RU2509073C1 - METHOD OF PRODUCING 3α-HYDROXY-10β-PINANONE-4 - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3α-hydroxy-10β-pinanone-4. The method involves oxidising 3α,4β-dihydroxy-10β-pinane in dimethylformamide without or in the presence of a MoCl₅ or Mo(CO)₆ catalyst for 1-2 hours while passing a current of chlorine dioxide gas. The reaction mixture is then extracted with diethyl ether or methyl-tert-butyl ether, washed and dried over anhydrous MgSO₄. The end product is separated by chromatography on SiO₂.

EFFECT: method enables to obtain 3α-hydroxy-10β-pinanone-4 with high output.

1 tbl, 2 ex

Description

The present invention relates to the field of organic chemistry, and in particular to a method for producing terpene α-hydroxyketone-3α-hydroxy-10β-pinanone-4. It is well known that terpene α-hydroxyketones are important building blocks in the complete synthesis of natural products, and are also used to produce chiral catalysts for various asymmetric reactions.

Only 2α-hydroxypinanone-3 has the greatest application of the pinan structure from α-ketols due to the simple synthesis method (oxidation of α-pinene KMnO ₄ in aqueous acetone) [Carlson RG and Pierce JK Synthesis and stereochemistry of the four isomeric pinane-2,3- diols // J. Org. Chem., 1971, 36 (16), p.2319-2324]. The literature describes four isomeric pinanoic α-hydroxyketones containing functional groups at 3 and 4 positions - 4α-hydroxy-10α-pinan-3-one, 3β-hydroxy-10α-pinan-4-one, 4β-hydroxy-10β- pinan-3-one, 4α-hydroxy-10β-pinan-3-one, but their synthesis is not preparative - the first three compounds are obtained with a small yield of hydrolysis of acetates formed by rearrangement of 2α-hydroxypinanone-3 in acetic anhydride, and the latter is synthesized through enol- and epoxyacetates of isopinocamphone with a yield of 10% [Hirata T., Stereochemical studies of monoterpene compounds. Xvi. Rearrangement of 2α-hydroxy-10β-pinan-3-one with acetic anhydride // Bulletin of the Chemical Society of Japan, 1972, 45 (2), p. 599-603; Höld KM, Sirisoma NS, Sparks SE and Casida JE Metabolism and mode of action of cis- and trans-3-pinanones (the active ingredients of hyssop oil) // Xenobiotica, 2002, 32 (4), p. 251-265] .

The disadvantage of these methods is the low yield of α-hydroxyketones I-IV as a result of the formation of a complex mixture of products, as well as difficulties in their chromatographic separation.

Synthesis of α-hydroxyketones I, II, and III [T. Hirata, Stereochemical studies of monoterpene compounds. Xvi. Rearrangement of 2α-hydroxy-10β-pinan-3-one with acetic anhydride // Bulletin of the Chemical Society of Japan, 1972, 45 (2), 599-603].

Compounds I, II and III were prepared as follows: 2α-hydroxy-pinanon-3 was boiled with acetic anhydride at 160 ° C for 6 hours. After cooling, H ₂ O was added to the reaction mixture and heated for 30 min at 50 ° C to destroy excess acetic anhydride. Then the reaction mixture was extracted with diethyl ether, the ether extract was washed with a solution of Na ₂ CO ₃ , H ₂ O and dried over Na ₂ SO ₄ . After removal of the solvent, the reaction products were separated by column chromatography on SiO ₂ , while five fractions were collected: 1 fr. - carvone (1.3%), 2 fr. - acetate of the starting compound (14%), 3 fr. - contains a practically inseparable mixture of two acetates in a ratio of 2: 1 (4α-acetoxy-10α-pinanon-3 and 4β-acetoxy-10α-pinanon-3) with a total yield of 59%, 4 fr. - contains 4β-acetoxy-10β-pinanon-3 (yield 17%), 5 fr. - unconverted starting ketol.

To separate the acetates that make up fraction 3, column chromatography on SiO ₂ with a mixture of ethyl acetate and hexane (1:99) is performed twice more, but individual esters are isolated in very small amounts - 13.2% and 2.2%, respectively, 81% is a mixture of ethers. Further, acetates are hydrolyzed to produce α-hydroxyketones. Compounds I and II were obtained as a mixture by hydrolysis of 4α-acetoxy-10α-pinan-3-one with a 3N solution of KOH in MeOH during the day. Column chromatography on SiO ₂ is again used for their separation. The yield of α-hydroxyketone I is 30%, and the yield of α-hydroxyketone II is 15%. The closest method to obtain terpene α-hydroxyketone is a method for producing ketol III, including hydrolysis of fraction 4 with 0.1N NaOH in methanol at 15 ° C for 30 min. The yield of compound III was 87%. Thus, the preparative yield of individual α-hydroxyketones was: 4% for compound I, 0.5% for compound II, and 15% for compound III.

Synthesis of α-hydroxyketone IV [Hold K.M., Sirisoma N.S., Sparks S.E. and Casida J.E. Metabolism and mode of action of cis- and trans-3-pinanones (the active ingredients of hyssop oil) // Xenobiotica, 2002, 32 (4), p. 251-265].

The synthesis of α-hydroxyketone IV includes the following stages: 1) oxidation of isopinocampheol with pyridinium bichromate in CH ₂ Cl ₂ at room temperature for 24 hours and isolation of isopinocamphon by chromatography on SiO ₂ (yield 98%); 2) preparation of the enol acetate mixture by boiling of isopinocamphon in isopropepyl acetate in the presence of anhydrous para-toluenesulfonic acid at 110 ° C for three days, isolation of the inseparable enol acetate mixture by chromatography on SiO ₂ (yield 67%, 4: 1 ratio); 3) synthesis of epoxyacetates by oxidation of a mixture of enolacetates with meta-chloroperoxybenzoic acid in CHCl ₃ with increasing temperature from 0 to 25 ° C for 3-4 hours. Isolation of the mixture of epoxyacetates by column chromatography on SiO ₂ (yield 98%); 4) rearrangement of the mixture of epoxyacetates in absolute methanol in the presence of sodium methylate (NaOMe) for 2 hours at room temperature and chromatographic isolation on SiO ₂ 4α-hydroxy-10β-pinanone-3. The preparative yield of ketol IV at all stages was ~ 10%. Physicochemical characteristics of IV are not given; only spectral data are given.

The closest functional compound is compound II, obtained in a yield of 0.5%.

The objective of the present invention is to develop a selective method for producing one of the isomers of 3-hydroxypinanone-4, which allows to obtain a new compound, namely 3α-hydroxy-10β-pinanon-4, by oxidation with chlorine dioxide (2). This is the technical result.

The technical result is achieved in that the method for producing 3α-hydroxy-10β-pinanone-4 involves the oxidation of 3α, 4β-dihydroxy-10β-pinan in dimethylformamide without or in the presence of MoCl ₅ or Mo (CO) ₆ catalysts within 1-2 hours, passing a stream of gaseous chlorine dioxide, extraction with diethyl or methyl tert-butyl ether, washing and drying over anhydrous MgSO ₄ reaction mixture, and the final product is isolated by SiO ₂ chromatography.

The starting compound is 3α, 4β-dihydroxy-10β-pinan (1), easily obtained by hydroboration - oxidation of verbenone or cis-verbenol [Uzarewicz J., Uzarewicz A., Zacharewicz W. Dzialanie dwuboranu na terpeny nienasycone z grupami funcy. II. Dzialanie dwuboranu i bis- (3-metylo-2-butylo) -boranu na cis i trans-werbenole oraz werbenon // Roczniki Chemi., Ann.Soc.Chim. Polonorum, 1965, 39, p.1051-1057]. Chlorine dioxide (an industrial product used for bleaching cellulose and purifying drinking water) is used as an oxidizing agent, dimethylformamide is used as a solvent, and MoCl ₅ and Mo (CO) _{6 are used} as catalysts.

The method is as follows.

A flow of chlorine dioxide gas is passed through a solution of the starting compound 1 in dimethylformamide without or in the presence of catalysts for molybdenum chloride (MoCl ₅ ) or molybdenum hexacarbonyl (Mo (CO) ₆ ) for 1-2 hours at a temperature of 0-45 ° C. The reaction was monitored by TLC, after the diol spot 1 disappeared, the reaction mixture was diluted with water, the reaction products were extracted with diethyl or methyl tert-butyl ether, the ether extracts were washed with saturated aqueous NaCl and dried over anhydrous MgSO ₄ . After removing the solvent, the products are analyzed by GLC, the selectivity of the formation of ketol 2 is 86-95%. The preparative yield of 3α-hydroxy-10β-pinanone-4 after chromatography on SiO ₂ (eluent petroleum ether or hexane: diethyl ether 20: 1) is 60-65%. The structure of ketol 2 was determined by IR, NMR spectroscopy and confirmed by X-ray diffraction.

Example 1

A solution of gaseous chlorine dioxide was passed through a solution of 1.5 g of diol 1 in 30 ml of DMF with stirring at room temperature. After two hours, the reaction mixture was diluted with 100 ml of water, the reaction products were extracted with diethyl ether (3 × 50 ml), the ether extracts were washed with saturated aqueous NaCl (3 × 50 ml) and dried over anhydrous MgSO ₄ . After removal of the solvent, the yield of crude product was 93%, the selectivity for the formation of ketol 2 was 95%. Column chromatography on SiO ₂ (eluent petroleum ether: diethyl ether 20: 1) was obtained 0.91 g of the target product (61%).

Example 2

A solution of chlorine dioxide gas was passed through a solution of 200 mg of diol 1 and 6 mg of MoCl ₅ in 5 ml of DMF with stirring at room temperature. After one hour, the reaction mixture was diluted with 30 ml of water, the reaction products were extracted with methyl tert-butyl ether (3 × 25 ml), the ether extracts were washed with saturated aqueous NaCl (3 × 20 ml) and dried over anhydrous MgSO ₄ . After removal of the solvent, the yield of crude product was 95%, the selectivity for the formation of ketol 2 was 86%. Column chromatography on SiO ₂ (eluent hexane: diethyl ether 20: 1) isolated 130 mg of the expected product (65%).

The experimental results are shown in the table.

Physicochemical characteristics and spectral data of 3α-hydroxy-10β-pinanone-4: [α] _D = + 159.3 (with 0.6 EtOH), T _pl. = 57-58 ° C. IR spectrum (ν, cm ^-1 ): 3452 (OH), 2958, 1716 (C = O), 1467, 1379, 1328, 1247, 1080, 1045, 983, 933, 842, 804. ¹ H NMR (300 MHz, DMSO-d ₆ , δ / ppm, J / Hz): 0.95 s (3H, CH3-8), 1.20 d (3H, CH3-10, J 7.3), 1.31 d (1H, H-7 , J 10.5), 1.32 s (3H, CH3-9), 1.93 dd (1H, H-2, J 5.5, J 7.3), 2.07 m (1H, H-1), 2.52 m (1H, H-5) , 2.69 m (1H, H-7, J 10.5), 3.79 d (1H, H-3, J 5.5). ¹³ C NMR (75 MHz, DMSO-d ₆ , δ, ppm): 212.33 (C-4), 76.27 (C-3), 58.08 (C-5), 47.41 (C-1), 43.33 ( C-2), 40.00 (C-6), 29.75 (C-7), 27.29 (C-9), 25.11 (C-8), 19.79 (C-10).

The oxidation results of 3α, 4β-dihydroxy-10β-pinan (1) with chlorine dioxide, time 1 h, catalyst 3 wt.%:

Table No. Catalyst Temperature ° C The conversion of diol 1,% Ketol 2 selectivity,% one - twenty 93-100 87-95 2 - 0 78 92 3 - 40-45 one hundred 87 four MoCl ₅ twenty one hundred 86 5 Mo (CO) ₆ twenty one hundred 88

Claims (1)

A method for producing 3α-hydroxy-10β-pinonone-4, including the oxidation of 3α, 4β-dihydroxy-10β-pinan in dimethylformamide without or in the presence of MoCl ₅ or Mo (CO) ₆ catalysts for 1-2 hours, passing a stream of chlorine dioxide gas extraction with diethyl or methyl tert-butyl ether, washing and drying over anhydrous MgSO _{4 of the} reaction mixture, and isolation of the final product by SiO ₂ chromatography.