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kilomentor | 16 February, 2007 07:22
The particular process development strategy of kilomentor emphasizes using non-traditional reversible derivatization to enable simple isolation of as many functional group classes at-scale as possible.
Kilomentor has already emphasized the importance of process intermediates that reversibly form salts such as carboxylic acids and amines, and has recommended the preparation of O-sulfates from alcohols, phenols and some amines. Herein Kilomentor will discuss what is known about the formation of inorganic non-Stoichiometric metal salt complexes with substances comprising a wide variety of neutral functional groups.
The only citation in the chemical literature, which points at the scope of this method, is the patent family of which US452988 is a member. The patent titled, Process for the Isolation of Organic Compounds and Lithium Salt Complexes useful in such Processes, lists alcohols, phenols, enols, amides, imides, carboxylic acids, primary and secondary amines having a pKa in water o at least 10-10 and sulfoxides as suitable for the method. Using the particular salts lithium perchlorate or lithium tetrafluoroborate the same methodology is disclosed to complex aldehydes and ketones. For our present purpose separation of amides, imides, stable enols and sulfoxides stand out in importance because few other reversible derivatives are available for isolation and purification. Although not disclosed or claimed, it would seem that sulfonamides might also work in the method.
One of the only non-patent references to this methodology is K. Barry Sharpless, Anthony O. Chung and James B. Scott’s paper, Rapid Separation of Organic Mixtures by Formation of Metal Complexes in J. Org. Chem. 40(9) 1252-1257 (1978). Sharpless teaches the use principally of calcium or manganese chloride complexes to separate mixtures of alcohols and to separate alcohols from non-alcohols. Although the paper was much commented on at the publication time very few citations of it in subsequent particular applications have emerged. It may be that anhydrous calcium and manganese chlorides are not so generally applicable as originally proposed. On the basis of everything that has been reported up to the present it would seem that the preferred regents are lithium and calcium bromide.
Literature published before these aforementioned contained examples, which limited the methodology to 3- hydroxy and 3-keto steroids. In GB 1555968, the authors used calcium bromide exclusively and taught the solvents- methyl isobutyl ketone (MIBK) or 5-methyl-2-hexanone (methyl isoamyl ketone, MIAK). This literature appears to teach:
Both MIBK and MIAK have useful binary azeotropes with water. MIAK has an azeotrope bp 94.7 C which is 37% by volume water and which separates into clean phases on cooling. MIBK has bp 87.9 C and removes 19.6% by volume of water and separates on cooling.
Besides the pharmaceutical application purifying prostaglandin intermediates in US 4529811, the only other particular application is in the isolation of finasteride without making any of the patented polymorphic forms. This is found in CA 2389666 for example.
In addition to the functional groups already mentioned there is some evidence that these complexes can be used for the isolation of phosphine oxides. Chem. Soc. (A) Inorg. Phys, Theor. 1968 449-450 where an adduct LiBr.4 Ph3PO is reported in Table 1 of that article. Since phosphine oxides are good Lewis bases this seems likely to be general.
Another salt which is likely to form complexes with alcohols in nickel (II) bromide. In the Kilomentor article discussing oxidizing reagents there is a reference to the use of nickel (II) bromide which states that alcohols form strong metal complexes and that this is the reason that primary alcohols are converted cleanly to acids rather than giving ester by-products; the alcohol substrate is bound strongly and is not freely available for making esters.
In addition there are many patents discussing complexes of phenols with inorganic salts for separation of complex mixtures of phenols, but such separations are not so interesting because dissociative extraction technology seems so much simpler and predictable for such tasks. For interest I list some pertinent patents:
Leston, US4423253; Burkholder, US 4420376; Leston, US 4424381; Leston, US 4267389; Davis et al. US 3981929.
Leston and Lauritzen also used inorganic complexes to separate mixtures of amines. This is referred to in the May 27, 1985 issue of Chemistry & Engineering News on pg. 60 where the Miami Beach ACS Meeting is reported.
There is a particular application of inorganic salt complexes to the isolation of polyalkyene polyamines in US 3755447.
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