Anhydride, succinic, concentration

To a mixture of 7.5 parts by weight of 1,2,4-triethoxybenzene, 40 parts by volume of tetra-chloroethane and 7.5 parts by weight of succinic anhydride are added 23 parts by weight of anhydrous aluminum chloride. The mixture is stirred for 1 hour at 25°C and for another 2 hours at 60°C. After addition of 50 parts by weight of ice and 50 parts by volume of concentrated hydrochloric acid, the reaction mixture is subjected to steam distiilation. 

Amine-terminated, G3 (PAMAM) dendrimer, (0.316 g 45.7 moles) was dissolved in anhydrous methyl sulfoxide (5 ml) in a 100 ml round-bottom flask flushed with dry nitrogen. After dendrimer had completely dissolved, succinic anhydride (Aldrich) (0.363 g 3.6 mmol) was added to the reaction mixture with vigorous stirring, and the mixture was allowed to react for 24 h at room temperature. The product solution was diluted with deionized water, transferred to 3500 MWCO dialysis tubing (Spectrum) and dialyzed against deionized water (18 Mil) for 3 d. The retentate solution was clarified by filtration through Whatman No. 1 filter paper, concentrated with a rotary evaporator, and lyophilized to yield a colorless powder (0.435 g, 94%). The product was analyzed by 13C-NMR, FT-IR, SEC and MALDI-MS. The analytical data were consistent with the expected carboxylic acid-terminated product. 

Much effort has been devoted to the optimization of the polyesterification reaction. For instance, different types of monomeric precursors structurally related to succinic acid (e.g., dimethyl succinate or succinic anhydride) were used. Different kinds of catalysts (e.g., phenolates, titanium alkoxides, tin octanoates) at different concentrations were studied. Different reaction temperatures (130-190 °C) were reached and different procedures for water elimination (vacuum drying under different conditions or toluene distillation) were adopted. Experimental results obtained showed that the use of different catalysts and different monomer precursors (succinic acid derivatives) did not significantly alter the polymerization kinetics or yield, and for this reason, they were abandoned. The procedure finally adopted is summarized below. 

Figure 1. Effect of succinic anhydride concentration on the e-NH2 groups modification and reduction...

Each of the proteins was dispersed in an alkaline medium (pH 7-9) and then treated with succinic anhydride amounting to 10 times the concentration level (molar basis) of amino groups present in the protein. The degrees of succinylation measured by a usual method (13) were as follows 98.0% for FPC, 95.2% for SPI, 94.0% for casein, 97.7% for ovalbumin, and 98.8% for gelatin. 

Under the influence of concentrated sulphuric acid, succinic anhydride(I) is first formed, and this condenses with the resorcinol(II) to yield succinyl-fluorescein(III). 

The product from Step 5 (0.024 mmol) was added to succinic anhydride (1.02 mmol) dissolved in 10 ml dry pyridine and the mixture stirred overnight. Thereafter, the reaction mixture was poured into 100 ml 2 M HCl and centrifuged. The precipitate was washed twice with water and dissolved in 25 ml 0.1 M aqueous NaOH. The solution was recentrifuged and the product isolated in 93% yield by acidifying the supernatant with concentrate with HCl acid. H-NMR, IR, and elemental analysis data supplied. 

R)-l-Amino-l-phenyl-but-3-yne hydrochloride (22.1 mmol), succinic anhydride (44.2 mmol) and 3.1ml triethylamine dissolved in 200ml toluene were refluxed 1 hour then cooled to ambient temperature. A second addition of 3.1 ml triethylamine was added and the mixture refluxed 18 hours. The aqueous layer was extracted with EtOAc, concentrated, purified by flash chromatography using EtOAc/heptane, 35 65, and the product isolated after re-crystallization in 2-propanol/heptane. 

In order to control the concentration of lower dibasic acid by-products in the system, a portion of the mother liquor stream is diverted to a purge treatment process. Following removal of nitric acid by distillation (Fig. 3, K), copper and vanadium catalyst are recovered by ion-exchange treatment (Fig. 3, N). This area of the process has received considerable attention in recent years as companies strive to improve efficiency and reduce waste. Patents have appeared describing addition of S02 to improve ion-exchange recovery of vanadium (111), improved separation of glutaiic and succinic acids by dehydration and distillation of anhydrides (112), formation of imides (113), improved nitric acid removal prior to dibasic acid recovery (114), and other claims (115). 

A suitable protein derivative is dissolved in 5.0 M guanidine hydrochloride at pH 8.0, and solid succinic anhydride (50 moles/mole of amino group) is added in small portions to a rapidly stirred solution at room temperature. The pH is maintained (by means of a pH-stat) by the addition of M NaOH. When the addition of succinic anhydride is complete, solid hydroxylamine hydrochloride is added to the reaction mixture to a concentration of 1 M, the pH is adjusted to 10 with NaOH and the mixture allowed to stand at room temperature for... 

It was decided that the most efficient method of identification was to couple succinic anhydride with the drug substance and isolate the peak of interest by preparative-scale HPLC. A solution of the drug substance was treated with dimethylaminopyridine and succinic anhydride. The resultant solution was stirred at room temperature for 48 hours. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was then treated with IN HC1. The two layers were shaken well, and the aqueous layer was removed. The organic layer was then washed with water, saturated sodium chloride solution, dried with magnesium sulfate, and concentrated by evaporation to afford a clear colorless oil (1.81 g). A suitable preparative HPLC method using a volatile mobile phase of 0.1% formic acid in water/ methanol was developed, and the crude reaction mixture was purified by preparative-scale HPLC. The solution was concentrated by evaporation and the water was removed from this solution by freeze-drying to afford a white lyophilate (40 mg). 

In a 2-1. three-necked, round-bottomed flask fitted with a mechanical stirrer and two reflux condensers are placed 68 g. (0.68 mole) of succinic anhydride (Org. Syn. 12, 66) and 350 g. (4.5 moles) of dry, thiophene-free benzene (Note i). The stirrer is started and 200 g. (1.5 moles) of powdered, anhydrous aluminum chloride is added all at once. Hydrogen chloride is evolved and the mixture becomes hot (Note 2). It is heated in an oil bath and refluxed, with continued stirring, for half an hour (Note 3). The flask is then surrounded by cold water, and 300 cc. of water is slowly added from a dropping fimnel inserted in the top of one of the condensers. The excess benzene is removed by steam distillation, and the hot solution is at once poured into a 2-1. beaker. After the mixture is cold the liquid is decanted from the precipitated solid and acidified with concentrated hydrochloric acid (about 20 cJs is required) 5 to 15 g. of benzoylpro-pionic acid separates and is filtered off (Note 4). The residual suspension in tl e beaker is. boiled for five hours with 1500 cc. of water containing 360 g. of commercial soda ash the resulting solution is filtered with suction, the filter cake washed with hot water, and the filtrate acidified with concentrated hydrochloric acid (about 300 cc.). The precipitated benzoylpropionic acid is filtered and washed with hot water after dr3dng for a day it weighs 95-100 g. (77-82 per cent of the theoretical amount) and... 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

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