One-pot aminolysis

Further improvement of the synthesis of the classic conjugates was achieved by using polymer precursors containing TT-reactive groups. Better stability of XT groups in aqueous solutions allowed one pot aminolysis of a polymer precursor with both Dox and antibody added to an aqueous polymer solution kept at constant pH and temperature. The obtained conjugate contained very small amounts of the free drug and unreacted antibody, which could be removed by gel filtration. 

Note. Only a one-pot indirect aminolysis has been reported. 3-Bromo-5-ethyl-l,6-naphthyridin-2( l//)-one (19) gave 3-bromo-5-ethyl-l,6-naphthyridin-2-amine (20) (POCl3, reflux, 16 h crude chloro compound NH3/EtOH, 100°C, sealed, 16 h 92% analogs likewise).590... 

New routes have been designed by Katritzky and co-workers using ben-zotriazole derivatives. Alkylation of primary thioamides has been achieved on the nitrogen atom using an aldehyde as a source of the alkyl group [42]. A variety of thioamides is accessible by a one pot reaction of a Grignard reagent with carbon disulfide (in THF), followed by treatment with benzo-triazole triflate and aminolysis of the activated thiocarbonyl intermediate [43, 44]. 

CDI 13 (33) allows one-pot amide bond formation and is also used for large-scale peptide chemistry (34). Initially, the mechanism may involve the formation of acyl carboxy imidazole and imidazole. Both intermediates react together to lead to the activated species as the acyl imidazole 14. Then the amine is added to undergo aminolysis (see Fig. 4). As imidazole is generated in situ, the reaction does not need an additional base and it is usually compatible with amine HCl salts (35). Incidentally, the acyl imidazole intermediate can also be isolated and stored. Some simple acyl imidazoles are even available commercially. 

Recently, DMTMM 75 has been described as an efficient, one-pot coupling reagent for ester and amide bond formation (102). This reagent first undergoes an SNAr reaction as in the case of cyanuric fluoride 9. The activated ester then undergoes aminolysis. The in situ liberation of A-methyl morpholine avoids the use of an additional base conveniently. The triazi-none 76 by-product is eliminated easily by an aqueous wash (see Fig. 16). 

Note The indirect aminolysis of tautomeric phthalazinones may be done via halogeno, alkoxy, thioxo, alkylthio, or other such derivatives. Convenient one-pot syntheses are exemplified here. 

There are, however, caveats that should be considered for each of the aforementioned approaches. It has been shown that aminolysis of RAFT end groups can lead to disulfide or even cyclic by-products depending on the polymer repeat unit so generally aminolysis and TEC are done in a one-pot reaction to avoid these deleterious reactions. With respect to azide-terminated polymers obtained by displacement of... 

Scheme P12.9.2 Conversion of the trithioccabonate end group of a RAFT polymer into colorless and stable thioether in a one-pot process combining (1) aminolysis of the trithiocarbonate function and (2) Michael addition of the formed thiol to an cr. -unsaturated carbonyl derivative.

SCHEME 13.76 One-pot Yonemitsu reaction/aminolysis to 3-substituted 3-indolepropionic amides 345. 

A series of new quinoxalines 474 were prepared in 55-61 % yields by the one-pot three-component condensation of epoxy ketones 466m with 1,2-DAB 155a in ethanol in the presence of catalytic amounts of AcOH (Scheme 2.100) (Nasar et al. 2007). The authors assumed that the reaction occurs as a tandem process comprising the following sequence of transformations acid-catalyzed aminolysis of... 

Keywords Aminolysis One-pot conjugation process Site-specific double postpolymerization modification Thiolactone chemistiy Thiol-click reaction... 

Compared with both hydrolysis and alcoholysis, aminolysis as the start of a multistep reaction sequence based on thiolactones is advantageous because it does not require any additives for it to occur. Although the related one-pot process proceeds in an unassisted way, it is not straightforward because, in many cases, orthogonality issues can arise as a result of the reactive nature of amines. On the other hand, it provides the opportunity to introduce a functional group into the reaction product via the amine (Scheme 1), which is very relevant for double modification purposes (vide infra). 

Scheme 5 One-pot thiolactone-based ctmjugation aminolysis of a thiolactone, followed by thiol-click conjugation. The in situ generated thiol can react according to three distinct reaction pathways (a) radical (UV-initiated) or (b) nucleophilic (thiol-Michael) addition of a thiol to a double bond (thiol-ene), and (c) thiol-disulfide exchange...

In addition to the radical amine-thiol-ene conjugation, the one-pot combination of aminolysis of a thiolactone unit and a nucleophilic thiol-ene conjugation (Michael addition) (Scheme 5, pathway b) was explored. The Michael addition between a nucleophile (e.g., thiol, amine, or stabilized carbanion) and an activated double bond (e.g., imidazole, acrylate, vinyl sulfone) is often the key step in polymer... 

There are two approaches for the transformation of linear polythiolactones. On the one hand, the PPM consists of two separate batch processes (aminolysis and thiol-click), with isolation of the polythiol. On the other hand, the double PPM can be conducted in a one-pot manner, thus avoiding any intermediate purification. Both approaches were investigated and the respective advantages and disadvantages evaluated. 

Scheme 14 One-pot reaction pathway (two-step batch process) to glycopolymers, employing a double modification (aminolysis and nucleophilic substitution) of thiolactone-containing copolymers...

An alternative route to disulfide formation is a thiol-disulfide exchange reaction [160, 167, 168] in the presence of a 2,2 -dipyridyl disulfide(or derivative) as a reactive disulfide. Two very recent studies revealed that the thiol-disulfide exchange reaction (pathway c in Scheme 5) offers better selectivity and control over the disulfide formation process. Moreover, the obtained mixed disulfide remains reactive towards thiols for further modification. In contrast to the above-described amine-thiol-ene conjugation, this approach is not 100% atom-efficient because 2-mercaptopyridine (or a derived structure) is released in the reaction medium. Monteiro and coworkers synthesized multifunctional nanostructures (worms and rods) with multiple chemical functionalities directly in water using a one-step RAFT-dispersion polymerization. The introduced functional handles originate from their presence in the R group on the CTA. In the case of thiolactone worms and rods, aminolysis with allylamine and subsequent one-pot scavenging of... 

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