Maleic acid anhydride reagent

NHj 1 -Flnoro-2,4-dinitrobenzene Acetanhydride Bolton-Hunter reagent Dansylchloride Formaldehyde Maleic acid anhydride N-Snccinimidyl propionate Phenylisocyanate Sodium borohydride Succinic anhydride... 

Acid Chloride Formation. Monoacid chlorides of maleic and fumaric acid are not known. Treatment of maleic anhydride or maleic acid with various reagents such as phosgene [75-44-5] (qv), phthaloyl chloride [88-95-9] phosphoms pentachloride [10026-13-8] or thionyl chloride [7719-09-7] gives 5,5-dichloro-2(5JT)furanone [133565-92-1] (4) (26). Similar conditions convert fumaric acid to fumaryl chloride [627-63-4] (5) (26,27). NoncycHc maleyl chloride [22542-53-6] (6) forms in 11% yield at 220°C in the reaction of one mole of maleic anhydride with six moles of carbon tetrachloride [56-23-5] over an activated carbon [7440-44-4] catalyst (28). 

Maleic acid is a linear four-carbon molecule with carboxylate groups on either end, similar to succinic acid, but with a double bond between the central carbon atoms. The anhydride of maleic acid is a cyclic molecule containing five atoms in its ring. Although the reactivity of maleic anhydride is similar other such reagents like succinic anhydride, the products of maleylation are much more unstable toward hydrolysis, and the site of unsaturation lends itself to additional side reactions. Acylation products of amino groups with maleic anhydride are stable at neutral pH and above, but they readily hydrolyze at acid pH values (around pH 3.5) (Butler etal., 1967). Maleylation of sulfhydryls and the phenolate of tyrosine are even more sensitive to hydrolysis. 

Sodium amalgam serves to reduce selectively the double bond in an olefinic acid containing the thiophene or furan ring. " This reagent is also employed to prepare olefinic acids by partial reduction of certain polyenoic acids, e.g., 3-pentenoic acid (60%) from vinylacrylic acid. Among the dibasic acids prepared by this method are succinic acid from maleic acid (98%) by catalytic hydrogenation over Raney nickel catalyst and alkylsuccinic acids from alkenylsuccinic acids made by the Diels-Alder reaction of simple olefins and maleic anhydride. ... 

A solution of the reagent is prepared by adding 39.2 g. (0.4 mole) of freshly crushed maleic anhydride to an ice-cold mixture of 11.6 g. of 90% hydrogen peroxide and I. SO ml. of methylene chloride and stirring until the solid dissolves. The reagent is somewhat less reactive than trifluoroperacetic acid and much more reactive than I he usual peracids. At room temperature, the titer of the solution falls off about 5% in 6 hrs. A reaction is carried out by adding the substance to be oxidized to the methylene chloride solution and eventually filtering the maleic acid which separates. 

The reactivity of 4,6-benzo[/ ][l,7]naphthyridine in Diels-Alder reactions with maleic acid and dimethyl acetylenedicarboxylate was examined. The reaction afforded adduct 332 (1996MI5). 6-Ethoxycarbonyl- 333a and phenacylmethylides 333b were used as 1,3-dipolar reagents in reactions with methacrylic acid, methyl methacrylate, butyl vinyl ether, methyl vinyl ketone, maleic anhydride and dimethyl acetylenedicarboxylate (1996MI5, 1999AJC149). 

Electrophilic Addition. Electrophilic reagents attack the electron-deficient bond of maleic anhydride (25). Typical addition reagents include halogens, hydrohaHc acids, and water. 

Citraconic anhydride (or 2-methylmaleic anhydride) is a derivative of maleic anhydride that is even more reversible after acylation than maleylated compounds. At alkaline pH values (pH 7-8) the reagent effectively reacts with amine groups to form amide linkages and a terminal carboxylate. However, at acid pH (3-4), these bonds rapidly hydrolyze to release citraconic acid and free the amine (Figure 1.86) (Dixon and Perham, 1968 Habeeb and Atassi, 1970 Klapper and Klotz, 1972 Shetty and Kinsella, 1980). Thus, citraconic anhydride has been used to temporarily block amine groups while other parts of a molecule are undergoing derivatization. Once the modification is complete, the amines then can be unblocked to create the original structure. 

The Diels-Alder cycloadduct of furan and maleic anhydride has played a key role in a new synthesis of butenolides (79S607). Treatment of the cycloadduct (24) with methanol affords a half acid ester which is reacted in turn with an excess of a Grignard reagent to produce the lactone (25) on acidic work-up. On heating this lactone at 150-180 °C, thermal fragmentation takes place to yield the 4,4-dialkylbutenolide (26) in high overall yield (Scheme 5). 

For this reason, although the first polymer-protein conjugates used clinically were streptokinase conjugated to dextran [8] and neocarzinostatins linked to succinic acid-co-maleic anhydride [5], from the 1980s onwards PEG became the polymer of choice, and all products that subsequently appeared on the market were based on this reagent. 

The starting compound 251 was reduced to 252 with sodium borohydride. The latter was heated under reflux in 6% sulfuric acid in methanol to afford compound 253. Treatment of the latter with maleic anhydride at 170° for 3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter was reduced with lithium aluminium hydride to the primary alcohol 256, which was oxidized to the aldehyde 257 with Ar,A -dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde 257 with an excess of the Grignard reagent prepared from l-bromo-3-benzyloxybutane afforded a mixture of diastereoisomers represented by the structure 258. 

The only disadvantage of the succinylation procedure (which is practical and amenable to conventional cell disruption processes) is that the final product is a succinylated protein. Succinyl groups cannot be removed from the succinylated proteins under mild conditions. This could be a problem if succinylated yeast protein was a major source of dietary proteins. Therefore we explored the feasibility of using reversible modifying reagents (citraconic anhydride and maleic anhydride) to separate proteins from NAs and subsequently remove the modifying groups under mild acidic conditions. 

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