H-NMR Tosylated precursors.5.esp M4(m) M2(m) M3(d) CHLRFRM-d M1(m) M5(s) M6(s) Current Data Parameters NAME BnTs-schanger EXPN 5 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S35

36 Normalized Intensity C-NMR Tosylated precursors.51.esp CHLRFRM-d Current Data Parameters NAME BnTs-schanger EXPN 51 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W Chemical Shift (ppm) ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S36

37 Normalized Intensity Phenylethyl p-toluenesulfonate (1d) 1 H-NMR Tosylated precursors.51.esp M4(m) M2(m) M3(m) CHLRFRM-d M1(m) M5(t) M6(t) M7(s) Current Data Parameters NAME 2-PhEtTs-schanger EXPN 51 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S37

38 Normalized Intensity C-NMR Tosylated precursors.511.esp CHLRFRM-d Current Data Parameters NAME 2-PhEtTs-schanger EXPN 511 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W Chemical Shift (ppm) ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S38

39 Normalized Intensity Phenylpropyl p-toluenesulfonate (1e) 1 H-NMR Tosylated precursors.52-3-phprts-hnmr.esp M4(m) M3(m) M2(m) CHLRFRM-d M1(m) M5(t) M6(m) M7(s) M8(m) Current Data Parameters NAME 3-PhPrTs-schanger EXPN 52 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S39

40 Normalized Intensity C-NMR Tosylated precursors.521.esp CHLRFRM-d Current Data Parameters NAME 3-PhPrTs-schanger EXPN 521 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S4

41 Normalized Intensity Phenylhexyl p-toluenesulfonate (1g) 1 H-NMR Tosylated precursors.63-phhexts-hnmr.esp M3(m) M4(m) M2(m) CHLRFRM-d M1(m) M5(t) M6(m) M7(s) M8(m) M9(m) Current Data Parameters NAME 6-PhHexTs-schanger EXPN 63 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG 6.34 DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S41

42 Normalized Intensity C-NMR Tosylated precursors.631.esp CHLRFRM-d Current Data Parameters NAME 6-PhHexTs-schanger EXPN 631 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W Chemical Shift (ppm) ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S42

43 Normalized Intensity Naphth-1-yl p-toluenesulfonate (1h) 1 H-NMR Tosylated precursors.35.esp M4(dd) M5(m) M3(m) M8(dd) M2(m) CHLRFRM-d M1(m) M6(m) M9(s) Current Data Parameters NAME 1-NaphTs-schanger EXPN 35 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S43

44 Normalized Intensity C-NMR Tosylated precursors.351.esp CHLRFRM-d Current Data Parameters NAME 1-NaphTs-schanger EXPN 351 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S44

45 Normalized Intensity Naphth-2-yl p-toluenesulfonate (1i) 1 H-NMR Tosylated precursors.36.esp M5(ddd) M7(ddd) M3(m) M8(m) M2(m) CHLRFRM-d M4(dd) M1(s) Current Data Parameters NAME 2-NaphTs-schanger EXPN 36 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S45

46 Normalized Intensity C-NMR Tosylated precursors.361.esp CHLRFRM-d Current Data Parameters NAME 2-NaphTs-schanger EXPN 361 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W Chemical Shift (ppm) ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S46

47 Normalized Intensity Phenylethyl p-toluenesulfonate (1j) 1 H-NMR Tosylated precursors.64.esp M6(m) M7(m) M5(m) CHLRFRM-d M4(m) M3(q) M2(s) M1(d) Current Data Parameters NAME 1-PhEt-Ts-schanger EXPN 64 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S47

48 Normalized Intensity C-NMR Tosylated precursors.641.esp CHLRFRM-d Current Data Parameters NAME 1-PhEt-Ts-schanger EXPN 641 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S48

49 Normalized Intensity ctyl p-toluenesulfonate (1k) 1 H-NMR Tosylated precursors.37.esp M2(m) CHLRFRM-d M1(m) M3(t) M4(s) M5(m) M6(m) M7(m) Current Data Parameters NAME ctts-schanger EXPN 37 PRCN 1 F2 - Acquisition Parameters Date_ Time 16.3 INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG 6.34 DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W.1 F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S49

50 Normalized Intensity C-NMR Tosylated precursors.371.esp CHLRFRM-d Current Data Parameters NAME ctts-schanger EXPN 371 PRCN F2 - Acquisition Parameters Date_ Time 16.6 INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC Chemical Shift (ppm) S5

51 Normalized Intensity Cyclohexyl p-toluenesulfonate (1l) 1 H-NMR Tosylated precursors.65.esp M2(d) CHLRFRM-d M1(m) M3(dt) M4(s) M5(m) M6(m) Current Data Parameters NAME CyTs-schanger EXPN 65 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC Chemical Shift (ppm) S51

52 Normalized Intensity C-NMR Tosylated precursors.651.esp CHLRFRM-d Current Data Parameters NAME CyTs-schanger EXPN 651 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W.3.2 ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S52

53 Normalized Intensity m-cresyl p-toluenesulfonate (1n) 1 H-NMR M-Cresyl.19.esp M5(m) M8(d) M7(m) M4(m) M6(d) M3(s) CHLRFRM-d Chemical Shift (ppm) M1(s) M2(s) Current Data Parameters NAME ct schanger EXPN 19 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC 1. S53

54 Normalized Intensity C-NMR M-Cresyl.191.esp CHLRFRM-d Current Data Parameters NAME ct schanger EXPN 191 PRCN F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE 299. K D1 2. sec D11.3 sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W Chemical Shift (ppm) ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S54

55 Normalized Intensity p-ethylylphenyl p-toluenesulfonate (1o) 1 H-NMR esp M7(m) M5(m) M6(m) M4(m) CHLRFRM-d Chemical Shift (ppm) M2(q) M3(s) M1(t) Current Data Parameters NAME Feb schanger EXPN 19 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE 299. K D1 2. sec TD 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC 1. S55

56 Normalized Intensity C-NMR esp CHLRFRM-d Current Data Parameters NAME Feb schanger EXPN 191 PRCN F2 - Acquisition Parameters Date_ Time 14.2 INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zgpg3 TD SLVENT CDCl3 NS 32 DS SWH Hz FIDRES Hz AQ sec RG DW 19.8 usec DE 6.5 usec TE 299. K D1 2. sec D11.3 sec TD ======== CHANNEL f1 ======== SF MHz NUC1 13C P1 1. usec PLW1 52. W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD2 9. usec PLW2 13. W PLW W PLW W Chemical Shift (ppm) F2 - Processing parameters SI SF MHz WDW EM SSB LB 1. Hz GB PC 1.4 S56

57 Normalized Intensity p-ethoxycarbonylphenyl p-toluenesulfonate (1p) 1 H-NMR P-CEtPh-Ts.34.esp M4(m) M3(dd) M1(m) CHLRFRM-d M2(m) M5(q) M6(s) M7(t) Current Data Parameters NAME Nov5-214-schanger EXPN 34 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM av4 PRBHD 5 mm PABB BB/ PULPRG zg3 TD SLVENT CDCl3 NS 16 DS SWH Hz FIDRES Hz AQ sec RG DW 62.4 usec DE 6.5 usec TE K D1 2. sec TD Chemical Shift (ppm) ======== CHANNEL f1 ======== SF MHz NUC1 1H P1 15. usec PLW1 13. W F2 - Processing parameters SI SF MHz WDW EM SSB LB.3 Hz GB PC 1. S57