Temperature effects on the stereospecificity of nucleophilic fluorination: formation of <i>trans</i>‐[<sup>18</sup>F]4‐fluoro‐<scp>l</scp>‐proline during the synthesis of <i>cis</i>‐[<sup>18</sup>F]4‐fluoro‐<scp>l</scp>‐proline
Bibliographic record
Abstract
Fluorine‐18 labeled (2 S ,4 S )‐4‐fluoro‐ l ‐proline ( cis ‐[ 18 F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2 S ,4 R )‐ N‐tert ‐butoxycarbonyl‐4‐( p ‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis ‐[ 18 F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis ‐[ 18 F]4‐FPro or trans ‐[ 18 F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2 S ,4 S ) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2 S ,4 R ) precursor produced a mixture of cis ‐[ 18 F]4‐FPro and trans ‐[ 18 F]4‐FPro diastereomers with cis ‐[ 18 F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C 18 Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis ‐[ 18 F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis ‐[ 18 F]4‐FPro occurs during the two‐step hydrolysis (H + followed by OH − ) of the intermediate, resulting in 5 ± 3% trans ‐[ 18 F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis ‐[ 18 F]4‐FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".