Amides safety

Backes BJ, EUman JA (1999) An alkanesulfon-amide safety-catch linker for solid-phase synthesis. J Org Chem 64 2322-2330... 

The conversion of a diazo ketone to an acid amide may be accomplished by treating a warm solution in dioxan with 10-28 per cent, aqueous ammonia solution containing a small amount of silver nitrate solution, after which the mixture is heated at 60°-70° for some time. Precautions should be taken (by use of a. safety glass shield) when heating mixtures containing ammoniacal silver nitrate. 

Function event trees include primarily the engineered safety features of the plant, but other systems provide necessary support functions. For example, electric power system failure amid reduce the effectiveness of the RCS heat-removal function after a transient or small UJ( A. Therefore, EP should be included among the systems that perform this safety function. Siipfiort systems such as component-cooling water and electric power do not perform safety functions directly. However, they significantly contribute to the unavailability of a system or group of systems that perform safety functions. It is necessary, therefore, to identify support systems for each frontline ssstcm and include them in the system analysis. 

Scheme 7.46 Solid-supported amide synthesis employingthe safety-catch principle.

Alitame, L-a-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanine amide, has undergone a series of safety studies. While most of the studies did not show adverse effects and no indications for carcinogenicity were found, a dose-dependent increase in liver weights was found at levels above 100 mg/kg which was identified as the no-effect level. While JECFA has allocated an ADI of 0-1 mg/kg12 only a few countries, but neither the European Union nor the USA, have approved alitame. 

The apparatus is assembled as shown in Fig. 5. Ammonia gas from a commercial cylinder (Note 1) enters the system at K. R is a mercury trap which would serve as a safety valve if the system should become blocked by solidification of the amide owing to an accidental drop in temperature. J is a U-tube containing just enough mercury to seal the bend, and it serves to estimate the rate of ammonia Sow. I is a Kjeldahl trap which prevents any mercury from being thrown into the fusion pot A, which (Note 2) is conveniently supported on a tripod set on bricks to raise it to a convenient height above the burner M. Through the cover of the fusion pot passes an outlet tube B, a thermometer well T, and the combined inlet tube CDE. The... 

Interest in the uses of HMPT has also been maintained, but a warning has been issued (by the E. I. du Pont de Nemours Company and the U.S. National Institute for Occupational Safety and Health) about its potential acute toxicity. HMPT has been used in the synthesis of 2,4-bis(dimethylamino)qui nolines,9 8 as a solvent for reactions between carbonyl compounds and sulphur," for the conversion of iV-benzylcarbox-amides into 3-phenylpropionitriles,100 in reactions between metals or organometallic compounds with a variety of organic substrates,101 and as a solvent for alkylation reactions of /J-keto-esters and related compounds in which the alkylation reaction is accompanied by de(alkoxycarbonylation) (Scheme 7).102... 

The pharmacological properties of etomidate (Amidate) are similar to those of the barbiturates, although its use may provide a greater margin of safety because of its limited effects on the cardiovascular and respiratory systems. Since it has a relatively short elimination half-life (ti/23 = 2.9 hours), in addition to its use as an induc-... 

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

Resin-bound amides generally need to be activated to make them susceptible to saponification under acceptably mild reaction conditions [114] (Table 3.5). Particularly elegant are those linkers that allow this activation to be realized as the final synthetic step before cleavage (safety-catch linkers [115-117]). The activation of some amide-based safety-catch linkers is outlined in Figure 3.9. 

Figure 3.9. Activation and nucleophilic cleavage of amide-based safety-catch linkers [118,119].

Amides are generally very resistant towards nucleophilic cleavage. Safety-catch linkers, such as those described in Section 3.1.2.3, can, however, be cleaved by amines to yield amides (Entries 1 and 2, Table 3.15). Entry 4 in Table 3.15 is an example of a... 

---