Succinic Ester Route

Very recently, a solvent-free variation of the succinic ester route under micro-wave assistance has been described [7]. 

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Scheme 11-4 Mechanism of DPP formation via the succinic ester route.

Butanediol. 1,4-Butanediol [110-63-4] tetramethylene glycol, 1,4-butylene glycol, was first prepared in 1890 by acid hydrolysis of N,]S3-dinitro-l,4-butanediamine (117). Other early preparations were by reduction of succinaldehyde (118) or succinic esters (119) and by saponification of the diacetate prepared from 1,4-dihalobutanes (120). Catalytic hydrogenation of butynediol, now the principal commercial route, was first described in 1910 (121). Other processes used for commercial manufacture are described in the section on Manufacture. Physical properties of butanediol are Hsted in Table 2. 

The sodium succinate ester is rapidly absorbed following intramuscular administration, with peak plasma concentrations obtained in 2 h. For parenteral administration in intensive or emergency therapy, methylprednisolone sodium succinate may be given by intramuscular or intravenous injection or by intravenous infusion. The intravenous route is preferred for its more rapid effect in emergency therapy. 

A second new route to DPP Pigments was developed and published 1983 In this route, succinic ester is condensed in a pseudo-Stobbe condensation with an aromatic nitrile in the presence of strong base to afford the desired DPP in good yield (Stdieme 11—4). Mechanistically, the formation of a DPP unit from succinic esters is believed to proceed along the pathway shown in Scheme 11—4. TTie initially formed enaminoesters 5C/5D cyclize to the pyrrolinone esters 6B, which further react under basic conditions with another benzonitrile. Subsequent ring closure affords the DPP 2. 

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). 

According to Thurston (702), the lower dibasic esters yield pure carbox5unonoguanamines so readily that this reaction is an excellent synthetic route, when confined to the lower esters. It has been apphed to 1-aryl- and alkyl-biguanides as usual, and to the alkali metal salts of half esters. The reaction involving diethyl malonate is represented below succinic acid esters (292, 699) react similarly. 

Alcoholysis of meso-cycYic anhydrides offers a versatile route to succinate and glu-tarate half-esters. Although a number of stoichiometric approaches to this problem have been investigated, a successful catalytic version of this reaction appeared as recently as 2003. ° Bolm and coworkers have developed a protocol for the metha-nolysis of a variety of succinic anhydrides using cinchona alkaloids [Eq. (10.50)]. The reaction may be made catalytic in alkaloid when pentamethylpiperidine is used as a stoichiometric additive. A moderate decrease in enantioselectivity is observed in a number of cases, although excellent selectivities are still attainable. More problematic is the reaction time (6 days under catalytic conditions) ... 

Glucocorticoids are available in a wide range of preparations, so that they can be administered parenterally, orally, topically, or by inhalation. Obviously the oral route is preferred for prolonged therapy. However, parenteral administration is required in certain circumstances. Intramuscular injection of a water-soluble ester (phosphate or succinate) formed by esterification of the C21 steroid alcohol produces peak plasma steroid levels within 1 hour. Such preparations are useful in emergencies. By contrast, acetate and tertiary butylacetate esters must be injected locally as suspensions and are slowly absorbed from the injection site, which prolongs their effectiveness to approximately 8 hours. 

Methyl- 1,3-cyclopentanedione is a key intermediate for the total synthesis of steroids.2 A number of methods have been described for its preparation, among them the condensation of succinic acid with propionyl chloride,3 and that of succinic anhydride with 2-buten-2-ol acetate,4 both in the presence of aluminum chloride. It has also been obtained from 3-methylcyclopentane-1,2,4-trione by catalytic hydrogenation5 and Wolff-Kishner reduction 6 The base-promoted cyclization of 4-oxohexanoic acid ethyl ester and diethyl propionylsuccinate with tertiary alkoxides was first reported by Bucourt.7 The present cyclization process provides an experimentally simple route to 2-methyl-1,3-cyclopentanedione. Using the same procedure, 4-oxoheptanoic acid ethyl ester has been cyclized to give 2-ethyl-l,3-cyclopentanedione in 46% yield... 

A low-cost route to 1,4-butanediol and tetrahydrofuran based on maleic anhydride has been disclosed (Davy process).343,344 Here dimethyl or diethyl maleate is hydrogenated over a copper catalyst. Rapid saturation of the C—C double bond forms diethyl succinate, which subsequently undergoes further slower transformations (ester hydrogenolysis and reduction as well as dehydration) to yield a mixture of y-butyrolactone, 1,4-butanediol, tetrahydrofuran, and ethanol. After separation both ethanol and y-butyrolactone are recycled. 

Recently, a,co-bis-hydroxy-terminated poly(l,3-propylene succinate) has been chain-extended to yield high molecular weight poly(ester-carbonates) [44] using a bischloroformate route. Thus, using a molar ratio of 1,3-propanediol to succinic acid of 1.02, an oligomer having Mn of 2,200 and Mw of 3,000 was ob-... 

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 ... 

To bias the direction the macro cycle takes at each of the transformations, temporary barriers would be required in order to restrict Brownian motion in one particular direction. Such temporary barriers are intrinsically present in [3]catenane 20 (Fig. 8 and Scheme 10). Irradiation at 350 nm of , -20 causes counter-clockwise rotation of the light-blue macrocycle to the succinic amide ester (orange) station to give Z,E-20. The light-blue macrocycle cannot rotate clockwise because the purple macrocycle effectively blocks that route. 

Related alkylation chemistry of (2) has provided a route to chiral succinic acid derivatives (11) (eq 7). In this chemistry, acetyl complex (2) was used to produce a succinoyl complex which was subsequently deprotonated a to the ester and alkylated with primary and secondary alkyl halides. This sequence of reactions has been used to produce the succinate fragment of actinonin, as... 

S-Benzyl-y-butyrolactones (44) for which convenient preparative procedures are available, and improved techniques for their a-alkylation and a-hydroxyalkylation, provide the most common synthetic route for these lignan sub-classes (39). The Stobbe condensation (40) of aryl aldehyde with dimethyl succinate (Scheme 9) leads to the half-ester (42) which can be catalytically hydrogenated at atmospheric pressure to give the dihydro half-ester (43). Selective reduction of the potassium salt of the latter can be effectively achieved by calcium borohydride (41)... 

The first enzymatic reaction investigated in the whole project concerned the introduction of chirality in route B (Fig. 2) by generation of succinic acid mononitrile (R)-12 from its racemic precursor. Since in a broad sense the nitrile ester substrate 10 can be interpreted as an amino acid analogue, proteases recommended themselves as catalysts to be tested. From the literature, 2-substituted succinic and butyric acid esters were known to be resolved by proteases [6, 7]. Proteases are... 

Route C (Fig. 2) starts from the extremely cheap bulk agents isobutylene and maleic anhydride 4 and provides diester 9 in two steps. When in the course of process development this attractive access to the potential enzyme substrate 9 could be established, work concentrated immediately on its enantio- and regioselective monohydrolysis. Thus, the sterically more hindered ester group had to be hydrolyzed to the target monoacid (R)-2 a. Protease-catalyzed reactions with the stated specificity had already been described for several 2-substituted succinate diesters, such as 2-... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

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