Methyl iodide labeled, synthesis

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). 

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... 

Labelled [2H3]dodecyltrimethyl ammonium iodide ([2H3]Ci2TMAI) was synthesised as an internal standard for the quantitative determination of dodecyltrimethyl ammonium chloride (Ci2TMAC) in sewage and river water samples by using FAB-MS [117]. The synthesis of [2H3]Ci2TMAI involved the reaction of dimethylamino dodecane with deuterated methyl iodide (CD3I) in methanol. 

Samuelsson, L. and LangstrOm, B., Synthesis of l (2 deoxy-2 -fluoro-(3-D-arabinofuranosyl)-[Me thy l-nc]Thymine ([nc]Fmau) via a Stille cross-coupling reaction with [nc]Methyl Iodide, J. Labelled Compd ... 

The antihypertensive drug prazosin 283 has been labelled270 with nC by reacting 1 -labelled methyl iodide with desmethylated compound 284 prepared from 283 HC1 by stirring it with 1.1 equivalent of BBr3 in CH2C12 under N2 (equation 112). The specific activity of 283 10 min after the end of a 25 min synthesis was 3500 Ci mmol-1. 

Synthesis of 11C-labelled radiopharmaceuticals in N-alkylation reaction with 11C-methyl iodide... 

D. Harman, T.D. Stewart, and S. Ruben, The Synthesis of Labelled Methyl Iodide, Journal of the American Chemical Society 64, 2294, 1942. 

Methylation of aryl thiols. PTC methylation of l C-aryl thiols with methyl Iodide (2 ) Is very useful for microscale synthesis of C-labeled aryl methyl sulfides (2j ). The reaction, using tetrabutylammonlum hydrogensulfate as catalyst and sodium hydroxide as base In methylene chloride and water, proceeds at ambient temperature In 50-100Z yield. 

When the chain is to be extended from the central part towards the ends of the polyene chain, acetonitrile is used as the starting material to label the positions 8, 9, 12, 13, 8, 9, 12 and 13 (Scheme 6). In a two-step, one-pot reaction, acetonitrile (/) is converted into the anion (18) of 2-(diethylphosphono)propionitrile. In this process, acetonitrile (1) is first deprotonated with one equivalent of BuLi at -70°C in THF, then, after 10 min, one equivalent of methyl iodide (19) is added to give propionitrile (20). In this way, propionitrile (20) can be synthesized with labels on any position or combination of positions. Propionitrile (20) is then converted in situ into the reactive anion (18) of 2-(diethylphosphono)propionitrile by reaction with two equivalents of LDA and one equivalent of diethyl chlorophosphate at -70°C, by a procedure similar to the synthesis of diethyl cyanomethylphosphate (3) from acetonitrile, described in Scheme 1. The anion is reacted with the aldehyde at 0°C, to give the C -elongated nitrile 21 in high yield. Reduction of this nitrile 21 with DIB AH in petroleum ether at -80°C yields the aldehyde 8. 

This route is especially convenient because no over-alkylation of the anion of acetonitrile occurs. Over-alkylation can be a problem in attempts to methylate the anion of diethyl cyano-methylphosphonate (4) directly a mixture of unalkylated, monoalkylated and dialkylated products in a ratio of 1 2 1 is formed. The same problem arises with the alkylation of triethyl phosphonoacetate (11). For the preparation of a Ca-ester synthon, an alternative method to the propionitrile route is used (Scheme 7). This method has been used in the synthesis of labelled Cio-central units, described in the next Section. The starting material is acetic acid (9) which is converted into ethyl bromoacetate (10) as described above (Scheme 3). The ethyl bromoacetate (10) is reacted with triphenyl phosphine in a nucleophilic substitution reaction the phosphonium salt is formed (yield 97%). The phosphonium salt is deprotonated in a two-layer system of dichloromethane and an aqueous solution of NaOH. After isolation, the phosphorane 22 is reacted at room temperature with one equivalent of methyl iodide (19) the product consists mainly of the monomethylated phosphonium salt (>90%) which is deprotonated with NaOH, to give the phosphorane 23 in quantitative yield relative to phosphorane 22, and 23 is reacted with the aldehyde in dichloromethane. The ester product 12 can subsequently be reduced to the corresponding alcohol and reoxidized to the aldehyde 8. An alternative two-step sequence for this has also been used. First, the ester 12 is converted into the A -methyl-iV-methoxyamide (16) quantitatively by allowing it to react with the anion of A, 0-dimethylhydroxylamine as described above (Scheme 5). This amide 16 is converted, in one step, into the aldehyde 8 by reacting it with DIB AH in THF at -40°C [46]. 

The requirement for a rapid tracer production means that the synthesis should be designed in such a way that the C atom is introduced as late as possible. This approach is exemplified by alkylation of carbon, nitrogen, oxygen, and sulfur nucleophiles with [ C]methyl iodide, a synthetic route that provides a general method for the labeling of many biomedically interesting compounds. 

A difficulty in the synthesis of the phosphorylide in the Wittig reaction is to add an equimolar amount of base to the alkyl halide. The use of epichlorohydrine, which forms one equivalent of base in situ by the reaction with iodide ions, obtained from the reaction of a C-labeled alkyl iodide with triphenyl phosphine is one method to overcome the problem. Some examples of useful precursors prepared from [ C] methyl iodide are shown in O Fig. 41.7. 

An example of different substrates amenable to transformation in the Fujimoto-Belleau reaction is shown by the treatment of benzazepine 15 with radioactively labeled methylmagnesium iodide. This was followed by quenching with water to afford diketone 17. In this two-step procedure the diketone was isolated in 80% yield, then treated with base to give the final a,) -unsaturated enone 18. The synthesis illustrates the utility of the Fujimoto-Belleau reaction in the production of radiolabelled 3-benzazepines using labelled methyl iodide. 

A method for incorporation of a carbon-14 label in the ring geminal methyl groups of retinyl acetate has been described by Colwell et aL (1979). The synthesis, shown in Fig. 14, involves monomethylation of 2,6-dimethylcyclo-hexanone (LII) with methyl-iodide as catalyzed by potassium hydride. The trimethylcyclohexanone (LIU), labeled in one methyl group, was condensed with the 11-carbon acetylenic side chain (LIV) to give the acetylenic carbinol... 

For many groups of compounds of pharmacological interest, a wide variety of labelling procedures are available and indeed two of the earliest compounds to be labelled with carbon-14 were meperidine [5] and morphine [6]. This procedure which involves the reductive alkylation of secondary amines with labelled formaldehyde is still the most widely used method for preparing N-methyl tertiary amines and it has also been used for the synthesis of nicotine [7] and chlorpromazine [8, 9] and, with slight modification, for the preparation of erythromycin [10] and acetylmethadol [11], The reaction of C-methyl iodide has also been used to prepare tertiary amines as in the case of codeine [6] and mepivacaine [12], as well as the tranquillisers, thioridazine [13] and methixene [14]. These examples illustrate that labelling of... 

Cleij and coworkers [59] used a homemade PEEK lined stainless steel loop reactor constructed from H P LC fittings to effectthe synthesis of [ C]flumazenil (Scheme 6.22). Reaction of amine (63) with labeled methyl iodide (59) afforded [ C]flumazenil (64) in 80% radiochemical yield at room temperature. The radiosynthesis itself took 5 min, while total processing was reported to be completed in 20 min. 

Hostettle, E. D., Terry, G. E., Burns, H. D., 2005. An improved synthesis of substituted [C-11]toluenes via Suzuki coupling with [C-11] methyl iodide. J. Labelled Compd. Radiopharm. 48 629-634. 

The devolatilization concept has been extended to certain commonly used isotope sources with the additional advantage of making them more stable or storable. [ H/ C]Methyl nosylate (17) has been developed as a substitute for tritiated or carbon-14-labeled methyl iodide, both of which are relatively unstable and difficult to handle (Figure 1.6). Ester 17 is a nonvolatile, easily purifiable solid that is substantially less radiolytically sensitive than the corresponding methyl halides ([ H]methyl nosylate at a specific activity of > 80 Ci/mmol suffered no appreciable decomposition after storage at 39 mCi/mL for 14 weeks at 4 °C in hexane/ethyl acetate ). This derivative is reported to possess similar reactivity to [ H/ C]methyl iodide in a variety of reactions, and to provide greater flexibUity during use in synthesis. 

Safety aspects and experimental scale apart, there are no fundamental differences in the reaction of aliphatic C—H acidic compounds with labeled or unlabeled methyl iodide. For example (Figure 5.56), the alkylation of deprotonated 2,6-dimethylcyclohexanone (202), key step in the synthesis of [ CJvitamin A , of the A,A-dimethyUiydrazone of dihydrotestosterone of mevinolin (20 and tricarbethoxymethane (208) , furnishing... 

Further applications of the HWE reagent 159 comprise the development of low molecular weight carbon-14-labeled building blocks for the three- to five-carbon extension of the skeleton of halides and carbonyl compounds. In the simplest case, alkylation of deprotonated 159 with methyl iodide furnishes the homologous propionate reagent 175. which has been employed as a starting material in the synthesis of [ C]E-5090 (179), an orally active IL-1 inhibitor. Reaction of 175 with the substituted 1-naphthalene-... 

An interesting approach to the generation of l4C-labeled rivastigmine needed for in vivo studies was published by Novartis (Scheme 11).57 The synthesis of 14C-labeled 2 was initiated by l4C-labeled cyanation of iodide 48 to provide 3-methoxybenzo-14C-nitrile (49) in 80% yield. Copper-mediated addition of methyl magnesium bromide to nitrile 49 formed an imine that was hydrolyzed with aqueous HC1 to the corresponding... 

A similar approach had been reported earlier by Bestmann and coworkers" in their synthesis of hexadeuteriated leukotriene A4 methyl ester. C-alkylation of the tetrahy-dropyranyl ether of 3-butyn-l-ol with 2,2,3,3-tetradeuterio-l-iodopentane, prepared in 4 steps from propargyl alcohol, and subsequent protective group removal afforded the tetradeuteriated acetylenic alcohol 46 (equation 30). Semideuteriation of the alkynol and further transformation by known methods produced the labeled key reagent 3,4,6,6,7,7-hexadeuterio-(Z)-(3-nonen-l-yl)triphenylphosphonium iodide (47). Wittig olefination of epoxy dienal 45 with the labeled ylide generated from 47 completed the synthesis of... 

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