Drugs silyl derivatives

Plasma and urine levels of the drug are determined by chromatographing the trimethyl-silyl derivative of dobutamine on a 6-foot column packed with 3.0% UC-W98 silicon gum rubber (methyl-vinyl) on Diatoport S operated at 260°C. The hydrogen flame detector is maintained at 280°C. Helium flow rate is 60 ml/min. The retention time of dobutamine derivative (TMS) under these conditions is 3.8 minutes. This method measures plasma levels as low as 1 ig/ml (4). 

Most of the silyl derivatives of drugs, described in literature till now, are trimethyl-silyl compounds, containing a Si-O, Si-N or Si-C bond between the silicon atom and the drug. 

The preparation of silyl derivatives with a Si—C bond between the silicon atom and the drug is not so easy to realize as compared with Si—O and Si—N systems. In most cases the Si-C bond must be constructed at the beginning of synthesis. This is shown for the triethylsilyl derivative (4) of phenethylamine (3) in Scheme 1 ... 

Different distribution characteristics were also observed39 for dopamine (5) and its tris(trimethylsilyl) and tetrakis(trimethylsilyl) derivatives 6 and 7, respectively. In contrast to 5, for which the blood-brain barrier is nearly impermeable, the much more lipophilic silyl derivatives 6 and 7 were found to exhibit central effects when given intraperitoneally to rats. At a dosage of 100 mg per kg, they influence positively the rigid akinetic syndrom, which was induced by reserpine. These results may be explained in terms of a pro-drug behavior of 6 and 7. (In this context see also Reference 40.)... 

The object of the first—silylating-derivatives of known physiological active compounds—is to generally increase the solubility to fats and increase the effect of the drugs. 

The collection edited by Rolf Kiiehnle contains 2200 mass spectra of drugs, pharmaceuticals and metabolites. The inclusion of the silylated derivatives as used for GC-MS analyses is of special value in this database. Additional information included are chemical structure, chemical name, molecular formula, molecular weight (nominal mass), base peak and the reference (Kiiehnle, R. (2006)). 

The statine-like moiety in one of the first drugs, saquinovir (23-8), comprises a transition state mimic for the cleavage of phenylalanylprolyl and tyrosylprolyl sequences. Constmction starts with the protection of the amino group of phenylalanine as its phthaloyl derivative (Phth) by reaction with phthalic anhydride this is then converted to acid chloride. The chain is then extended by one carbon using a Friedel-Crafts-like reaction. The required reagent (21-2) is prepared by reaction of the enolate obtained from the /7A-silyl ether (21-3) of glyoxylic acid and lithio... 

Gas chromatographic separation has not gained wide acceptance in spite of being quite sensitive and specific. This mode of separation is complicated by the need for derivatization of sulfonamide residues before gas chromatographic analysis. These drugs are subjected to derivatization via methylation with diazomethane (223, 224, 253, 254, 271), or double derivatization via methylation followed either by silylation with Ai-methyl-Ai-trimethylsilytrifluoroacetamide (261) or by acylation with A-methyl-bis(trifluoroacetamide) (256). This derivatization step is required not only to form the volatile derivatives of the sulfonamides but also to improve their chromatographic properties (thermal stability and decreased polarity). 

The silylation procedure has been accepted as a routine method for the trace analysis of preparations of thyroid hormones and drugs containing them. Quantitative evaluation was achieved by using T2 as an internal standard [314], The method has not been applied to the analysis of hormones in serum. Silylation does not seem suitable for this purpose as the derivatives partially decompose if sub-nanogram amounts are injected. 

Silylation is often used for the preparation of the derivatives of pharmaceuticals. In addition to the above-mentioned examples, it was applied to the GC—MS of cambenda-zole [561], the TMS derivatives of which were prepared by heating for 30 min at 60°C with BSA in pyridine. Lauwereys and Vercruysse [562] analysed different hypnotica and carried out the silylation directly on the point of the needle in the falling needle injection system (see p. 22). In order to obtain good reproducibility of the method, they recommended conventional silylations as alternative procedures. Anticonvulsant drugs were also silylated with the aid of BSA and analysed on 5% of OV-101 [563]. 

Owing to the urgent need of new drugs for the treatment of AIDS, many methods for converting the title lactones into antiviral dideoxynucleosides have been devised within the past few years. A viable synthesis of the potent anti-HIV agent 3 -deoxy-2, 3 -dehydrothymidine (d4T, 21) relies on trans selective sulfenylation of the lactone-derived silyl ketene acetal (20) with iV-(phenylthio)- -caprolactam (eq 11). In comparable fashion, (21) and related nucleosides have been prepared through seleneny-lation of (20). ... 

This technique may be used in two distinct ways. The drug may be labeled at a specific site(s) and the mass spectra of metabolites derived from the labeled compound compared with those obtained from the unlabeled drug. Recent examples of this application include reports on the metabolism of oxybutynin,tocainide, and ketamine. Alternatively, a heavy isotope (usually H) is introduced into the metabolite of interest by reaction with a labeled derivatizing reagent. For example, perdeutero-methylation results in a mass difference of 3 daltons between labeled and unlabeled derivatives per methyl group. Structures of metabolites obtained from caffeine and phenytoin have been confirmed by this technique. Tri(deuteromethyl)silylation has been employed in the identification of metabolites of carbamazepine and afloqualone. ... 

Another example of the quantitative determination of a drug is provided by LSD. Because of the very high retention index (3595) of the LSD-TMS derivative, chromatography is not easy. Well-deactivated silylated inserts are recommended. The extracts from a human specimen should be free of matrix (reextraction). For the derivatization, the extremely dry residue is taken up in BSTFA/TMCS (Fluka 15238) and derivatized for 20 min at 70°C. Instead of pure BSTFA/TMSC, a 30-50% solution in a dry solvent such as acetic acid, diethyl ether or dioxan can be used. 

When highly water-soluble CyD derivatives are investigated for application in drug formulations, random modifications of hydroxyl groups to hydroxypropyl, sulfo-propyl, carboxymethyl, or silyl groups can be easily achieved [14]. On the other hand, if a supramolecular behavior is to be investigated using CyD derivatives, the... 

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