Bases, salt formation from

For pharmaceuticals, most of the reactive crystallization processes are salt formation from an acid and base. In this situation, the reaction rate is generally much faster than the mixing or crystallization rate, and the mixing sensitivity depends primarily upon the magnitude of the induction time, or Da for nucleation. 

Salt Formation from Free Acid/Base... 

In salt formation from free acid or base, the free acid/base of the drug substance is combined with the base/acid containing the desired counterion in specific molar ratios in a suitable solvent system. There must be adequate solubility of each reactant in the solvent system chosen. The product can be isolated in different ways, often simply by evaporation of the solvent. 

N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine. Efforts to obtain solid seed samples of the salts with hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, and with a number of organic acids, all failed. The salt formation from this free-base will be discussed below. 

Until recently, pyridine-type bases have been commonly used to produce conjugated enones from 2-halo ketones yields are usually poor °° and these reactions are frequently accompanied by rearrangement, reduction and salt formation. Thus, Warnhoff found that dehydrobromination of (28) with 2,4-lutidine gave a mixture of (29), (30) and (31) in the ratio 55 25 20. Collidine gave a ratio of 38 25 37, whereas pyridine gave mainly the salt (32). 

Heterocyclic bases which readily form quaternary salts with the more usual reagents will also react with suitably activated aryl and heterocyclyl halogen compounds, the classic case being the salt formed from pyridine and l-chloro-2,4-dinitrobenzene. Reactions of this type have been studied by Chapman et Salt formation between... 

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

Although some examples of C-substitutions of silylated Schiff bases and iminium salts, in particular the formation of / -lactams, have already been mentioned in Sections 5.1.3 and 5.1.5 (cf. also C-substitutions of lactones and amides in Section 4.8) in this section several additional and typical C-substitutions of 0,0- and 0,N-acetals and of iminium salts derived from carbonyl groups are discussed. 

Ellis Wilson (1991, 1992) examined cement formation between a large number of metal oxides and PVPA solutions. They concluded that setting behaviour was to be explained mainly in terms of basicity and reactivity, noting that cements were formed by reactive basic or amphoteric oxides and not by inert or acidic ones (Table 8.3). Using infrared spectroscopy they found that, with one exception, cement formation was associated with salt formation the phosphonic add band at 990 cm diminished as the phosphonate band at 1060 cm" developed. The anomalous result was that the acidic boric oxide formed a cement which, however, was soluble in water. This was the result, not of an add-base readion, but of complex formation. Infrared spectroscopy showed a shift in the P=0 band from 1160 cm" to 1130 cm", indicative of an interaction of the type... 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

For preparative diazotisations it is important to use a sufficient excess of acid and to keep the temperature down. Two moles of acid are required for each mole of amine, one for salt formation and one for liberating the nitrous acid from the nitrite. As a rule 2-5-3-0 moles are used. The excess is required to prevent condensation of the diazonium salt with unchanged base to diazoamino-compound such condensations take place in a faintly acid medium. The test for unchanged amine, accordingly, consists in buffering the free mineral acid with sodium acetate, and so providing a solution faintly acid with acetic acid, under which conditions the diazoamino-compound is formed. The latter is decomposed by mineral acids into diazonium salt and amine salt, e.g. 

It has also been shown that the disproportionation reaction, with the generation of the ionic componnd from thioamide-iodine complexes, exhibits pressure dependence [2]. A pressnre increase, leads to the ionic iodonium salt (iii) from (ii) (Scheme 13.2). The favouring of [MBZIM) ] [I3] (24a) formation, is also proven by compntational stndies, based on energetic gronnds [6]. 

Lu and coworkers have synthesized a related bifunctional cobalt(lll) salen catalyst similar to that seen in Fig. 11 that contains an attached quaternary ammonium salt (Fig. 13) [36]. This catalyst was found to be very effective at copolymerizing propylene oxide and CO2. For example, in a reaction carried out at 90°C and 2.5 MPa pressure, a high molecular weight poly(propylene carbonate) = 59,000 and PDI = 1.22) was obtained with only 6% propylene carbonate byproduct. For a polymerization process performed under these reaction conditions for 0.5 h, a TOF (turnover frequency) of 5,160 h was reported. For comparative purposes, the best TOF observed for a binary catalyst system of (salen)CoX (where X is 2,4-dinitrophenolate) onium salt or base for the copolymerization of propylene oxide and CO2 at 25°C was 400-500 h for a process performed at 1.5 MPa pressure [21, 37]. On the other hand, employing catalysts of the type shown in Fig. 12, TOFs as high as 13,000 h with >99% selectivity for copolymers withMn 170,000 were obtained at 75°C and 2.0 MPa pressure [35]. The cobalt catalyst in Fig. 13 has also been shown to be effective for selective copolymer formation from styrene oxide and carbon dioxide [38]. 

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