Method for synthesis of 3,4-epoxycarane from 3-carane with simultaneous production of 3-caren-5-one and 3-carene-2,5-dione

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 3,4-epoxycarane of formula I

with simultaneous production of 3-caren-5-one of formula II

and 3-carene-2,5-dione of formula III

, involving the following: 3-carene is treated with diluted hydrogen peroxide in acetonitrile in conditions for catalytic action of manganese sulphate in the presence of sodium bicarbonate and salicylic acid with subsequent extraction of the reaction mixture with methylene chloride, vacuum distillation of crude epoxy and release of 3,4-epoxycarane with 88% purity and 45% output. 3-caren-5-one II and 3-carene-2,5-dione III are separated through chromatograph on an inverted C-18 phase with output of 13% and 7% respectively.

EFFECT: design of a method for synthesis of intermediate compounds for a range of medical, industrial and perfume preparations.

1 cl, 4 ex

The invention relates to the field of chemistry terpene compounds, namely to obtain 3,4-epoxybutane formula I with the simultaneous receipt of the products of allylic oxidation of 3-Karen-3-Karen-5-she formulas II and 3-Karen-2,5-dione of the formula III.

Monoterpenoid extracted from available and renewable vegetable raw materials, were always of interest as objects for further functionalization with the purpose of obtaining valuable synthons. In particular, in a series of 3-carene is necessary to develop ways to oxidize the molecule without destroying the frame substrate with access to valuable oxygenated intermediates, which find wide application in the future. Thus, compound I can be used to obtain products used as intermediate in the synthesis of various aromatic (fragrant), pharmaceutical and perfumery preparations [A.L.Villa de P., D.E. De Vos, C. Montes de C., P.A. Jacobs. Tetrahedron Letters, 1998, 39, 8521; Naima Fdil, Abderrahmane Romane, Smail Allaoud et al. J. Molec. Catal. A: Chemical, 1996, 108, 15]. Another promising use of 3,4-epoxybutane I is its transformation into carandiru [K.Watanabe, N.Yamamoto, A.Kaetsu, Y.Yamada. Patent US 5608088, 1997]. The synthons II and III are a promising source compounds for obtaining the acid components optically active pyrethroids and can be used in regiospecifically and stereoselective org the technical synthesis [Gaellic, Flagellin, Vchat, Waitin, Eggelton. Zhur.org.chem., 1995, 31, 1149; Flagellin, Waitin, Rasulullah, Oscurament, Lamalera, Gaellic. WPI. An. Ser. chem., 1998, 183].

3,4-Apoksiomen get epoxydecane 3-carene, which is easy enough to epoxidase the olefins [Rvices, Whiteskin, Ipecac, Jammaster // Liquid-phase oxidation of unsaturated compounds in the olefin oxide. - Kiev.: Naukova Dumka. 1986. S.226].

There are several ways of conversion of 3-carene in epoxide:

1) oxidation of the double bond with oxygen, catalyzed by a mixture of zeolite CoNaY or Co(MO₃)₂in the presence of isobutyl aldehyde in solution of acetonitrile [.A.Kholdeeva, I.V.Khavrurutskii, V.N.Romannikov, A.V.Tkachev, K.I.Zamaraev. Selective alkene epoxidation by molecular oxygen in the presence of aldehyde and different type catalyst containing cobalt, 3^rdWorld Congress on Oxidation Catalysis, 1997, 947]. The reaction is carried out at 24°C by passing air through the mixture of 0.3 mmol of 3-carene, 2.3 mmol of isobutyl aldehyde and catalyst in 3 ml of acetonitrile. The disadvantages of this method are the testing method for small quantities of substrate and the necessity of using large quantities of aldehyde (approximately 8-fold molar excess relative to the substrate) and acetonitrile. Close variant oxidation catalyzed by compounds of praseodymium, in the presence of propionic aldehyde [US 4721798] requires expensive cat who lyst.

2) the Effect of nakilat, such as metaglidasen [..Brown, .Suzuki. J. Am. Chem. Soc., 1967, 89, 1933] and peracetic [B.A.Arbuzov. AH, 1939, 9, 255]. In the first case, to a solution of 0.5 mole of 3-carene in 750 ml of chloroform, add a solution of 0.54 mole metacompetencies acid in 1200 ml of chloroform. The excess of nagkalat neutralized with sodium bisulfite, the organic layer washed with sodium bicarbonate solution. After drying and removal of the solvent 3,4-Apoksiomen allocate by vacuum distillation. The disadvantage of these methods is the use of corrosive and explosive oxidant is peracetic or meta-chlormadinone acids. It should also be noted as a disadvantage of the use of large quantities of chloroform, sodium bisulfite, sodium bicarbonate and potassium hydroxide.

3) the Action of hydrogen peroxide in a mixture of methanol, acetonitrile and water [.Watanabe, N.Yamamoto, A.Kaetsu, Y.Yamada. Patent US 5608088, 1997] within 24 hours. To a mixture of 0.3 mol of 3-carene, methanol, water, acetonitrile, and hydrogen phosphate sodium add 0.75 mol of a 50%aqueous hydrogen peroxide at 60°C. the Total duration of the reaction is 24 hours. Then the reaction mass is then cooled, neutralized the excess peroxide, watching the rise of temperature, the solvent is distilled off under reduced pressure and to the residue is added a saturated solution of sodium chloride. The organic layer is separated and washed in the water, receiving the crude product is suitable for the synthesis of carandiru. This method is not very convenient, because it requires the use of 50%hydrogen peroxide, the reaction requires the creation of an inert atmosphere, high temperature and duration, the treatment of the reaction mixture complicated.

For oxidation of 3-carene was also used 60%aqueous hydrogen peroxide in an inert atmosphere [MSA van Vliet, I.W.C.E. Arends, R.A. Sheldon. Synlett, 2001, 248; M.C.A. van Vliet, I.W.C.E. Arends, R.A. Sheldon. Synlett, 2001, 1305]. The experimental procedure is heated in an atmosphere of nitrogen a solution of 5 mmol of 3-carene, 1 mmol dibutylamino ether, 10 mmol of 60%hydrogen peroxide and 5 mole percent hydrogen phosphate sodium in 5 ml of triptoreline. The use of 60%hydrogen peroxide, high temperature and inert atmosphere creates inconveniences for work.

Compound II can be obtained by oxidation of 3-carene oxygen in the autoclave in the presence of a catalyst of ethylhexanoate cobalt and pyridine at elevated temperature (50°C) [Gaellic, Flagellin, Vchat, Waitin, Eggelton. Zhur.org.chem., 1995, 31, 1149]. In the autoclave load 0.1 mol of 3-carene, 0.6 g of ethylhexanoate cobalt, 0.65 ml of pyridine and after sealing pump a mixture of oxygen (15 ATM) and nitrogen (40 ATM). Stirred for 5 h at 50°C. After a long time and a large number of herds is th extraction procedure was obtained a fraction, containing only 60% of the basic substance. The disadvantages of this method include the need for a process in an autoclave under high pressure and subsequent complicated processing of the reaction mixture. It can also be noted that the catalyst of the hard-and pyridine - toxic reagent with a sharp odor. Individual compound II in this way the authors could not be obtained, there was obtained only a fraction enriched compound II.

Oxidation of 3-carene oxygen in the presence of cobalt stearate and copper acetate (II) to obtain compound II [A.N.Misra, V.K.Yadav, R.Soman, D.Sukh. Patent IN 155122, 1985] also involves carrying out the process under pressure and at elevated temperature. The product selected with low yield (about 30%) by fractional distillation in vacuum.

Compound III is also produced by oxidation of 3-carene oxygen in the autoclave, but at a higher temperature (80°C) and longer time duration of the process (24 h). As the catalyst used cobalt stearate [Flagellin, Waitin, Rasulullah, Oscurament, Lamalera, Gaellic. WPI. An. Ser. chem., 1998, 183]. Conditions and time and the number of stages of the procedure of selection of the target product create a serious inconvenience and limit the use of this method of obtaining. The output is soedineniya III is quite low (24%).

As a prototype of the selected epoxidation of 3-carene by the action of hydrogen peroxide in the presence of methyltrioxorhenium (MTO) [A.L.Villa de P., D.E. De Vos, C. Montes de S., P.A.Jacobs. Tetrahedron Letters, 1998, 39, 8521; R.Saladino, V.Neri, A.R.Pellicia, E.Mincione. Tetrahedron, 2003, 59, 7403]. The process of epoxidation is carried out at room temperature. A mixture of 3-carene and pyridine (pyridine 42 mol.% from 3-carene) in a solution of methylene chloride is added to a solution of ito in 35%hydrogen peroxide. The molar ratio of 3-Karen: MTO: H₂O₂is 1:0.005:~2. The reaction mass is filtered from the catalyst and dried over sodium sulfate. After that, the solvent is distilled off and the crude product subjected to flash chromatography. The yield of epoxide I is 75%. The disadvantages of this method include the fact that the catalyst methyltrioxorhenium remote and roads, and pyridine - toxic reagent with a sharp odor.

The purpose of this invention is to provide a simple, economical, suitable for industrial application of the method of obtaining 3,4-epoxybutane together with the products of allylic oxidation of 3-carene.

The chemical structure of the solution of the task is the gradual interaction of 3-carene with aqueous hydrogen peroxide in an aqueous solution of polar solvent in the presence of a catalytic system consisting of manganese sulfate, BIK is rbonate sodium and salicylic acid. The most complete conversion of 3-carene is achieved by using a 10 fold molar excess of hydrogen peroxide. Manganese sulfate can be used in amounts of 1-2 mol. % (based on loaded 3-Karen. Next, the reaction mixture is extracted methylene chloride 3,4-Apoksiomen I together with unreacted 3-Karen and products of allylic oxidation to 3-Karen-5-one II 3-Karen-2,5-dione III. The resulting solution is concentrated by evaporation of the solvent. 3,4-Apoksiomen I stands out from concentrate (epoxide raw) vacuum distillation. Outputs 3,4-epoxybutane I reach 45%. 3-Karen-5 he II and 3-Karen-2,5-dione III allocate chromatography on a reversed phase C-18 C outputs 13% and 7% respectively. The solvent can be reused.

Applying the above catalytic system containing manganese sulfate, sodium bicarbonate and salicylic acid, for epoxidation of 3-carene not described.

The proposed method of producing 3,4-epoxybutane I simultaneously receive two valuable products II and III allows education oxiranes ring in 3-Karen simple, industrially available and non-toxic reagents. Instead of exotic methyltrioxorhenium used as a catalyst in the method-prototype and synthesized on the basis of hard-to-reach rhenium complex technology is AI, it is proposed to use cheap manganese sulfate and salicylic acid, and instead of toxic and environmentally unfriendly pyridine - sodium bicarbonate solution and cheap solvent.

The invention is illustrated by the following examples.

Example 1. In a glass reactor with mechanical, rapidly rotating stirrer, thermometer and fitting for the fluid fill 1.15 g (8.0 mmol) 95%3-carene, 13.5 ml of acetonitrile, fall asleep 0.024 g (0.16 mmol) of anhydrous manganese sulfate and 0.044 g (0.32 mmol) of salicylic acid. Within 2.5 hours evenly fed into the reactor a mixture of 11.6 ml of a 0.4 molar sodium bicarbonate solution and 3.3 ml of 36%aqueous hydrogen peroxide. The temperature in the reactor is maintained in the range 18-22°C. Stir the mixture at this temperature for another 30 minutes. The reaction mixture was treated 3 times with methylene chloride, the extract washed with water, dried, the solvent is distilled off in vacuum at temperatures up to 25°C. Obtain 1.06 g of the epoxide raw, containing according to a joint analysis methods¹H NMR, GC and HMS 58% 3,4-epoxybutane I, 4% of the original 3-carene, 16% 3-Karen-5-it II, 8% 3-Karen-2,5-dione III and 13% of unidentified impurities. The yield of 3,4-epoxybutane I is 50%. Distilled solvent containing trace amounts of 3-carene and 3,4-epoxybutane I use for extraction from the reaction mixture in the following t is cle epoxidation of 3-carene.

Example 2. In the reactor described in example 1 is poured 2.30 g (16.0 mmol) 95%3-carene, 26.5 ml of acetonitrile, fall asleep 0.048 g (0.32 mmol) of anhydrous manganese sulfate and 0.088 g (0.64 mmol) of salicylic acid. Within 2 hours evenly fed into the reactor a mixture of 23.2 ml of a 0.4 molar sodium bicarbonate solution and 13.2 ml of 36%aqueous hydrogen peroxide, maintaining the temperature in the reactor in the range 18-22°C. Stir the mixture at this temperature for another 2 hours. The reaction mixture was treated 3 times with methylene chloride, the extract washed with water, dried, the solvent is distilled off in vacuum at temperatures up to 25°C. Obtain 2.19 g of the epoxide raw, containing according to a joint analysis methods¹H NMR, GC and HMS 66% 3,4-epoxybutane I, trace amounts of the original 3-carene, 15% 3-Karen-5-it II, 8% 3-Karen-2,5-dione III and 10% of unidentified impurities. The yield of 3,4-epoxybutane I is 59%. Distilled solvent containing trace amounts of 3-carene and 3,4-epoxybutane I use for extraction from the reaction mixture in the next cycle epoxidation of 3-carene.

Example 3. In the reactor described in example 1 is poured 1.15 g (8.0 mmol) 95%3-carene, 13.5 ml of acetonitrile, fall asleep 0.012 g (0.08 mmol) of anhydrous manganese sulfate and 0.044 g (0.32 mmol) of salicylic acid. Within 2.5 hours evenly fed into the reactor a mixture of 11.6 ml of a 0.4 molar rest the RA of sodium bicarbonate and 6.6 ml of 36%aqueous hydrogen peroxide, maintaining the temperature in the reactor in the range 18-22°C. Stir the mixture at this temperature for another 2 hours. The reaction mixture was treated 3 times with methylene chloride, the extract washed with water, dried, the solvent is distilled off in vacuum at temperatures up to 25°C. Obtain 1.05 g of the epoxide raw, containing according to a joint analysis methods¹H NMR, GC and HMS 59% 3,4-epoxybutane I, trace amounts of the original 3-carene, 16% 3-Karen-5-it II, 8% 3-Karen-2,5-dione III and 16% of unidentified impurities. The yield of 3,4-epoxybutane I is 51%. Distilled solvent containing trace amounts of 3-carene and 3,4-epoxybutane, is used for the extraction of the reaction mixture in the next cycle epoxidation of 3-carene.

Example 4. The selection of products of epoxide raw.

The mixture of epoxides-raw synthesized in examples 1-3, is subjected to distillation at a residual pressure of 5 mm Hg from a flask with a reflux condenser. In the scheme of acceleration establish a cooled trap. The initial mixture contains 62% of the epoxide of 3-carene. The fraction of the epoxide is distilled at temperatures up to 90°C (a cube) and 45-60°C (pair). From 4.3 g of the mixture to obtain 2.2 g of the target product, containing 88% 3,4-epoxybutane, 2% 3-carene and unidentified compounds, and 1.8 g of the cubic residue.¹H NMR spectrum of the target product corresponds to the range of 3.4-epoxybutane.¹The NMR: 0.42 (DDD, With¹or⁶), 0.49 (DDD, With¹or⁶), 0.70 (s, C⁸H₃), 0.98 (s, C⁹H₃), 1.25 (s, C¹⁰H₃), 1.47 (DD,), 1.61 (dt, C²C⁵), 2.11 (DD, C²), 2.26 (DDD, C⁵), 2.80 (t, C⁴). The yield of 3,4-epoxybutane when the distillation is 73%. The total yield per 3-Karen amounted to 45%.

0.23 g of the cubic residue chromatographic on reversed phase C-18. As eluent using aqueous methanol (gradient methanol concentration varies in the range from 35% to 55% by volume). Using the GC method selected fractions containing individual compounds II and III. The methanol is evaporated at room temperature in a water-jet vacuum pump, and the water extracted with ethyl ether. After the distillation of sulphuric ether get 0.078 g of 3-Karen-5-it II (yield 13%) and 0.043 g of 3-Karen-2,5-dione III (yield 7%). The structures of products were confirmed methods¹H NMR and CMS.¹H NMR spectrum of compound (II): 0.72 (C¹), 1.02 (s, C⁸H₃), 1.18 (s, C⁹H₃), 1.83 (s, C¹⁰H₃), ~1.3 (m, C⁶), ~2.3, ~2.6 (m, C²H₂), 5.84 (sh, C⁴).¹H NMR spectrum of compound III: 1.28 (s, C⁸H₃C⁹H₃), 1.95 (sh, C¹⁰H₃), 2.32 (m, C¹C⁶), 6.48 (sh, C⁴).

The way to obtain 3,4-epoxybutane General formula I with simultaneous 3-Karen-5-she formulas II and 3-Karen-2,5-dione of the formula III:

by reacting 3-carene with hydrogen peroxide in a solvent in the presence of a catalyst at room temperature, characterized in that as the catalyst, a mixture of manganese sulfate, sodium bicarbonate and salicylic acid, the solvent is acetonitrile, and the selection of target products is carried out by extraction of methylene chloride, followed by vacuum distillation 3,4-epoxybutane I and chromatography VAT residue on reversed phase C-18 with 3-Karen-5-it II and 3-Karen-2,5-dione III.