Synthesis of Anhydrides

Symmetric and asymmetric anhydrides are readily affordable [46, 170] starting from aliphatic or benzylic halides (emd pseudo-halides) and car-boxylates, using cobalt catalysts (Table VII). 

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Scheme 6. Acid-catalyzed equilibration synthesis of anhydride-terminated polydimethylsi-loxane oligomers [44]...

Synthesis of anhydrides (i) n-butane to maleic anhydride and (ii) o-xylene to phthalic anhydride. 

The specificity in the synthesis of anhydrides from n-butane and n-pentane, typical of the vanadyl pyrophosphate, which likely arises from its property of electrophilic 0-insertion onto... 

Kates and Schauble from Villanova University reported [77] in 1996 the third synthesis of anhydrides of chaetomellic acids A and B. This five-... 

Polystyrene carbodiimide is useful for the synthesis of anhydrides It can also be used for the Moffatt oxidation of alcohols to aldehydes and ketones. Even the labile prostaglandin intermediate (A) is readily converted to the desired aldehyde (B) (Scheme 6). 

A convenient synthesis of anhydrides has been described by the reaction of potassium or sodium salts of carboxylic acids with activating halides (ethyl chloroformate, cyanuric chloride and benzyl chloroformate) in acetonitrile in the presence of 18-crown-6. Using this procedure, cinnamic acid, p-nitrobenzoic acid, benzoic acid, acetic acid and propionic acid are also converted into their anhydrides (Scheme 30). 

Synthesis of Anhydrides from Dicarboxylic Acid Dicarboxylic acids can be converted into anhydrides (Scheme 22) in the presence of isopropenyl acid (which acts as a water scavenger) under microwave irradiation using montmorillonite-KSF. The driving force is the formation of acetone. 

This triphosgene-mediated reaction for the synthesis of anhydrides has a niun-ber of advantages over the existing methods, in that the reaction is carried out im-der neutral conditions and does not use highly toxic or allergenic (as with carbo-diimides) reagents. Furthermore, no elaborate apparatus is needed for this one-pot reaction, which proceeds conveniently to completion in minutes at ice-water temperature. 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

In aprotic conditions acetic anhydride sodium acetate induces formation of a fused ring through an intra molecular condensation. It results in a pyrrolo[2,l-fc]thiazole (39), which constitutes an interesting intermediate for the synthesis of dyes (Scheme 18) (40). 

Using benzene acetic anhydride and 1 propanethiol as the source of all the carbon atoms along with any necessary inorganic reagents outline a synthesis of the compound shown... 

The customary method for the laboratory synthesis of acid anhydrides is the reac tion of acyl chlorides with carboxylic acids (Table 20 1)... 

Therapeutics. Compounds containing the furan or tetrahydrofuran ring are biologically active and are present in a number of pharmaceutical products. Eurfurjdamine [617-89-0] is an intermediate in the diuretic, furosemide. Tetrahydrofurfurylamine [4795-29-3] may also have pharmaceutical applications. 5-(E)imethyiaininomethyi)furfuryi alcohol [15433-79-17 is an intermediate in the preparation of ranitidine, which is used for treating ulcers. 2-Acet5dfuran [1192-62-7] prepared from acetic anhydride and furan is an intermediate in the synthesis of cefuroxime, a penicillin derivative. 2-Euroic acid is prepared by the oxidation of furfural. Both furoic acid [88-14-2] and furoyl chloride [527-69-5] are used as pharmaceutical intermediates. 

Acetic Acid and Anhydride. Synthesis of acetic acid by carbonylation of methanol is another important homogeneous catalytic reaction. The Monsanto acetic acid process developed in the late 1960s is the best known variant of the process. 

The synthesis of 2,4-dihydroxyacetophenone [89-84-9] (21) by acylation reactions of resorcinol has been extensively studied. The reaction is performed using acetic anhydride (104), acetyl chloride (105), or acetic acid (106). The esterification of resorcinol by acetic anhydride followed by the isomerization of the diacetate intermediate has also been described in the presence of zinc chloride (107). Alkylation of resorcinol can be carried out using ethers (108), olefins (109), or alcohols (110). The catalysts which are generally used include sulfuric acid, phosphoric and polyphosphoric acids, acidic resins, or aluminum and iron derivatives. 2-Chlororesorcinol [6201-65-1] (22) is obtained by a sulfonation—chloration—desulfonation technique (111). 1,2,4-Trihydroxybenzene [533-73-3] (23) is obtained by hydroxylation of resorcinol using hydrogen peroxide (112) or peracids (113). 

HemimeUitic acid is not manufactured commercially but is available as a laboratory chemical in a hydrate form (99). Like ttimesic acid, it is formed when coal-like materials are oxidized, but can be synthesized in a purer form by oxidizing hemimeUitene [562-73-8] (1,2,3-trimethylbenzene) or hemimeUitol [526-85-2]. HemimeUitic anhydride can be produced by thermal dehydration of the acid in trichiorohenzene at 261°C (147). Synthesis of hemimellitic acid and anhydride have been described (148). There are no reported uses which ate unique to hemimellitic acid. 

Inositols, ie, hexaliydrobenzenehexols, are sugars that have received increasing study and are useful in the treatment of a wide variety of human disorders, including vascular disease, cancer, cirrhosis of the Hver, frostbite, and muscular dystrophy (269). Myoinositol esters prepared by reaction with lower fatty acid anhydrides are useful as Hver medicines and nonionic surfactants the aluminum and ammonium salts of inositol hexasulfate are useful anticancer agents (270). Tetraarjloxybenzoquinones are intermediates in the preparation of dioxazine dyes (266,271). The synthesis of hexakis(aryloxy)benzenes has also beenpubUshed (272). 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

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