Purified intermediates

The purified intermediate melted at 210°C. 70.9 g (0.10 mol) of the intermediate was dissolved in 150 ml dimethyl acetamide, and 15 g (0.08 mol) tributylamine was added. The mixture was heated to 50°C, and 56.6 g (0.62 mol) 1,3-dihydroxyisopropylamine (2-amino-1,3-pro-panediol) dissolved in 80 ml dimethylacetamide was added drop by drop. The reaction went to completion within a few hours, and the reaction mixture was evaporated to dryness in a vacuum. The oily residue was added to 350 ml methylene chloride with vigorous agitation, and the resuiting precipitate was filtered off and purified by repeated suspension of warm methyiene chioride. 

The Amb a 1 concentration of the final purified intermediate bulk is determined by an absorbance method chosen for its precision, accuracy, and simplicity. Because Amb a 1 bulk intermediate will now be conjugated to 1018 ISS (and the number of linked 1018 ISS affects the activity of the resulting AIC), it is essential to quantitate the Amb a 1 concentration accurately and precisely. A significant over- or underestimation of protein concentration will result in an over- or underestimation of the heterobifunctional linker required to activate the protein for coupling to 1018 ISS. The absorbance method, more dependent on well-calibrated instrumentation than lab technique, was chosen because it is an easy procedure to transfer to the production site. Dilution skills are the only requirement for robust performance of a well-developed and validated absorbance method. Hence a contract manufacturing site could readily quantitate Amb a 1 without the... 

Chemical synthesis can include chlorination, alkylation, nitration, and many other substitution reactions. Separation processes include filtration, decantation, extraction, and centrifugation. Recovery and purification are used to reclaim solvents or excess reactants as well as to purify intermediates and final products. Evaporation and distillation are common recovery and purification processes. Product finishing may involve blending, dilution, pelletizing, packaging, and canning. Examples of production facilities for three groups of pesticides foUow. 

The synthesis of thiophenol 326 according to equation 78 is assumed to proceed via an intermediate organolithium compound 325. There is a warning against trying to purify intermediate 325 and similar metallated compounds due to a danger of explosion . ... 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates are obtained in >10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone. Further optimization of the stereoselectivity was obtained by choice of the silyl substituents. The purified intermediates were then converted to the juvabione stereoisomers. 

Polymer-assisted methodology has been used several times for parallel-array synthesis of libraries involving three to five synthetic steps. Scheme 11 shows a three-step solution-phase synthesis of 2-thioxo-4-dihydro-pyrimid-inones wherein the key purification step involved amine resin 1 to sequester excess aldehydes and isot,hiocyanates from upstream transformations. Thermal cyclization of the purified intermediates gave the desired 2-thioxo-4-dihydropyrimidinones in excellent yields and purities.83... 

A 124 g portion of the above intermediate was added in small portions to 930 g of polyphosphoric acid at 85°C. The temperature rose to 95°C during the addition, and the mixture was stirred at 90°C for 30 minutes after the addition was complete, and was then stirred an additional 45 minutes while it cooled without external heating. One liter of crushed ice was then added to the mixture, and an external ice bath was applied to control the temperature while the ice melted and diluted the acid. 500 ml of additional water was added, and the light pink precipitate was filtered off and washed, first with water and then with methanol. The solids were dried under vacuum at 40°C to obtain 119 g of crude 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene. The crude product was slurried in hot methanol, filtered, and washed with cold methanol, and the solids were recrystallized from 4 liters of ethyl acetate, filtered, washed with hexane and dried to obtain 68 g of purified intermediate product, m.p. 187°-190.5°C. 

In the synthesis of a compound library of allosteric Akt kinase inhibitors 39, Lindsley and coworkers employed different HTS techniques (Scheme 24) [54]. A polymer-supported base and a fluorous thiol scavenger were used in the alkylation reaction of 40. F-SPE purified intermediate was then used for microwave-assisted cycloaddition of 41. Similar intermediates have been used for generation of an unnatural canthine alkaloid library 42 by performing cycloaddition reactions with an indo-tethered acyl hy-drazide [55]. 

We routinely purify intermediates and products, when applicable, by low temperature crystallization from pentane or hexane, using a vacuum-jacketed glass filter similar to the one described by Schlenk (8). Quantities of material ranging from one gram to several hundred grams can be conveniently and efficiently purified by this method. 

A flask was charged with the eatalyst from Step 2 (42 mg) and 1 ml diethyl ether. 1,2-Meso cyclopentane epoxide (0.060 mmol) was added and the mixture stirred 15 minutes at which time trimethylsilylazide (3.15 mmol) was added and the mixture stirred an addition 28 hours. Thereafter, the solution was concentrated and the residue filtered through a 10 ml plug of silica gel with 5% to 20% EtOAc/hexanes mixture. Desilylation was performed by dissolving the purified intermediate into 5 ml methyl alcohol to which was added (lS)-(+)-10-camphorsulfonic acid (0.15 mmol), the mixture stirred 30 minutes, purified by flash chromatography, and the product isolated in 80% yield, 94% ee. 

FD C dyes Today, FD C dyes are synthetic organic molecules produced from highly purified intermediates derived from petrochemicals and other sources. The stigma of the association of FD C dyes with coal tar no longer exists because of these starting materials. They are marketed in a number of physical forms, such as powder, granular, pastes, liquids, and dispersions. Many of these forms are customized for specific uses and are selected by the user for their particular application. 

Supplies of purified intermediate, 2) loading capacity of the column, 3) size of column and cost of packing. 

Naturally, the above method of integrating the chemical reaction and purifica-hon, through electrophoretic separation, could be applied to a range of other reactions that have been performed within EOF pumped devices [29-33], However, when conduchng mulhstep reactions it needs to be determined if it is necessary to sequenhaUy purify intermediates as they are formed or whether it is possible to simply purify the product at the end of the reaction sequence. 

However, a critical view on flow systems reveals that various difficulties have to be considered. The realization of reaction sequences by flow-through processes is hampered by (a) limitations in the maximum number of sequential reaction steps, (b) inert properties of all materials toward a large variety of different organic solvents, (c) the necessity to switch the solvent for selected reaction steps, (d) efficient regeneration of reaction columns, and (e) facilities to purify intermediates. In addition, the reaction times for transformation should... 

Furthermore, reductive amination of fiiranose aldehydes 63 with secondary amines 68 yielded tertiary amines 69. Here, after removal of borates with Amberlite lRA-743, polymer-supported isocyanate scavenged out excess amine. The resulting acetonides 69 were treated with alcohols 70 in the presence of acid to yield mixed acetals 71. A final treatment with polymer-supported piperidine removed trace amounts of acid and ensured long-term stability of acetals 71. These library syntheses highlighted the use of functionalized scavenger resins to purify intermediates and products. 

---