Sulfathiazoles, methylation with

Sulfathiazoles, methylation with, 37 UV spectra of, 20 see also Sulfonamidothiazoles Sulfenamido thiazides, preparation of,... 

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

The reactivity of sulfathiazoles has been reviewed (65). Methylation in alkaline solution with dimethyl sulfate gives only the ring methylated derivative (85). Mixtures of products are obtained with diazomethane as alkylating agent (see p. 37). Other alkyl halides in aqueous alkali lead also to ring-alkylated products (85. 251, 650. 669-671). 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

However, some drug-polymer combinations can be converted to the amorphous form during the milling process as has been shown for piroxicam with either PVP, methyl cellulose, or Soluplus (Kogermann et al. 2013), indomethacin with PVP (Ke et al. 2012), and sulfathiazole or sulfadimidine with PVP (Caron et al. 2011). To prevent solid-state changes, the milling time has to be optimized for each drug-polymer pair. 

---