Carbonyl diimidazole amidation

Procedures for the preparation of several compounds of considerable utility are described. These include 1,1 -carbonyl-diimidazole, which has been used in the preparation of esters, amides, and anhydrides, the hydrochloride and methiodide of l-ethyl-3-(3-dimethylamino)-propylcarbodiimide, which can be used for similar purposes and are especially useful in the preparation of peptides, and (+)- and (— )-< -(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid (TAPA), which is used for the resolution of polycyclic aromatic compounds. 

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

Inhibitors of the blood clotting factor thrombin would in principle prove useful in preventing inappropriate clot formation that potentially leads to stroke and heart attack. Reaction of the carboxylic acid (56-2) with thionyl chloride leads to the corresponding acid chloride (56-3). Treatment of that intermediate with the substituted pyridyl amine (56-1) leads to the amide (56-4). Catalytic hydrogenation of (56-4) reduces the nitro group to the primary amine (56-5). Condensation of that ortho-diamine with the carboxyhc acid (56-6) in the presence of carbonyl diimidazole... 

A quinazolodione provides the nucleus for yet another eompound that inhibits aldose reductase. The sequence for the preparation of this agent starts with the isatoate acid (90-1) from 4-chloroantharanilic acid. Heating the compound with the substituted benzylamine (90-2) results in the formation of the ring-opened amide (90-3) with a loss of carbon dioxide. The ring is then reclosed, this time by reaction with carbonyl diimidazole, to afford the quinolodione (90-4). The anion from the reaction of this last intermediate with sodium hydride is then alkylated with ethyl bromoacetate. Saponification of the ester completes the preparation of zenarestat (90-5) [100]. 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

MfV -carbonyl diimidazole (CDI). We wanted to use the same solvent for the activation as for the reduction as this would allow simple processing and efficient solvent recovery. Eventually we selected CDI on the basis that the very high chemical yield using that reagent, 96% yield over three chemical reactions, outweighed the small additional reagent cost. CDI costs around 8/mol. The amine 6 and the imidazolide are both highly soluble in ethyl acetate as is the main by-product imidazole. In contrast, the desired amide 10 had very low solubility. This led to a very simple process where the streams are mixed, reacted, and the product collected by filtration. There are no aqueous workups involved. Subsequently, a name has been coined for this type of efficient process—direct-drop or direct-isolation process. The preparation of compound 9 is another example of a direct-drop process. 

The last two items of Table 9.6 are related. The seventh item shows that the techniques already discussed that employ dicyclohexylcarbodiimide and carbonyl-diimidazole to activate a carboxylic acid for attack by primary and secondary amines in order to forge the bond between the carbon of the carbonyl and the nitrogen of the amine to yield amide (vide supra. Scheme 9.119) can also be employed in ester formation (Scheme 9.122). The particular alcohol chosen, 3-(hydroxymethyl)-3-methyloxetane, although typical in its reactivity for primary alcohols in general and thus capable of serving as a prototype for ester, was also chosen because, as shown in item 8 of Table 9.6, it can subsequently be used to convert the ester to an orthoester of the corresponding carboxylic acid (Scheme 9.123). Such orthoesters are used to protect the carboxylic acid function and preserve it, while manipulations... 

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