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Diastereomeric salts, crystallization

At present moment, no generally feasible method exists for the large-scale production of optically pure products. Although for the separation of virtually every racemic mixture an analytical method is available (gas chromatography, liquid chromatography or capillary electrophoresis), this is not the case for the separation of racemic mixtures on an industrial scale. The most widely applied method for the separation of racemic mixtures is diastereomeric salt crystallization [1]. However, this usually requires many steps, making the process complicated and inducing considerable losses of valuable product. In order to avoid the problems associated with diastereomeric salt crystallization, membrane-based processes may be considered as a viable alternative. [Pg.126]

The three most interesting routes identified between 1990 and 1995 are compared in Table 12.2 in terms of manufacturing costs, investment, environmental impact, and complexity. Although chiral chromatography is relatively complex compared to diastereomeric salt crystallization or synthesis from a chiral precursor, these figures are clearly in favor of the MCC process, mainly because of manufacturing costs and environmental impact. [Pg.264]

Sakai, K. (1999) Application of habit modification of diastereomeric salt crystals obtained from optical resolution via crystallization manufacture of enantiomerically pure 1-phenylethylamine,./. Org. Synth. Chem. Jpn, 57, 458-465. [Pg.190]

As described in this chapter, it is useful to study the crystal structures of diastereomeric salt crystals, which precipitate upon resolution, for understanding the chiral discrimination mechanism of the diastereomeric resolution in a molecular level. The authors studies on the crystal structures described... [Pg.259]

Naphfhylglycolic acid was also effective for the enantioseparation of a wide variety of p-substituted 1-phenylethylamine derivatives (Table 5.5) [13]. Figure 5.11 shows the typical crystal structures of a pair of the diastereomeric salts. The crystal structures are quite similar to each other, suggesting that another factor is contributing to the stabilization of the diastereomeric salt crystals odier than hydrogenbonding and van der Waals interactions. Precise examination of the crystal struc-... [Pg.137]

Thus, there are three factors for the stabilization of diastereomeric salt crystals... [Pg.138]

No crystal was obtained from solutions of tert-butyl methyl ether (MTBE) and MTBE-EtOH, which were favorable solvents for the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-inandelic acid, or from other organic solvents, such as 2-butanol, ethyl acetate, ethyl methyl ketone and diethyl ether. In sharp contrast, fine crystals with acceptable diastereomeric purity (75%) deposited, when water was used as a solvent, although the yield was rather low (20%). The spectral and elemental analyses revealed that the salt crystallized from water was mono hydra ted the water molecules stabilizing the less-soluble diastereomeric salt crystal as a result of the close molecular packing with the amine and acid molecules. [Pg.144]

In order to improve the resolution efficiency, i. e. to increase the yield of the less-soluble three-component diastereomeric salt without any deterioration in the diastereomeric purity, the effect of water in ethanol was examined for a range of 2-75% (w/w) water contents. Table 5.10 shows that the enantiomeric excess of the amine recovered from the less-soluble diastereomeric salt increased and then decreased with decreasing water content, until finally no crystal was obtained. This result indicates that the presence of water in a solvent is essential for the formation of the less-soluble diastereomeric salt and that the three-component salt could possibly deposit in a larger quantity from a solvent less polar than ethanol. On the basis of this consideration, less polar alcohols were used as solvents in the presence of a small amount of water (Table 5.11). When 2-butanol containing two moles of water was used as a solvent, the highest resolution efficiency was achieved. The diastereomeric salt crystals, obtained in all the systems shown in Table 5.11, contained an equimolar amount of water as a component. These results obviously show that water plays a very important role in the formation of stable diastereomeric salt crystals with satisfactory diastereomeric purity. The recrystaUization of the crude salt once from aqueous 2-butanol gave the diastereomeric three-component salt with diastereomeric purity of more than 95 %. The final product (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol with more than 99.5% ee was obtained upon treatment of the recrystaUized salt with aqueous sodium hydroxide, followed by extraction with 2-butanol and crystallization from toluene [21]. [Pg.144]

A particularly important application is in the synthesis of diltiazem, for which two routes have been proposed. The original route developed by Tanabe (see Sheldon, 1996) involving late resolution via diastereomeric salt crystallization... [Pg.256]

The resolution of mandelic acid by way of its diastereomeric salts with the natural chiral base cinchonine is illustrated in Figure 3.9. Racemic mandelic acid and optically pure (+)-cinchonine (Cin) are dissolved in boiling water, giving a solution of a pair of diastereomeric salts. Diastereomers have different solubilities, and when the solution cools, the less soluble diastereomeric salt crystallizes. This salt is collected and purified by further recrystallization. The filtrates, richer in the more soluble diastereomeric salt, are concentrated to give this salt, which is also purified by further recrystallization. The purified diastereomeric salts are treated with aqueous HCl to precipitate the nearly pure enantiomers of mandelic acid. Cinchonine remains in the aqueous solution as its water-soluble hydrochloride salt. [Pg.178]

SCHEME 56.1. Production of enantiopure (S)- +)-5, a key intermediate of aprepitant (Emend), via diastereomeric salt crystallization. [Pg.1670]

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. [Pg.57]

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. [Pg.152]

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. [Pg.57]

Since the enantiomers of the carboxylic acid 42-H can easily be separated via its diastereomeric salts (Scheme 10) [59], many of the other bicyclopropylidene derivatives can also be obtained in enantiomerically pure form by transformations of the acids (R)- and (S)-42-H. The absolute configuration of (i )-42-H was proved by an X-ray crystal structure analysis of its (f )-a-phenylethylamide [59]. [Pg.100]

The first S3mtheses of optically active p-BL involves more step sequences, including fractional crystallization of the diastereomeric salts formed from (f ,5)-p-bromobutyiic acid and (/ )-a-phenylethylamine. Ring-closure to respective lactones was achieved by infernal Sa 2 attack of the neighboring carboxylate anion on the sam-rated carbon to yield samples of the desired stereochemistry up to an enantiomeric... [Pg.80]

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). [Pg.93]

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. [Pg.143]


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