C-methylation

The radioactive isotopes available for use as precursors for radioactive tracer manufacturing include barium [ C]-carbonate [1882-53-7], tritium gas, p2p] phosphoric acid or pP]-phosphoric acid [15364-02-0], p S]-sulfuric acid [13770-01 -9], and sodium [ I]-iodide [24359-64-6]. It is from these chemical forms that the corresponding radioactive tracer chemicals are synthesized. [ C]-Carbon dioxide, [ C]-benzene, and [ C]-methyl iodide require vacuum-line handling in weU-ventilated fume hoods. Tritium gas, pH]-methyl iodide, sodium borotritide, and [ I]-iodine, which are the most difficult forms of these isotopes to contain, must be handled in specialized closed systems. Sodium p S]-sulfate and sodium [ I]-iodide must be handled similarly in closed systems to avoid the Uberation of volatile p S]-sulfur oxides and [ I]-iodine. Adequate shielding must be provided when handling P P]-phosphoric acid to minimize exposure to external radiation. 

Synthetic chemical approaches to the preparation of carbon-14 labeled materials iavolve a number of basic building blocks prepared from barium [ CJ-carbonate (2). These are carbon [ C]-dioxide [ CJ-acetjlene [U— C]-ben2ene, where U = uniformly labeled [1- and 2- C]-sodium acetate, [ C]-methyl iodide, [ C]-methanol, sodium [ C]-cyanide, and [ CJ-urea. Many compHcated radiotracers are synthesized from these materials. Some examples are [l- C]-8,ll,14-eicosatrienoic acid [3435-80-1] inoxn. [ CJ-carbon dioxide, [ting-U— C]-phenyhsothiocyanate [77590-93-3] ftom [ " CJ-acetjlene, [7- " C]-norepinephrine [18155-53-8] from [l- " C]-acetic acid, [4- " C]-cholesterol [1976-77-8] from [ " CJ-methyl iodide, [l- " C]-glucose [4005-41-8] from sodium [ " C]-cyanide, and [2- " C]-uracil [626-07-3] [27017-27-2] from [ " C]-urea. All syntheses of the basic radioactive building blocks have been described (4). 

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

Many organic hahdes, especially alkyl bromides and iodides, react direcdy with tin metal at elevated temperatures (>150° C). Methyl chloride reacts with molten tin metal, giving good yields of dimethyl tin dichloride, which is an important intermediate in the manufacture of dimethyl tin-ha sed PVC stabilizers. The presence of catalytic metallic impurities, eg, copper and zinc, is necessary to achieve optimum yields (108) ... 

Deuteration of C-methyl protons in simple methylpyrimidines and their amino and hydroxy derivatives has been studied under acidic and basic conditions. The exchange is acid/base catalyzed with, for example, a minimal rate at pH 4 for 1,4,6-trimethylpyrimidin-2(lH)-imine (67JCS(B)171). 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

Pyrazole and its C-methyl derivatives acting as 2-monohaptopyrazoles in a neutral or slightly acidic medium give M(HPz) X, complexes where M is a transition metal, X is the counterion and m is the valence of the transition metal, usually 2. The number of pyrazole molecules, n, for a given metal depends on the nature of X and on the steric effects of the pyrazole substituents, especially those at position 3. Complexes of 3(5)-methylpyrazole with salts of a number of divalent metals involve the less hindered tautomer, the 5-methylpyrazole (209). With pyrazole and 4- or 5-monosubstituted pyrazoles M(HPz)6X2... 

The acidic character of the hydrogen atoms of C-methyl groups linked to the pyrazolium ring (Figure 22 Section 4.04.2.1.1(11)) facilitates a number of reactions difficult to carry out with neutral pyrazoles. Since efficient methods of dealkylation have been described (Section 4.04.2.3.lO(ii)), the synthesis via the pyrazolium salt is a useful alternative. The same behaviour is observed for indazolium salts, for example, nucleophilic addition to aromatic aldehydes (78JOC1233). 

Piperidine, l-(2-hydroxythiobenzoyI)-neutron diffraction, 2, 116 Piperidine, 4-hydroxy-2,2,6-trimethyI-as local anaesthetic, 1, 179 Piperidine, JV-methoxycarbonyl-electrolytic oxidation, 2, 374 Piperidine, 2-methyl-synthesis, 2, 524 Piperidine, 3-methyI-mass spectrometry, 2, 130 Piperidine, C-methyl-NMR, 2, 160 Piperidine, JV-methyl- C chemical shifts, 2, 15 catalyst... 

Methyl 2,4-DI-0-acelyl-3,6-dldeoxy-3-C-methyl-3-nliro-a-L-glucopyrannoslde (4). Methyl-o-L-rhamnopyrannoslde 3 (100 g, 0.55 mol) in water (1000 mL) was treated with Nal04 (200 g, 0 83 mol) at 20°C. After 3 h NaHCOa was added, the mixture poured into EtOH (4000 mL) and filtered The filtrate was concentrated atxl extracted with hot EtOH. The extract was cooled, filtered and treated with nilroethane (104 5 g, 1.4 mol) followed by a solution of Na (12 g, 0.52 at. g) In EtOH (750 mL). After 4 h at 20°C Ihe solution was treated with CO2, filtered and concentrated The mixture was treated with pyridine (400 mL) and AC2O (300 mL) at 20°C lor 12 h. Workup left a residue which dissolved In Et20 petroleum ether (1 1) (500 mL) and cooled afforded 36 g of 4 (19%), rryj 137-138"C, (alQ- O C (c 1). 

Syn 3-(EthyltHloniethyl)-4-hydroxy-6-pt)enyl-2-hexanone (4) and anti (5) To ethanethiol (10 0 mg 0 17 mmol) in THF (2 mL) was added 1 54 M n butyltittnum m hexane (0 11 mL) at 0 C under Ar Stannous triflate (69 0 mg 017 nvnol) was added and alter 20 mm the mocture was cooled to 4S°C Methyl vinyl Ketone 1 (118 mg 1 98 mmol) m THF (1 5 mL) was added followed by 3 phenyiptopanal 3 350 mg 2 61 mmol) m THF (1 S mL) Alter 12 h aq cilnc acid was added and the organic material extracted with OHjClj The resxlue after evaporation was dissolved in MeOH and treated with citric acxt After 30 min stimng, the mixture was quenched with pH 7 phosphate buffer extracted with CH2CI2, the solvent evaporated and the residue chromatographed to afford 336 mg ot 4 (75%), syn anti (90 10)... 

Preparation of IQ- C-testosterone acetate has been achieved by methyla-tion of a 19-nor-seco-androstane derivative (266) with C-methyl iodide. 

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