C-Carbonylation Reactions Using Gas-Liquid Segmented Microfluidics

Supporting Information Table of

After completed entrapment, the trap was heated to room temperature (r.t.) while release the 11 CO using the µ-mass flow controller (Bronkhorst, Ruurlo, Netherlands) at 100 µl/min into a the MF reactor.A six-port, two-way valve (V5, Valco, P/N C2-2006D) was used to direct the 11 CO/He flow from the 11 CO trap to the MF reactor.At the same time the premixed coupling reagents solution (aryl halide, Pdligand and nucleophile in anhydrous THF) was infused into the MF reactor at a constant flow rate (30 µl/min) using a syringe pump.The micro reactor (deactivated fused-silica capillary, length = 5-m, i.d.= 200 µm, P/N 160-2205-5, Agilent technologies) was pre-heated to 100 o C using an oil bath.A mixing-tee (150 µm i.d., P/N P-890-01, INEX Heath & Science) was enplayed to generate a sufficient gas and liquid contact and facilitate µ-bubble formation.The pressure inside the micro reactor was kept at 7 Bar (100 psi) using a back-pressure regulator (Supelco, P/N 5-9284).A product collection vial was connected to the reactor outlet with a leak-tight gas bag in series to receive volatile radioactive products (e.g. 11CO).The synthesis process was controlled and monitored with in-house developed software (Labview, National Istruments).

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The radioactivity inside the collaction vial and the leak-tight gas bag were determined using a calibrated radioisotope calibrator (Capintec INC, USA).The radioactivity inside the collaction vials was measured a second time after flushing the head-space with N 2 to remove unreacted 11 CO (Fig. 2).The 11 CO trapping efficiency (TE) was calculated by deviding the radioactivity still remaining within the collation vial after flushing with N 2 , with the sum of all radioactivity exiting the micro reactor.The crude reaction mixture was diluted with mobile phase (1:1, acetonitrile:water) and the radiochemical purity (RCP) was established with radio-HPLC.The product peak area as a percentage of the sum of all radioactive peak areas, with the correction for trapping efficiency, was used to estimate the radiochemical conversion (RCC).

Preparation of N-benzyl-[carbonyl-11 C]benzamide ([ 11 C
]3) using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodobenzene (2 mg, 10 µmol) were dissolved in anhydrous THF (0.9 ml).The mixture was purged for 15 min with nitrogen before benzylamine (50 mg, 467 µmol) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
The mixture was purged for 5 min with nitrogen and heated at 100 o C for an additional 5 min before benzylamine (50 mg, 467 µmol) was Preparation of [ 11 C]4 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and 2-iodobenzyl alcohol (5 mg, 21 µmol) were dissolved in anhydrous THF (0.9 ml).The mixture was purged for 15 min with nitrogen.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]5 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodobenzene (2 mg, 10 µmol) were dissolved in anhydrous THF (0.8 ml).The mixture was purged for 15 min with nitrogen before 0.35 M NaOH solution (200 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]6 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodobenzene (2 mg, 10 µmol) were dissolved in anhydrous THF (0.4 ml).The mixture was purged for 15 min with nitrogen before methanol (400 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]7 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodobenzene (2 mg, 10 µmol) were dissolved in anhydrous THF (0.4 ml).The mixture was purged for 15 min with nitrogen before ethanol (400 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]9 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and methyl iodide (2 mg, 14 µmol) were dissolved in anhydrous THF (0.9 ml).The mixture was purged for 15 min with nitrogen before amineprecursor (10 mg, 23 µmol) was added by briefly removing the rubber septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]10 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodo-precursor (5 mg, 10 µmol) were dissolved in anhydrous THF (0.6 ml).The mixture was purged for 15 min with nitrogen before 2 M dimethylamine in THF (400 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.

Preparation of [ 11 C]11 using conditions
A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodo-precursor (5 mg, 11.5 µmol) were dissolved in anhydrous THF (0.5 ml).The mixture was purged for 15 min with nitrogen before 2 M dimethylamine in THF (500 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]12 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodo-precursor (5 mg, 10 µmol) were dissolved in anhydrous THF (0.9 ml).The mixture was purged for 15 min with nitrogen before piperidine (43 mg, 506 µmol) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preparation of [ 11 C]13 using conditions B. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd 2 (π-cinnamyl)Cl 2 (2 mg, 3.9 µmol), xantphos (4 mg, 6.9 µmol) and bromo-precursor (3 mg, 8.3 µmol) were dissolved in anhydrous THF (0.5 ml).The mixture was purged for 15 min with nitrogen before 2 M ethylamine in THF (500 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
Preperative production of compound [ 11 C]12 using conditions A. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd(PPh 3 ) 4 (4 mg, 3.5 µmol) and iodo-precursor (5 mg, 10 µmol) were dissolved in anhydrous THF (0.9 ml).The mixture was purged for 15 min with nitrogen before piperidine (43 mg, 506 µmol) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.The reaction was carried out in accordence with the general procidure, after which the crude reaction mixture quenched with 4 ml of a 1:1 ratio between mobile phase and 0.1 M NH 4 HCO 2 .Semi-preparative HPLC purification was performed on a reversed-phase column (µBondapak -C18, 10 µm, 10 х 300 mm) eluted with an isocratic mobile phase consisting of acetonitrile and 0.1 M NH 4 HCO 2 (40:60, v/v) at a flow rate of 6 ml/min to afford [ 11 C]12 (t r = 18 min) in a isolated yield of 1200 MBq.HPLC analysis t r = 6.100 min; >99% radiochemical purity and a Specific Radioactivity (SRA) of 49 GBq/µmol (1070 Ci/mmol).
Preperative production of compound [ 11 C]13 using conditions B. An oven-dried disposable 4 ml vial (chromacol) was equipped with a rubber septum, evacuated and cooled under nitrogen.All solid reagents were added by briefly removing the rubber septum: Pd 2 (π-cinnamyl)Cl 2 (2 mg, 3.9 µmol), xantphos (4 mg, 6.9 µmol) and bromo-precursor (3 mg, 8.3 µmol) were dissolved in anhydrous THF (0.5 ml).The mixture was purged for 15 min with nitrogen before 2 M ethylamine in THF (500 µl) was added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.
The reaction was carried out in accordence with the general procidure, after which the crude reaction mixture quenched with 4 ml of a 1:1 ratio between mobile phase and 0.1 M NH 4 HCO 2 .Semi-preparative HPLC purification was performed on a reversed-phase column (µBondapak -C18, 10 µm, 10 х 300 mm) eluted with an isocratic mobile phase consisting of acetonitrile and 0.1 M NH 4 HCO 2 (25:75, v/v) at a flow rate of 6 ml/min to afford [ 11 C]12 (t r = 15 min) in a isolated yield of 2800 MBq.HPLC analysis t r = 5.110 min; >99% radiochemical purity and a Specific Radioactivity (SRA) of 52 GBq/µmol (1470 Ci/mmol).
to RCS Advances added via syringe through the septum.The reaction mixture was loaded to syringe pump of the syntheses module 5 min prior to start of synthesis.