Labeled compounds, synthesis

Acknowledgments. The preparation of the radiolabeled materials by the Labeled Compound Synthesis Group of MSDRL, the dosing and handling of the cattle and swine and the tissue preparation by Animal Metabolism/Branchburg Farm and the generation and interpretation of the nmr and ms data by Drs. Byron Arison and Lawrence Colwell are all greatly appreciated. 

This research was, in part, supported by a grant from the Labeled Compound Synthesis Department of Merck Research Laboratories. We also acknowledge support from the Clare Booth Luce Fund at Seton Hall University for providing summer research internships A. Villoresi and J. Brice. We are grateful for Prof. N. 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Generally, labeled compounds are prepared by procedures which introduce the radionuchde at a late stage of the synthesis. This allows for maximum radiochemical yields, and reduces the handling time of radioactive material. When dealing with short half-life isotopes, a primary consideration is the time required to conduct synthetic procedures and purification methods. 

In the structure sections, labelled compounds have often been used to solve a spectroscopic problem involved in microwave (Section 4.04.1.3.2), nitrogen NMR (Section 4.04.1.3.5), IR (Section 4.04.1.3.7(i)) or mass spectrometry (Section 4.04.1.3.8). The synthesis usually involves non-radioactive compounds ( H, N) by classical methods that must be repeated several times in order to obtain good yields. 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

When specifically labelled compounds are required, direct chemical synthesis may be necessary. The standard techniques of preparative chemistry are used, suitably modified for small-scale work with radioactive materials. The starting material is tritium gas which can be obtained at greater than 98% isotopic abundance. Tritiated water can be made either by catalytic oxidation over palladium or by reduction of a metal oxide ... 

Table V indicates the incorporation and distribution of labeled compounds into kasugamycin (1), when they are added during the production of this antibiotic. Glucose is incorporated into kasugamine and d-inositol. Mt/o-inositol is mainly incorporated into the d-inositol moiety, suggesting the synthesis of d-inositol moiety through myo-inositol or its derivative from glucose or other carbon sources.

Trager, W.F. (1988). Isotope effects as mechanistic probes of cytochrome P450-catalysed reactions. In Synthesis and Application of Isotopically Labelled Compounds Proceedings of the Third International Symposium T.A. Baillie and J.R. Jones (Eds.) Amsterdam Elsevier 333-340. 

Introduction of F2 into 3,4,6-tri-O-acetyl-D-glucal (61) in CCI3F (Freon 11) at —78° in a manner used for the non-labeled compound (so-called cold synthesis) gave a 4 1 mixture of 3,4,6-tri-0-acetyl-2-deoxy-2-[ F]fluoro-a-D-gluco- (574) and ) -D-manno-pyranosyl fluorides (575),... 

Reddy PV, Rabago-Smith M, and Borhan B. 2002. Synthesis of all-frans-[10 -H-3]-8 -apo-P-carotenoic acid. Journal of labelled Compounds Radiopharmaceuticals 45(1) 79-89. 

Various other radiation-induced reactions have been studied for potential use in the industry on a pilot-plant scale. Among these may be mentioned hydrocarbon cracking (i.e., production of lower-molecular-weight hydrocarbons from higher-molecular-weight material), isomerization of organic molecules, and synthesis of labeled compounds with radioactive nuclei. When organic compounds are irradiated in the pure state or in aqueous solution, dimeric... 

The synthesis, analysis and applications of labeled compounds is an area in which basic and applied research go hand-in-hand. Over the last quarter of a century the field has seen considerable expansion as reflected in the emergence of a specific journal (Journal of Labeled Compounds and Radiopharmaceuticals) and the publication of the proceedings of international conferences held at three-yearly intervals. The formation of the International Isotope Society is also an indication of the increasing importance of isotopes and isotopically labeled compounds. 

The use of deuterated organosilicon hydrides in conjunction with proton acids permits the synthesis of site-specific deuterium-labeled compounds.59 126 221 Under such conditions, the deuterium atom in the final product is located at the charge center of the ultimate carbocation intermediate (Eq. 62). With the proper choice of a deuterated acid and organosilicon hydride, it may be possible to use ionic hydrogenation in a versatile manner to give products with a single deuterium at either carbon of the original double bond, or with deuterium atoms at both carbon centers.127... 

In Fischer-Tropsch synthesis the readsorption and incorporation of 1-alkenes, alcohols, and aldehydes and their subsequent chain growth play an important role on product distribution. Therefore, it is very useful to study these reactions in the presence of co-fed 13C- or 14 C-labeled compounds in an effort to obtain data helpful to elucidate the reaction mechanism. It has been shown that co-feeding of CF12N2, which dissociates toward CF12 and N2 on the catalyst surface, has led to the sound interpretation that the bimodal carbon number distribution is caused by superposition of two incompatible mechanisms. The distribution characterized by the lower growth probability is assigned to the CH2 insertion mechanism. 

Electrochemical synthesis was utilized to prepare labeled compounds. Tetramethyllead labeled with 14C was prepared in a double compartment cell in DMF with NaClC>4, by electrolyzing 14CH3l on lead electrodes. The method is reported as superior to transmet-allation with methylmagnesium halide. It is also possible to incorporate lead isotopes. 2i°Pb2+ ions were deposited on a Cu foil and the latter was used as a sacrificial electrode in solutions of CH3I. The yield of labeled tetramethyllead was 85%65. Synthesis of 210Pb-labeled chlorotrimethylplumbane was also described66. 

R. N. Hanson, in Proceedings of the Third International Symposium on the Synthesis and Applications of Isotopically Labelled Compounds (Eds. T. A. Bailie and J. R. Jones), Elsevier, Amsterdam, 1989, pp. 275-281. 

The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

We then studied group 5 metals, especially tantalum-for which the laboratory already had great experience. Because of the studied reaction, alkyl or hydride-type compounds such as those developed in the laboratory could not be employed. Consequently, we became interested in alkoxo-type derivatives, either synthesized by reaction of the grafted complex with an alcohol or obtained by direct synthesis starting from an alkoxy-tantalum compound grafted on silica. In all cases, resulting complexes have been characterized by surface organometallic chemistry techniques, especially EXAFS and solid-state NMR (ID and 2D with C-labeled compounds). Indeed various compounds bonded by one, two or three surface bonds have been prepared and characterized. 

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