The way to obtain (6r,10r)-6,10,14-trimethylpentene-2-it (fiona)

 

(57) Abstract:

The invention relates to the field of synthesis of terpenoid ketones, and in particular to an improved method of obtaining Fiona, which can be used in the synthesis of vitamins E and K. the method consists in the extraction of leaves of nettle (urtica dioica) with acetone, followed by ozonolysis of the resulting extract in aqueous acetone by passing it of ozone-oxygen mixture in the presence of barium hydroxide. After that, the precipitate is filtered off, the filtrate evaporated and the residue chromatographic, elwira a mixture of hexane-ethyl acetate. The method avoids the time-consuming operations hydrolysis of chlorophyll, separation and purification of the phytyl side-chain. The product is obtained with a yield of 20%.

The invention relates to the field of synthesis of terpenoid ketones, specifically - 6,10,14-trimethylpentene-2-it (Fitna).

Fitton is a key synthon for vitamins E and K [C. M. Berezovsky, "the Chemistry of vitamins) Food industry, 1973, S. 223-249, 278-282]. This natural compound included in the composition of essential oils isolated from different plant species [Ueyama Yoshitaka, Seiji Hashimoto, Nii Hiromichi, Kiyoshi Furukawa, "The chemical composition of the essential oil of Daphne genkwa Sieb. et Zucc", J. Essent Oil Res, 1990, 2(5), S. 247; C. A. (1991), 114, 127), S. 402. C. A. 1991, 114, 20978a; Sakagami Hatsuko, Iseda junkō, Fujimori Takane, Hara Yoshiki, Mitsuo Chihara, "Volatile constituents in marine green algae", Nippon Suisan Gakkaishi, 1991, 57(3), S. 527; C. A. 1991, 115, a].

Based on synthesized in racemic form of Fiona developed methods of producing practically valuable isoprenoid alcohols - phytyl side-chain and isophytol, condensation of which with trimethylhydroquinone get-tocopherol (vitamin E). [O. Isler, O. Wiss, "Vitamins Hormones", 1959, 17, c.53].

Optically active natural 6R,10R-fitton used in the synthesis of CIS-(7R, 11R)-phytyl side-chain and (7R,11R)-isophytol, which in turn is used to produce (7R', 11R')-fellaheen and (4R',8R')--tocopherol [Methods in Enzymology, vol. XVIII, Part C. Vitamins and Coenzymes. Academ. Press. New York. London, 1971, S. 492-497, 500-501].

6R,10R-fitton is also commonly used in the synthesis of analogues of tocopherol and vitamin K1[Sato K., Inoue, S., Momotari T., "Preparation of a-tocopherol homolog", JP 01233276 (1989); C. A. (1990), 112, P179519 g; Moto So, Masakazu S. , Yoshinori A. "Gidroksilirovanii aliphatic compounds m-chlormadinone acid. Synthesis gidroksietilirovanny analogues of vitamin K1". Bull. Chem. Soc. Jpn. (1985), 58, 2669].

The most known and practically important methods of obtaining racemic Fiona are based on the use of pseudonana (1), the serial of transformation 18the ketone (8) (scheme 1 at the end of the description) [R. Karrer, R. Ringier. Helv. Chim. Acta(1939), 22, 610].

More rational is the synthesis, according to which Pseudomonas 1 turns fitton 8 by condensation of the ketone 2 with acetylene and subsequent partial hydrogenation of the triple bond of acetylene alcohol 9 in the presence of Lindlar catalyst and further condensation of tertiary vinyl alcohol 10 with acetoacetic ether, giving the ketone 11, hydrogenation of which leads to the target compound 8 (scheme 2 at the end of the description) [O. Isler, L. H. Chopard-dit-Jean, A. Winterstein, O. Wiss, "Synthesis and isolation of vitamin K2and isoprenologous compaunds", Helv. Chim. Acta. 1958, 41, 786; R. U. Gloor, A. Langemann, M. Kofler, C. Von Planta, G. Ryser, O. Isler, "Die Totalsynthese von Solanesol". Helv. Chim. Acta 1960, 43, 1745; M. Maurit, T. C. Smirnova, E. A. Parfenov, I. K. Sarychev, N. A. Transfiguration, "total synthesis of 2,5,7,8-tetramethyl-2-(4',8',12'-trimethylacetyl)-6-oxirane (vitamin E-tocopherol) and its derivatives", DAN SSSR, 1961, 140, 1330; C. I. Gunnar, S. I. Zavialov, "a New synthesis of the phytyl side-chain", DAN USSR, 1960, 132, 829; I. K. Sarychev, Y., Molotkovsky, G. A. Vorobyov, N. A. Transfiguration. GOH, 1959, 29, 1123].

The described methods have a number of serious disadvantages. They multistage and based on hard-to-source connection - pseudonana, which is obtained from digitalia, which synthesis is carried out using metal complex catalysts based on copper salts and palladium [G. Mignani, S. Chevalier, F. Grass, Q. Allmang, D. Morel, "Synthesis of new unsaturated enynes catalyzed by complexes of cu(1)". Those Les, 1990, 31(36), 5161; G. Mignani, F. Grass, M. Aubrang, D. Morel, "Synthesis of new unsaturated esters catalyzed by palladium-phosphine complexes". Those Le, 1989, 30(18), 2383]. However, these methods large preparative do not matter.

Optically active (6R,10R)-fitton or (6R,10R)-hexahydrophthalate (14) is obtained by ozonolysis of the phytyl side-chain (13), isolated from chlorophyll 12 plants - nettles, alfalfa, peppermint.

Method of obtaining of the phytyl side-chain 13, for example, from nettle (urtica dioica) is the extraction of chlorophyll 12 acetone from air-dried leaves of the herb in the composition of the lipid fraction with subsequent alkaline hydrolysis of ester groups and fatty chlorophylline acids, leading to the removal of the phytyl side-chain of chlorophyll. To clean the phytyl side-chain from the essential oils contained in the lipid fraction from the residue of sodium salts of fatty and chlorophyllins acids, as well as formed by alkaline saponification of the condensation products is the number of time-consuming operations: processing of unsaponifiable residue Pius at a residual pressure of ~10-3mm RT. Art. [A. A. Swischuk, B. G. Savinov, "Getting phytyl side-chain of chlorophyll of plants." Ukrain. chem. log. 1956, XXII, vol.4, 518]. Ozonolysis selected so the phytyl side-chain 13 is carried out in a solution of methylene chloride containing pyridine (at 0oC) or in methanol (-18oC) (scheme 3 at the end of the description). [N. Mowag, O. Isler. "Absolute configuration of natural-tocopherol". Helv. Chim. Acta, 1963, 46, 963; Moto Tori, Masakazu Sono, Yoshinori Asakawa. Gidroksilirovanii aliphatic compounds m-chlormadinone acid. Synthesis gidroksietilirovanny analogues of vitamin K1. Bull. Chem. Soc. Jpn., 1985, 58, 2660].

The disadvantage of this method is the most labor intensive operations hydrolysis of chlorophyll, separation and purification of the phytyl side-chain.

The goal of the proposed method to obtain 6R,10R-Fiona 14 is to avoid the time-consuming stages of isolation and purification of the phytyl side-chain 13 from 12 chlorophyll. This goal is achieved by ozonolysis solution of chlorophyll obtained by extraction of the leaves of plants such as nettle (urtica dioica), acetone (scheme 4 in the end of the description).

The invention consists in the extraction of the green leaves of plants, such as air-dried nettle leaves, acetone and subsequent ozonolysis receive the Noah temperature by passing an excess (~5 mol. EQ.) ozone-oxygen mixture in the calculation of chlorophyll (chlorophyll content in air-dried nettle leaves is ~1%). The precipitate compounds barium (BA(OH)2BA2ABOUT2) is filtered off, the filtrate is evaporated. The remainder chromatographic on a column with SiO2, elwira mixture (10:1) hexane-ethyl acetate, receive 6R,10R-fitton (9).

The invention is illustrated by the following example.

60 g of air-dried leaves of nettle (urtica dioica) is extracted in to conventional Soxhlet extractions with acetone (300 ml) chlorophyll (mixed with lipids) up until sponsorhouse extract will not lose dark green in color. The extract is evaporated, the residue (2.0 g) dissolved in 30 ml of acetone, added 8.6 g of BA(OH)2and 2 ml of N2O and passed at a rate of ~30 l/h of ozone-oxygen mixture at room temperature for 20 min (performance ozonator ~11 mmol/h). The precipitate is filtered off, washed with acetone (~ 30 ml), acetone evaporated in vacuo, the residue chromatographic on silica gel (20 g SiO2, eluent mixture (10:1) hexane-ethyl acetate) to give 0.12 g of Fitna (0.2% by weight of air-dried nettle leaves), the physical constants which are the same as described in the literature: nD221.4504 [D. McHall, P. Mamalis, J. Green, S. Mar-cinkie P. Schudel, O. Isler, "Absolute configuration of natural-tocopherol". Helv. Chim. Acta, 1963, 46, 963].

The IR spectrum of cm-1: 1720 (C=0); NMR Spectrum1N (, memorial plaques, J, Hz): 0.82, and 0.85 (s, N, CH3(C6), CH3(C10), CH3(C14), N(15)); 1.25 (m, N, CH2); 1.52 (m, 1H, H(6), N(10)); 2.10 (C. 1H, H(1)); 2.38 (t, 2H. (H3)). Range 13C NMR (, memorial plaques): 13.97, 19.46, 19.62, 21.34, 22.49, 22.57, 24.34, 24.72, 27.65, 29.62, 32.60, 32.71, 36.42, 37.17, 37.22, 37.34, 39.30, 43.98, 208.75.

The way to obtain (6R, 10R)-6,10,14-trimethylpentene-2-it (Fiona), including ozonolysis of chlorophyll obtained by extraction with acetone leaves of nettle (urtica dioica), characterized in that the solution of chlorophyll in aqueous acetone ozoniruyut by passing it of ozone-oxygen mixture taken in excess in relation to the chlorophyll in the presence of barium hydroxide, after which the precipitate is filtered off, the filtrate evaporated and the residue chromatographic, elwira a mixture of hexane - ethyl acetate.

 

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