Succinic acid adduct

Drug Substance Succinic Acid Adduct Degradant... 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Thiols and phosphines add to maleic anhydride to give a-thiosuccinic anhydrides (82) and phosphoranylidene—maleic anhydride adducts (83). Triethyl phosphite [122-52-1] reacts with maleic anhydride to give the yhde stmcture (23) (84). Hydrolysis of this adduct (23) leads to succinic acid... 

Various techniques have been proposed for the recovery of pure succinic acid, including extraction (141—145), selective crystalliza tion (146—151), heating to dehydrate the acid and subsequent recovery of succinic anhydride by distillation (152), esterification foUowed by fractionation of the mixture of the esters (65—69), and separation as urea adduct (118,119). 

Figure 1.10 Diels-Alder Reaction of Cyclopentadiene with a Diacrylate (A). Diels-Alder Reaction of Cyclopentadiene with an Adduct of an Acrylate with Succinic Acid (B). The Product can be Dimerized with PEG.

The simplest unsaturated dicarboxylic acids are maleic acid and fumaric acid, both of which are cheap, commercially available, materials. They are geometric isomers maleic acid is the (Z) isomer (19), and fumaric acid is the (E) isomer (20). Maleic acid forms an internal anhydride, maleic anhydride (21), which is widely used to form adducts with conjugated dienes (the Diels-Alder reaction, Section 7.6). The formation of the anhydride from maleic acid and the conversion of maleic acid into fumaric acid are described in Expt 5.218. The hydrogenation of maleic acid to succinic acid is of value as a means of evaluating the activity of a catalyst for use in hydrogenations at atmospheric pressure the experimental procedure is given in Section 2.17.1, p. 87. 

It is noteworthy that the orientation of addition of the carbamoyl radical to the a, [1-unsaturated ester is towards the (3-carbon. From the two possible isomeric amide esters (1 1 adducts) only the derivatives of succinic acids were obtained. The initial attack of the radical on the double bond may follow two routes ... 

Of particular interest is the oxidation of the complexes Fea CjoH R Og (XXXI R = R = CH3 or H) with aqueous ferric chloride to give a product of composition (RC2R)Fe(CO)6 [190). Oxidation of the dimethyl derivative with cold concentrated nitric acid gives dimethylmaleic anhydride (XXXII). The derivative (HC2H)Fe(CO)6 forms a Diels-Alder adduct (XXXIII) with cyclopentadiene the adduct may be oxidized to succinic acid. All of these data indicate that the derivatives (RC2R)Fe(CO)6 are cyclic derived from maleic acid derivatives. Four of the six carbonyl groups are metal... 

Methylindole and acetylenedicarboxylic acid is reported to give two unidentified products, but with the dimethyl ester the crs and trans (61) adducts were obtained. It was suggested that the major product had the trans configuration but this was not proved. Hydrogenation of both adducts gave the corresponding succinic ester, which was also obtained from 2-methylindole and maleic anhydride, followed by esterification. 

Attempts to isolate 2,3-dimethoxyfuran (156) have, as yet, been fruitless (79JCS(P1)1893), but it may be generated in situ and trapped with the propiolate (155) the initial adducts (157) are unstable under the acidic conditions and yield the biphenyls (158) and (159) (Scheme 67). 2,5-Bis(trimethylsilyloxy)furans, readily available from succinic anhydrides in one step, are also more reactive than furan in Diels-Alder reactions (80TL3423). They readily undergo reaction with both DMAD and ethyl acrylate. Thus at 50 °C in carbon tetrachloride the furan (160) with DMAD followed by detrimethylsilylation gave only the quinone (163). At 80 °C, however, the hydroquinone (164) is the major product. Both the intermediates (161) and (162) may be detected by ]H NMR spectroscopy. The formation... 

Cyclic anhydrides react well with trimethyl(trifluoromethyl)silane however, a stoichiometric amount of tctrabutylammonium fluoride is required. - For example, succinic anhydride undergoes efficient addition of trimethyl(trifluoromethyl)silane to initially form an adduct, which upon hydrolysis aflbrds the trifluoromethyl-substiluted 0x0 carboxylic acid 27. Simple amides, such as benzamide and acetamide, do not react with trimetliyl(trifluoromethyl)silane even when a molar quantity of tetrabutylainmonium fluoride is used. Furthermore, lactams, such as caprolactam, do not react with trimethyl(trifluoromethyl)silane under similar conditions. An activated amide carbonyl, such as that in A -methylsuccinimide. however, reacts smoothly to afford an interesting adduct, which upon acid hydrolysis affords the hcmiaminal 28. 

Instead of epoxides carbonyl compounds may be used as electrophiles to generate the y-hydroxy carboxylic acid intermediate. In the classical Stobbe reaction (equation 79) succinic esters are deprotonated and treated with aldehydes or ketones to form, via the unstable adduct (211), the paraconic ester (212). 

Methoxy- and 2-acetoxy-furans are available from 2,5-dimethoxy- and 2,5-diacetoxy-2,5-dihydro-furans (18.1.1.4) via acid-catalysed elimination. They undergo Diels-Alder cycloadditions the adducts can be further transformed into benzenoid compounds by acid-catalysed opening. 3,4-Dihydroxyfuran is undetectable in tautomeric equilibria between mono-enol and dicarbonyl forms the dimethyl ether behaves as a normal furan, undergoing easy a-electrophilic substitution, mono- or dilithiation at the a-position(s), and Diels-Alder cycloadditions. 2,5-Bis(trimethylsilyloxy)furan is synthesised from succinic anhydride it too undergoes Diels-Alder additions readily. Both furan-2- and -3-thiols can be obtained by reaction of lithiated furans with sulfur in each case the predominant tautomer is the thiol form. ... 

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