RU2400465C1 - Method for synthesis of 3,4-epoxycarane from 3-carane with simultaneous production of 3-caren-5-one and 3-carene-2,5-dione - Google Patents

Abstract

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

Description

The invention relates to the field of chemistry of terpene compounds, in particular to the production of 3,4-epoxyrana of formula I with the simultaneous production of allylic oxidation products of 3-karen-3-karen-5-one of formula II and 3-karen-2,5-dione of formula III .

Monoterpenoids extracted from accessible and renewable plant materials have always been of interest as objects for further functionalization in order to obtain valuable synthons. In particular, in the 3-Karen series, it is necessary to develop methods that allow the molecule to be oxidized without destroying the backbone of the substrate with access to valuable oxygen-containing intermediates, which will be widely used in the future. So, compound I can be used to obtain products used as intermediates in the synthesis of various aromatic (fragrant), pharmaceutical and perfume preparations [A.L. Villa de P., D.E. De Vos, C. Montes de S., 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-epoxycaran I is its conversion to quarandiols [K.Watanabe, N. Yamamoto, A. Kaetsu, Y. Yamada. Patent US 5608088, 1997]. Sintons II and III are promising starting compounds for the preparation of the acid component of optically active pyrethroids and can be used in regiospecific and stereoselective organic synthesis [G.A. Tolstikov, F.Z. Galin, V.K. Ignatyuk, Yu.A. Kashina, E.G. Galkin. ZhORKh, 1995, 31, 1149; F.Z. Galin, Yu.A. Kashina, R.A. Zaynullin, O.S. Kukovinets, L.M. Khalilov, G.A. Tolstikov. Izv. AN Ser. Chem., 1998, 183].

3,4-Epoxikaran is obtained by epoxidation of 3-karen, which is a relatively easily epoxidized olefin [R.V. Kucher, V.I. Timokhin, I.P. Shevchuk, Ya.M. Vasyutin // Liquid-phase oxidation of unsaturated compounds in oxide olefins. - Kiev .: Naukova Dumka. 1986. P.226].

Several methods are known for converting 3-karen to epoxide:

1) Oxidation of the double bond with oxygen, catalyzed by a mixture of zeolite CoNaY or Co (MO ₃ ) ₂ in the presence of isobutyl aldehyde in a solution of acetonitrile [O. A.Kholdeeva, IVKhavrurutskii, VNRomannikov, AVTkachev, KIZamaraev. Selective alkene epoxidation by molecular oxygen in the presence of aldehyde and different type catalyst containing cobalt, 3 ^rd World Congress on Oxidation Catalysis, 1997, 947]. The reaction is carried out at 24 ° C, passing air through a mixture of 0.3 mmol of 3-karen, 2.3 mmol of isobutyl aldehyde and catalyst in 3 ml of acetonitrile. The disadvantages of this method are the approbation of the method on small amounts of the substrate and the need to use large quantities of aldehyde (approximately 8-fold molar excess relative to the substrate) and acetonitrile. A close variant of oxidation with oxygen catalyzed by praseodymium compounds in the presence of propionic aldehyde [US 4721798] requires an expensive catalyst.

2) The effect of peracids, such as methachloroperbenzoic [N.S. Brown, A. Suzuki. J. Am. Chem. Soc., 1967, 89, 1933] and peracetic [B.A. Arbuzov. MOX, 1939, 9, 255]. In the first case, a solution of 0.54 mol of methachloroperbenzoic acid in 1200 ml of chloroform is added to a solution of 0.5 mol of 3-karen in 750 ml of chloroform. Excess peracid is neutralized with sodium bisulfite, the organic layer is washed with sodium bicarbonate solution. After drying and distilling off the solvent, 3,4-epoxyran is isolated by vacuum distillation. The disadvantage of these methods is the use of corrosive and explosive oxidizing agents - peracetic or meta-chloroperbenzoic acids. It should also be noted as a drawback the use of a large amount of chloroform, sodium bisulfite, sodium bicarbonate and potassium hydroxide.

3) The effect of hydrogen peroxide in a mixture of methanol, acetonitrile and water [K. Watanabe, N. Yamamoto, A. Kaetsu, Y. Yamada. Patent US 5608088, 1997] within 24 hours. To a mixture of 0.3 mol of 3-karen, methanol, water, acetonitrile and sodium hydrogen phosphate was added 0.75 mol of 50% aqueous hydrogen peroxide at 60 ° C. The total reaction time is 24 hours. Then the reaction mass is cooled, the excess of peroxide is neutralized, following the rise in temperature, the solvent is distilled off under reduced pressure, and a saturated solution of sodium chloride is added to the residue. The organic layer was separated and washed with water to obtain a crude product suitable for the synthesis of quarantiols. This method is not very convenient, since it requires the use of 50% hydrogen peroxide, the reaction requires the creation of an inert atmosphere, elevated temperature and duration, processing of the reaction mixture is complicated.

For the oxidation of 3-karen, 60% aqueous hydrogen peroxide in an inert atmosphere was also used [M.S.A. 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 consists in heating in a nitrogen atmosphere a solution of 5 mmol of 3-karen, 1 mmol of dibutyl ether, 10 mmol of 60% hydrogen peroxide and 5 mole percent of sodium hydrogen phosphate in 5 ml of trifluoroethanol. The use of 60% hydrogen peroxide, elevated temperature and inert atmosphere creates inconvenience to work.

Compound II can be obtained by oxidation of 3-Karen with oxygen in an autoclave in the presence of a catalyst of cobalt ethyl hexanoate and pyridine at an elevated temperature (50 ° C) [G.A. Tolstikov, F.Z. Galin, V.K. Ignatyuk, Yu.A. Kashina, E.G. Galkin. ZhORKh, 1995, 31, 1149]. 0.1 mol of 3-karen, 0.6 g of cobalt ethylhexanoate, 0.65 ml of pyridine are loaded into the autoclave and, after sealing, a mixture of oxygen (15 atm) and nitrogen (40 atm) is injected. Stirred for 5 hours at a temperature of 50 ° C. After a long time and a large number of stages separation procedure, a fraction was obtained 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 the subsequent complicated processing of the reaction mixture. It can also be noted that the catalyst used is difficult to access, and pyridine is a toxic reagent with a sharp unpleasant odor. The authors failed to obtain individual compound II in this way; only the fraction enriched in compound II was obtained.

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

Compound III is also obtained by oxidation of 3-Karen with oxygen in an autoclave, but at a higher temperature (80 ° C) and a longer process time (24 hours). As a catalyst, cobalt stearate is used [F.Z. Galin, Yu.A. Kashina, R.A. Zaynullin, O.S. Kukovinets, L.M. Khalilov, G.A. Tolstikov. Izv. AN Ser. Chem., 1998, 183]. The conditions and the long time and number of stages of the procedure for isolating the target product create serious inconvenience and limit the use of this production method. The yield of compound III is quite low (24%).

As a prototype, epoxidation of 3-karen by the action of hydrogen peroxide in the presence of methyltrioxorene (MTO) was chosen [ALVilla de P., DE De Vos, C. Montes de C., PA Jacobs. Tetrahedron Letters, 1998, 39, 8521; R. Saladino, V. Neri, ARPellicia, E. Mincione. Tetrahedron, 2003, 59, 7403]. The epoxidation process is carried out at room temperature. A mixture of 3-Karen and pyridine (loading of pyridine 42 mol.% Of 3-Karen) in a solution of methylene chloride is added to a solution of MTO in 35% hydrogen peroxide. The molar ratio of 3-carne: MTO: H ₂ O ₂ is 1: 0.005: ~ 2. The reaction mass is filtered off from the catalyst and dried over sodium sulfate. After that, the solvent was distilled off, and the crude product was flash chromatographed. The yield of epoxide I is 75%. The disadvantages of this method include the fact that the methyltrioxorenium catalyst is difficult to access and expensive, and pyridine is a toxic reagent with a sharp unpleasant odor.

The present invention is the creation of a simple, economical, suitable for industrial use method for producing 3,4-epoxycaran in conjunction with the products of allylic oxidation of 3-karen.

The chemical scheme for solving this problem consists in the gradual interaction of 3-Karen with aqueous hydrogen peroxide in an aqueous solution of a polar solvent in the presence of a catalytic system consisting of manganese sulfate, sodium bicarbonate and salicylic acid. The most complete conversion of 3-karen is achieved using a 10-fold molar excess of hydrogen peroxide. Manganese sulfate can be used in an amount of 1-2 mol. % based on loaded 3-Karen. Next, 3,4-epoxycaran I is extracted from the reaction mixture with methylene chloride along with unreacted 3-karen and allylic oxidation products - 3-karen-5-one II and 3-karen-2,5-dione III. The resulting solution was concentrated by evaporation of the solvent. 3,4-epoxyran I is isolated from the concentrate (raw epoxide) by vacuum distillation. The yields of 3,4-epoxycaran I reach 45%. 3-Karen-5-one II and 3-Karen-2,5-dione III are isolated by C-18 reverse phase chromatography in 13% and 7% yields, respectively. Solvents can be reused.

The use of the above catalyst system containing manganese sulfate, sodium bicarbonate and salicylic acid for epoxidation of 3-karen is not described.

The proposed method for the production of 3,4-epoxycaran I with the simultaneous production of two valuable products II and III allows the formation of the oxirane ring in the 3-Karen by the action of simple, industrially available and non-toxic reagents. Instead of the exotic methyltrioxorenium used as a catalyst in the prototype method and synthesized based on hard-to-reach rhenium by a complex technology, it is proposed to use cheap manganese sulfate and salicylic acid, and instead of toxic and non-environmentally friendly pyridine, a solution of sodium bicarbonate and cheap solvents.

The invention is illustrated by the following examples.

Example 1. 1.15 g (8.0 mmol) of 95% 3-karen, 13.5 ml of acetonitrile are poured into a glass reactor with a mechanical, intensively rotating stirrer, a thermometer and a nozzle for supplying liquid, 0.024 g (0.16 mmol) of anhydrous manganese sulfate and 0.044 are added g (0.32 mmol) of salicylic acid. For 2.5 hours, a mixture of 11.6 ml of a 0.4 molar solution of sodium bicarbonate and 3.3 ml of 36% aqueous hydrogen peroxide is uniformly fed into the reactor. The temperature in the reactor is maintained between 18-22 ° C. Stir the mixture at this temperature for another 30 minutes. The reaction mixture is treated 3 times with methylene chloride, the extract is washed with water, dried, the solvent is distilled off in vacuum at a temperature of up to 25 ° C. Obtain 1.06 g of raw epoxide containing, according to the results of a joint analysis by ¹ H NMR, GLC and ChMS, 58% 3,4-epoxycaran I, 4% of the initial 3-karen, 16% 3-karen-5-one II, 8% 3 -karen-2,5-dione III and 13% of unidentified impurities. The yield of 3,4-epoxycaran I is 50%. A distilled solvent containing trace amounts of 3-karen and 3,4-epoxyran I, is used for extraction from the reaction mixture in the next cycle of epoxidation of 3-karen.

Example 2. In the reactor described in example 1, pour 2.30 g (16.0 mmol) of 95% 3-karen, 26.5 ml of acetonitrile, add 0.048 g (0.32 mmol) of anhydrous manganese sulfate and 0.088 g (0.64 mmol) of salicylic acid. For 2 hours, a mixture of 23.2 ml of a 0.4 molar solution of sodium bicarbonate and 13.2 ml of 36% aqueous hydrogen peroxide is uniformly fed into the reactor, maintaining the temperature in the reactor at 18-22 ° C. Stir the mixture at this temperature for another 2 hours. The reaction mixture is treated 3 times with methylene chloride, the extract is washed with water, dried, the solvent is distilled off in vacuum at a temperature of up to 25 ° C. Obtain 2.19 g of raw epoxide containing 66% 3,4-epoxycaran I, trace amounts of the initial 3-karen, 15% 3-karen-5-one II, 8% 3 according to the joint analysis by ¹ H NMR, GLC and HMS methods -karen-2,5-dione III and 10% unidentified impurities. The yield of 3,4-epoxycaran I is 59%. A distilled solvent containing trace amounts of 3-karen and 3,4-epoxyran I, is used for extraction from the reaction mixture in the next cycle of epoxidation of 3-karen.

Example 3. In the reactor described in example 1, pour 1.15 g (8.0 mmol) of 95% 3-karen, 13.5 ml of acetonitrile, pour 0.012 g (0.08 mmol) of anhydrous manganese sulfate and 0.044 g (0.32 mmol) of salicylic acid. For 2.5 hours, a mixture of 11.6 ml of a 0.4 molar solution of sodium bicarbonate and 6.6 ml of 36% aqueous hydrogen peroxide is uniformly fed into the reactor, maintaining the temperature in the reactor at 18-22 ° C. Stir the mixture at this temperature for another 2 hours. The reaction mixture is treated 3 times with methylene chloride, the extract is washed with water, dried, the solvent is distilled off in vacuum at a temperature of up to 25 ° C. Obtain 1.05 g of raw epoxide containing, according to the joint analysis by ¹ H NMR, GLC and HMS, 59% of 3,4-epoxycaran I, trace amounts of starting 3-karen, 16% 3-karen-5-one II, 8% 3 -karen-2,5-dione III and 16% unidentified impurities. The yield of 3,4-epoxycaran I is 51%. A distilled solvent containing trace amounts of 3-karen and 3,4-epoxyran is used for extraction from the reaction mixture in the next 3-karen epoxidation cycle.

Example 4. Isolation of products from raw epoxide.

The mixture of raw epoxides 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 acceleration circuit, a cooled trap is installed. The initial mixture contains 62% 3-karen epoxide. The epoxide fraction is distilled off at temperatures up to 90 ° C (cube) and 45-60 ° C (vapors). From 4.3 g of the starting mixture, 2.2 g of the expected product is obtained containing 88% 3,4-epoxycaran, 2% 3-karen and unidentified compounds, as well as 1.8 g of bottoms. ¹ H NMR spectrum of the target product corresponds to the spectrum of 3,4-epoxycaran. ¹ H NMR: 0.42 (dd, C ¹ or C ⁶ ), 0.49 (dd, C ¹ or C ⁶ ), 0.70 (s, C ⁸ H ₃ ), 0.98 (s, C ⁹ H ₃ ), 1.25 (s, C ¹⁰ H ₃ ), 1.47 (dt,), 1.61 (dt, C ² , C ⁵ ), 2.11 (dd, C ² ), 2.26 (dd .d, C ⁵ ), 2.80 (t, C ⁴ ). The yield of 3,4-epoxycaran upon distillation was 73%. The total yield per 3-karen was 45%.

0.23 g of the bottom residue is chromatographed on a C-18 reverse phase. Aqueous methanol is used as the eluent (the gradient of methanol concentration varies from 35% to 55% by volume). Using the GLC method, fractions containing individual compounds II and III are selected. Methanol was evaporated at room temperature in a vacuum of a water-jet pump, and water was extracted with sulfuric ether. After distillation of the sulfuric ether, 0.078 g of 3-karen-5-one II (yield 13%) and 0.043 g of 3-karen-2,5-dione III (yield 7%) are obtained. Product structures were confirmed by ¹ H NMR and HMS. ¹ H NMR spectrum of compound II: 0.72 (C ¹ ), 1.02 (s, C ⁸ H ₃ ), 1.18 (s, C ⁹ H ₃ ), 1.83 (s, C ¹⁰ H ₃ ), ~ 1.3 (m, C ⁶ ), ~ 2.3, ~ 2.6 (m, C ² H ₂ ), 5.84 (bs, C ⁴ ). ¹ H NMR spectrum of compound III: 1.28 (s, C ⁸ H ₃ , C ⁹ H ₃ ), 1.95 (br s, C ¹⁰ H ₃ ), 2.32 (m, C ¹ , C ⁶ ), 6.48 (br. s, C ⁴ ).

Claims (1)

A method for producing 3,4-epoxycaran of general formula I with the simultaneous preparation of 3-karen-5-one of formula II and 3-karen-2,5-dione of formula III:

by reacting 3-Karen with hydrogen peroxide in a solvent in the presence of a catalyst at room temperature, characterized in that the catalyst is a mixture of manganese sulfate, sodium bicarbonate and salicylic acid, acetonitrile is used as the solvent, and the target products are isolated by extraction with methylene chloride with subsequent vacuum distillation of 3,4-epoxyrana I and chromatography of the bottom residue on the reversed phase of C-18 to obtain 3-karen-5-one II and 3-karen-2,5-dione III.