Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/04—Solvent extraction of solutions which are liquid
  • B01D11/0492—Applications, solvents used
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
  • C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
  • C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
  • C07C37/72—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by liquid-liquid treatment
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/42—Separation; Purification; Stabilisation; Use of additives
  • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment

Definitions

• the present application relates to the fractionation of cashew nut shell liquid (CNSL).
• 3- Alkenyl salicylic acids (1) also called gingkolic acids or anacardic acids
• 3-alkenylresorcinols (2) also called resorcinolic lipids or bilobols or cardols
• Anacardic acids inhibit prostaglandin synthase (Kubo, I., Chem. Letters, 1987, 1101-1104), glycerol-3 -phosphate dehydrogenase (the inhibition of this enzyme is related with prevention of triglyceride accumulation in cells) (Rejman,J., Kozubek,A., Cell Mol. Biol. Lett., 1997, 2, 4, 411-419), glucosidase and invertase (Toyomizu M., Sugiyama S., Jin RL, Nakatsu T., Phytotherapy Research, 1993, 7, 3, 252-254), tyrosinase (Kubo, I.
• Anacardic acids show bactericide activity against Bacillus subtilis, Escheria coli, Streptococcus mutans (the bacteria responsible for tooth decay), Propionibacterium acnes (the bacteria responsible for acne) (Kubo I, Muroi, H., Hijema M., J. Agric. Food. Chem., 1993, 41, 1016-1021), Helicobacter pilori (Kubo, J, Lee R.J., Kubo, I., J. Agric.
• anacardic acid shows an activity similar to fluazinam, a commercial fungicide.(Begum, P., Hashidoko,Y., Islam M.T., Ogawa,Y., Tahara,S., Z. Naturforsch, 2002, 57, 874-882.).
• Anacardic acids have been considered as the main cause of the resistance to aphids, spiders and small pests of pest resistant geraniums (Schultz D.J., Medford J.I.,Cox-Foster D., Grazzini R.A., Craig R., Mumma R.O., Advances in Botanical Research Incorporating Adassembles in Plant Pathology, 2000, 31 : 175-192).
• Anacardic acids also exhibit an uncoupling effect on oxidative phosphorylation of rat liver mitochondria' (Toyomizu, M, Okamoto, K., Teru I., Chen Z., Nakatsu T., Life Sciences, 2000, 66, 3,229-234), inhibit ⁇ -lactamase, (Hird NW, Milner PH, Bioorganic and Medicinal Chemistry Letters, 1994, 4, 12, 1423-1428) and the tissue factor (TF) Vila complex (Dandam W., Girard,T.J., Kasten T..P., LaChance, R.M., Miller- Wideman, M.A. Durley R., J.Nat.Prod., 1998, 61, 1352-1355).
• TF tissue factor
• Cardols have been detected recently in plants as active ingredients with cytotoxic activity (Lee J.S., Cho, Y.S., Eu J.P., Jinwoong ., Oh, W.K., Lee H.S., Ahn, J.S., J. Nat. Prod, 1998, 61, 867-871) anti-tuberculosis (Sun, W.Y.S., Zong Q, Gu RL, Pan BC Natural Product Letters, 1998, 11, 193-200) and cardiological (Roufogalis BD, Li Q, Tran VH, Kable EPW, Duke CC, Drug dev. Res. , 1999, 46, 3-4, 235-249) related properties.
• Anacardic acid has reported activity as a potentiator of penicillin, (US5776919); in the prevention or treatment of coccidiosis (US5725894); and as an anti-obesity and fat reducing agent (US5240962).
• Cardols have been shown to lower intra-occular pressure (US4083868) and as anti- obesity and fat reducing agents (US 5240962). Cardol (15:0) is 100 times more active than diethylcarbamazine, a drug commonly used against worms. (Suresh, M., Ray, R.K., Curr. Set, 1990, 59, 477-479). Cardols (with a 13 carbon chain) have been isolated as the active ingredient in a medicinal Chinese plant which demonstrated 80% efficiency in tuberculosis treatment. The syrup of this plant is commercial in the USA (Sun W.Y., Natural Product Letters, 1998, 11,193-200. Gonzalez, MJ.T.G., DeOliveira, C.J.C., Fernandez, J.O., Kijoa, A., Herz W., Phytochemistry, 1996, 43, 1333- 1336).
• anacardic acids and cardols have been found in a number of botanical families, anacardic acids have been found in Anacardiaceae, Ginkgoaceae, and Myristiceae (Jones TH, Brunner SR, Edwards AA, et al., J. Chem., Ecology 2005, 31, 2, 407-417), while cardols have been found in Gramineae, Primulaceae, Iridaceae, Compositae, Leguminoseae, Anacardiaceae, Ginkgoaceae, and others (Kozubek, A., Tyman, JPH, Chem.Rev., 1999, 1, 1-29). However the major botanical source of this chemicals is the cashew tree (Anacardium occidentale Linn).
• the cashew is a tree originally from the Amazon. Historically, the cashew tree was commonly cultivated by the Indians from the rain forest; the Portuguese took the tree to India, Eastern Africa, and others countries. The cashew tree produces very peculiar apples (a swollen peduncle that gives a sweet flavourful j uice). At the end of this peduncle, the cashew nut grows externally in its own grey coloured kidney shaped hard shell, which is 2.5-4 cm long. This shell (about 0.3 cm thick) has a soft leathery outer skin and a thin hard inner skin. Between these skins is a honeycomb structure containing a liquid called the cashew nut shell liquid.
• the nuts consist of the kernel (20-25%), the shell liquid (20-25%), and the testa (2%), the rest being the shell.
• the kernel is presently the more valuable product from the cashew factories: the cashew nut shell liquid is a by-product looked on mainly as a waste.
• cashew nuts it is not possible to use straightforward nut-cracking techniques to recover the kernel and extract the shell liquid, therefore more specialised processes have been introduced.
• the most popular is the so-called 'hot-bath method'. The principle is to soften the outer shell, by immersion in water at 22-25°C, treatment with steam to open the pores, followed by heating in a bath of hot (180 °C) CNSL itself for 1.5-4 min.
• Natural CNSL is the liquid as it exists in the plant and technical CNSL is the liquid obtained in factories that use the hot-bath oil process of extraction.
• a) refers to methylcardol and cardol
• b) Most of these compounds are reported to be non-volatile, and are assumed to be polymeric.
• Table 1 and in the formulae shown below the main constituents of CNSL are anacardic acid (formula 1), cardanol (formula 2) and cardol (formula 3).
• Anacardic acid is a salicylic acid, while cardanol and cardol are substituted phenols.
• the heat treatment carried out during the processing of cashew nuts to obtain the kernels results in the decarboxylation of the anacardic acid:
• Figure 5 shows a typical proton NMR spectrum for technical CNSL.
• Signals labelled “1” correspond to the aromatic protons of cardanols, and the signal “5" to both cardols and methylcardols, which are minor compounds in the oil.
• the signals corresponding to the protons of the terminal vinyl groups are “2" and “4".
• Signal “3” represents the hydrogens of the internal alkenes.
• Signal “7” corresponds to the benzylic protons of cardanols, and the small shoulder labelled as “8” to the benzylic protons of cardols and methylcardols.
• FIG. 6 A typical the HNMR of Indian cashew nuts obtained by Petrol soxlhet extraction is shown in Fig. 6.
• Signals labelled “1", “2” and “3” correspond to the aromatic protons of the anacardic acids, "4" to all cardols protons.
• the remaining signals are also in the technical CNSL HNMR and correspond to the terminal vinyl groups, the internal alkenes, the benzylic protons, protons a to two double bonds, a to one double bond, a to the benzylic protons, to the remaining hydrogen in the carbon chain, and to the terminal methyl groups.
• Liquid-liquid extractions of phenols from industrial effluents are currently performed on a large scale.
• this technique uses the selective partitioning of the main constituents of technical and/or natural CNSL between a non-aqueous, non-polar solvent like petrol and an insoluble non-aqueous polar solvent (like ethylene glycol, propanediol, etc.).
• a non-aqueous, non-polar solvent like petrol
• an insoluble non-aqueous polar solvent like ethylene glycol, propanediol, etc.
• a fraction of the cardanols remains in the non-polar solvent while the remainder, with all the cardols, migrates to the polar solvent.
• anacardic acid remains in the non-polar layer and cardol migrates to the polar one.
• Ethyl acetate is a non-selective modifier (some cardols migrate to the non-polar layer); selective modifiers must be immiscible in the non-polar phase.
• the literature procedure washed this layer with dilute sodium hydroxide. This led to losses in the aqueous layer.
• To recover the cardols from the polar layer a new approach was to extract it from the methanol-ammonia layer with ethyl acetate. It was claimed that it was possible to obtain cardols (100 % purity by HPLC), in high yield.
• Cardanols and cardols have been extracted from CNSL by supercritical extraction with carbon dioxide using propanol as co-solvent. Due to the high pressure involved this process is not inexpensive, although in some circumstances the elevated cost may be justified on the grounds of the high potential value of cardols (JP 0500979). vi) Fractional crystallization
• Natural CNSL i Extraction of anacardic acid by treatment of natural CNSL with a base
• JP 8217720 uses liquid-liquid extraction with a petrol-diol solvent system to separate anacardic acid from natural CNSL. Reported anacardic acid recovery varies between 8- 14%. iv) Use of supercritical extraction
• the present invention has been made from a consideration of these drawbacks, and provides a technically and economically useful solvent-solvent extraction method for the separation of CNSL.
• a method for the fractionation of cashew nut shell liquid comprising solvent-solvent extraction using a polar solvent component and a non-polar, non-acidic, non-basic solvent component; wherein the polar solvent component is a mixture comprising:
• a second solvent comprising a solvent satisfying the following parameters:
• This aspect of the present invention provides a solvent-solvent extraction method by which anacardic acid and cardol can be separated and obtained from natural CNSL, and cardanol and cardol can be separated from technical CNSL.
• the prior art solvent-solvent procedures either imply too great a number of extraction-re-extractions, or were not reproducible. It has now been found that solvent-solvent extraction using the mixture of solvents in accordance with this aspect of the present invention provides a feasible separation of CNSL, with relatively easy, relatively low-cost solvent recovery.
• this aspect of the present invention may also be considered a method of production of anacardic acid and/or cardol from CNSL, or a method of production of cardanol and/or cardol from technical CNSL.
• the components may be obtained in excellent purity, and have a number of uses, including use as intermediates in synthetic processes for making complex structures based on anacardic acid or cardols skeletons.
• the selectivity (measured as a ratio between the concentration of the two compounds to be separated in the extract-rich phase);
• the capacity (measured as a ratio of the solute concentration between the raffmate and the extract phase);
• fluorinated solvents provide high selectivity to cardol, but very low capacity.
• the capacity of these fluorinated solvents can be increased by the addition of the second solvent in the mixture.
• the solvent mixture of the first and second solvents provides a polar solvent component for use in conjunction with a non- polar solvent component in the solvent-solvent extraction procedure.
• the non-polar solvent component typically comprises a non-polar, non-acidic, non basic solvent.
• the second solvent is selected on the basis of its Hildebrand parameter ( ⁇ ) being greater than 10 (kcal dm -3 ) 0,5 .
• Hildebrand parameter ( ⁇ ) being greater than 10 (kcal dm -3 ) 0,5 .
• a comprehensive collection of Hildebrand parameters may be obtained from the literature (Kamlet M. J., Carr P. W., Taft R.W., Abraham M. H., Journal of American Chemical Society, 1981, 103, 6062-6066; Par J. H., Lee Y. K., Cha J. S., Kim S. K., Lee Y. R., Lee C.-S., Carr P. W., Microchemical Journal, 2005, 80, 183- 188; Barton A. F. M., Chemical Reviews, 1975, 75, 731).
• the dipolarity/polarizability ( ⁇ ) measures the ability of the solvent to stabilize a charge or a dipole by virtue of its dielectric effect. Values of ( ⁇ ) for solvents with a single dominant moment dipole have been shown to be proportional to dielectric constant and the refractive index.
• Hydrogen bond acidity (a) describes the ability of the solvent to donate a proton to solute.
• Hydrogen bond basicity ( ⁇ ) provides a measure of the solvent's ability to accept a proton.
• a second aspect of the present invention provides a solvent mixture for use in the fractionation of cashew nut shell liquid by solvent-solvent extraction, wherein the solvent mixture comprises:
• a second solvent comprising a solvent satisfying the following parameters:
• a third aspect of the present invention provides the use of a solvent mixture in the fractionation of cashew nut shell liquid by solvent-solvent extraction, wherein the solvent mixture comprises:
• a first solvent comprising a fluorinated solvent
• a second solvent comprising a solvent satisfying the following parameters: a) Hiidebrand parameter greater than 10 (kcal dm -3 ) 0'5 ; and
• the solvent mixture of the first and second solvents provides a polar solvent component for use in conjunction with a non-polar solvent component in the solvent- solvent extraction procedure.
• the non-polar solvent component typically comprises a non- polar, non-acidic, non basic solvent.
• this comprises a fluorinated solvent.
• the fluorinated solvent include fluoroalcohols, fluoroamines and nitrofluorinated solvents, including, e.g., trifluoroethanol, fluorophenols, fluroxene, enflurane, isoflurane, methoxyflurane or hexafluoro-2-propanol, or any combination thereof.
• the first solvent comprises trifluoroethanol (TFE). It has been found that TFE has high selectivity but low capacity, the capacity of the solvent mixture being improved by the second solvent.
• TFE trifluoroethanol
• this comprises a solvent with a Hildebrand parameter greater than 10 (kcal dm -3 ) 0'5 .
• This parameter is a measure of the energy needed to separate two molecules of solvent. Solvents with such a low parameter solubilize the other solvents present in the mixture and both anacardic acid and cardols.
• the values of the dipolarity/polarizability ( ⁇ ), hydrogen bond acidity (a) and hydrogen bond basicity ( ⁇ ) are limited by the following mathematical relations: ⁇ /( ⁇ + ⁇ + ⁇ ) > 0.5; ⁇ /( ⁇ + ⁇ + ⁇ ) ⁇ 0.8; and ⁇ /( ⁇ + ⁇ + ⁇ ) > 0.3.
• Fig. 1 includes a number of non-limiting examples of suitable solvents.
• Preferred solvents include acetonitrile and nitromethane.
• the two-component polar solvent system selectively solubilises cardol.
• the non- polar solvent preferentially solubilises anacardic acid and cardanol.
• the non-polar solvent is not a necessary component of the mixture as the cardol will partition in the two-solvent system, itself immiscible with the remaining anacardic acid/cardanol milieu.
• the cashew nut shell liquid may comprise natural CNSL or technical CNSL, or any other corresponding oil extracted from the cashew shell by a range of methods (such as steam extraction, activated steam extraction, and other methods known in the art).
• the mixture of the first and second solvents may of course contain additional components useful in separation procedures, examples of which will be apparent to the skilled person, such as an anti-foam agents, rheological modifiers, etc.
• aspects of the present invention provide methods for obtaining a range of anacardic acids or cardol derivatives by selectively cleaving natural anacardic acids or cardols mixture at the C-8 double bond.
• any suitable method may be employed, as will be understood by the skilled person.
• the methods include co-current, counter-current, and one-step extractions. Counter-current extraction methods are preferred.
• the ratio of feed/solvent may vary, e.g. between around 0, 1 to around 50, and the temperature of extraction may vary, e.g. between around -25°C to around 70°C.
• the non-polar solvent component typically a non- polar, non-acidic, non-basic solvent
• the polar solvent mixture may be used in the absence of a non-polar solvent.
• the mixture of the first and second polar solvents may be used to selectively extract cardol from CNSL in the absence of a non- polar solvent.
• the non-polar solvent may be useful in industrial processes to reduce the viscosity of the CNSL mixture in the extraction column.
• the non-polar solvent may comprise any suitable solvent or mixture of solvents, including, e.g., aliphatic solvents, pentane, hexane, heptane, octane or other alkanes, isoalkanes, or a mixture of a range of chemical entities, such as petroleum ether.
• suitable solvent or mixture of solvents including, e.g., aliphatic solvents, pentane, hexane, heptane, octane or other alkanes, isoalkanes, or a mixture of a range of chemical entities, such as petroleum ether.
• impurities which may be present may flocculate when the solvent- solvent extraction is carried out.
• the impurities may be removed by filtration.
• one embodiment of the present invention provides a method of producing low viscosity CNSL from CNSL by solvent-solvent extraction to flocculate any impurities which may be present in the CNSL, and removing the flocculated impurities.
• the CNSL is technical CNSL.
• any impurities in the CNSL may be flocculated using the first solvent as hereinbefore described or the second solvent as hereinbefore described, or any mixture of the first and second solvents.
• the sovent-solvent extraction is carried out using a mixture of nitromethane or acetonitrile with petrol.
• the solvents may be removed by, e.g., vacuum distillation.
• Scheme 1 relates to the separation of cardol and cardanol from a technical CNSL with high concentration of degradation products
• Scheme 2 relates to the separation of anacardic acid and cardol from natural CNSL.
• the standard approach to determine industrial feasibility of an extraction process is to determine as a function of equilibrium data and rate of feed/solvent the number of theoretical extraction column plates. This parameter is then used in empirical correlations provided by equipment manufacturers to estimate the real number of plates and therefore the dimensions of the extraction column. The technical feasibility may then be estimated, so, for instance, if the counter-current column is 50 m high it is not technically feasible.
• the present invention provides a technically feasible system for use in fractionation of CNSL.
• Experimental data show that a solvent mixture according to an aspect of the present invention may be used in a counter-current system to separate cardanols from cardols (obtaining cardanols pure, and cardols 87 %).
• a unit providing 3.75 kg/h cardols operating at a ratio of solvents petrol:TFE:ACN (10:5:0.25) would need to be 1.72 m high, and 0.27 m in diameter.
• An increase of capacity to 20 kg/h would correspond to a column of 2.4 m height and 0.6 m in diameter.
• HPLC analysis was carried out by taking an aliquot (25 mg) and adding 4-hexylresorcinol (5 mg) as internal standard. The mixture was dissolved in THF and filtered through a nylon Aldrich cartridge. The cartridge was eluted with further THF (3 x 3 ml), and the combined eluant was made up to 50 ml into a volumetric flask. TLC analysis of the extract of the cartridge with ether showed that no cardanol or cardol was retained. The solvent (acetonitrile- water-acetic acid (78:20:5) for 30 min followed by gradient elution with THF-water over an additional 30 min.) was pumped at 1 ml/min.
• the sample was introduced automatically, allowing 20 ⁇ analyte to be injected into a guard column before passing through a Phenomenex Luna HPLC column, 4.6 x 150 mm, packed with 5 ⁇ PhenylHexyl silica.
• the detector was set at 280 nm. Pure constituents of cardanols and cardols, and their hydrogenated congeners were obtained using the method described below.
• the relative response factor of cardanols to cardol was 1.09. For different CNSL samples the areas from the chromatograms are presented in Table 2:
• Natural CNSL was obtained by solvent extraction from shells of Indian and Kenyan cashew nuts .
• Cashew nuts from India were stored overnight in a freezer to make the shell brittle.
• the nuts were then bisected by light hammering with a knife along the junction of the halves of the shell.
• the internal kernel testa lining was then separated, and parts of the testa still in the shell were removed by knife/ and brushing.
• Cleaned shell (710 g) was powdered in a home coffee mill, and the ground shell was extracted by percolation over a column filled with the powdered shells, using successively dichloromethane (3 x 1 1), ethyl acetate (3 x 1 1), and methanol (3 1 1).
• the combined extracts were filtered on a celite/silicagel pad and evaporated to constant weight, under vacuum, at room temperature giving a reddish oil (174 g).
• Cardols (100 mg) were dissolved in methanol (3 ml) and ammonium hydroxide (2 ml). This solution was extracted with ethyl acetate (4x 2ml), to afford, after removal of the organic solvent, cardol, pure by HNMR, (45 mg).
• Natural CNSL (10.00 g) was injected to a separating funnel containing petrol (10 ml) and ACN (10 ml). Immediately after shaking, two liquid phases separated. After evaporation of the solvents, the petroleum layer gave a brown oil (1.93 g, 19 %) (anacardic acid by NMR), while the ACN layer gave also a brown oil (8.02 g, 80 %) (mixture of anacardic acid/cardol, ratio by NMR: 2.1 (mol/mol )).
• CNSL Bras (9100 mg) was partitioned in a two-phase system (petrol (100 ml), TFE (100 ml) and ACN (5 ml)).
• the petrol layer gave, after removing the solvent, an oil fraction (5621 mg), which was removed, as well as the flocculated solid (2010 mg) (with traces of solvent).
• the TFE-ACN layer was also evaporated to give an oil (1560 mg). An aliquot of the polar layer was removed for HPLC characterization, and the remainder was dissolved in TFE-ACN. This layer was re-extracted with same volume of petrol, and after removing the solvents, both fractions were weighed. HPLC analysis was performed using the same methodology for technical CNSL analysis previously described.
• Natural CNSL (8750 mg), was partitioned in a two-phase system (petrol (100 ml), TFE (100 ml) and ACN (5 ml)), to afford a petroleum layer (7030 mg) and a TFE- ACN layer (1681 mg). An aliquot of the polar layer was removed for 1 HNMR, and HPLC (see Table 13). HPLC analysis was performed using the same methodology as for natural CNSL analysis hereinbefore described.
• CNSL (1 g) was also submitted to the same procedure and provided (640 mg) of a mixture of cardanols-cardols and 320 mg of a black solid. Treated CNSL gave U tube viscosity of 73.1 cps. The NMR spectrum of the resinous black flocculate was broad, and its MS-EI and IR spectra were similar to those of crude CNSL.

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