RU2794756C1 - Method for obtaining trans-myrtanoic acid - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: method for producing trans-myrtanic acid, which consists in the oxidation of trans-myrtanol in acetic acid with a solution of CrO₃ in a mixture of acetic acid and water at a molar ratio of trans-myrtanol: CrO₃ – 1:2-3 by the direct method of mixing the reagents by adding dropwise a solution of the starting compound to the solution of the oxidizing agent or in the reverse way - by adding dropwise the solution of the oxidizing agent to the solution of the starting compound, while the mixing of the reagents is carried out at room temperature, the isolation of trans-myrtanoic acid is carried out through a water-soluble salt.

EFFECT: one-stage method for the synthesis of trans-myrtanoic acid and increase in its preparative yield up to 58-74% of the theoretically possible.

1 cl, 3 ex

Description

The invention relates to the field of organic chemistry, and in particular to a method for producing trans -myrtanoic acid. Terpenic acids are used to prepare optically active peracids for the enantioselective oxidation of olefins to epoxides, prochiral sulfides to sulfoxides, azomethines to oxaziridines [Collins, JF, & McKervey, MA (1969). Preparation of some optically active peracids. The Journal of Organic Chemistry, 34(12), 4172-4173. doi:10.1021/jo01264a096]. On the basis of cis -myrtanoic acid, a number of derivatives containing amide and acetylthiourea fragments with fluorine atoms, with a nitro group or a trifluoromethyl group, which have significant fungicidal activity against some fungi pathogenic for plants [Shi, Y., Si, H., Wang, P ., Chen, S., Shang, S., Song, Z., Wang, Z., Liao, S. (2019). Derivatization of Natural Compound β-Pinene Enhances Its In Vitro Antifungal Activity against Plant Pathogens. Molecules, 24(17), 3144-3159. doi:10.3390/molecules24173144]. A number of terpenic acids (myrtenic, camphenilanic, cis -pinone and cis -pinonone) have found application in the synthesis of chlorine-terpene conjugates with reduced dark and increased photoinduced cytotoxicity compared to methyl pheophorbide- a , which significantly improves their characteristics as photosensitizers for medical purposes [Mal 'shakova, MVM, Pylina, YI, Frolova, LL, Alekseev, JH, Patov, SA, Shadrin, DM, … Belykh, DV (2016). New Chlorin-Terpene Conjugates: Synthesis, Photoinduced and Dark Cytotoxicity. Macroheterocycles, 9(3), 238-243. doi:10.6060/mhc160753b].

The literature describes methods for obtaining trans -myrtanoic acid by oxidation of trans -mirtanol with a KMnO ₄ -H ₂ SO ₄ -H ₂ O system followed by vacuum distillation [Fossey, J., Lefort, D., & Sorba, J. (1986). Trapping of the 6,6-dimethylbicyclo[3.1.1]hept-2-yl free radical by S _H 2 reaction with peracid. The Journal of Organic Chemistry, 51(19), 3584-3587. doi:10.1021/jo00369a006] or reduction of myrtenic acid with sodium in alcohol [The terpenes. vol. II. The dicyclic terpenes, sesquiterpenes and their derivatives., by JL SIMONSEN, Cambridge Univ. Press, New York, 1932. p. 192]. In both cases, the yield of the product is not indicated.

Trans -myrtanoic acid is synthesized by oxidation of trans -mirtanol with KMnO4 at a molar ratio of alcohol:oxidizer 1:1.4 in the presence of cyclohexyl-18-crown-6 in dichloromethane at room temperature for 60 hours. Acid yield 70%. [Botteghi, C., Chelucci, C., Chessa, G., Delogu, G., Gladiali, S., & Soccolini, F. (1986). Optically active nitrogen ligans. Journal of Organometallic Chemistry, 304(1-2), 217-225. doi:10.1016/s0022-328x(00)99687-6]

In [Ghalehshahi, HG; Madsen, R. Silver-Catalyzed Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols. Chem. Eur. J. 2017, 23 (49), 11920-11926. doi:10.1002/chem.201702420.] describes a rather complicated and time-consuming method for obtaining acids from primary alcohols using silver nanoparticles formed in situ (Ag ₂ CO ₃ -MnBr ₂ -KOH-polyvinylpyrrolidone PVP) by boiling in mesitylene. Under these conditions, cis -mirtanol is completely converted into the thermodynamically more stable trans -myrtanic acid (reaction temperature 164°C, 20 hours, 78% yield).

An equally complex system for the synthesis of acids is proposed by the authors of [Santilli, C., Makarov, IS, Fristrup, P., & Madsen, R. (2016). Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols and Hydroxide Catalyzed by a Ruthenium N-Heterocyclic Carbene Complex. The Journal of Organic Chemistry, 81(20), 9931-9938. doi:10.1021/acs.joc.6b02105] - N-heterocyclic complex [RuCl ₂ (I i Pr)(p-cymene)] - tricyclohexylphosphine tetrafluoroborate P(C ₆ H ₁₁ ) ₃ •HBF ₄ -KOH. Under these conditions, the more stable trans -myrtanoic acid is also formed from cis -myrtanol (inert atmosphere, toluene, 110°C, 18 hours, 76% yield).

For the prototype selected known method for producing trans -myrtanic acid [Eigenmann, GW, & Arnold, RT (1959). Stereospecific Hydrogenation of α-Pinene Derivatives. Journal of the American Chemical Society, 81(13), 3440-3442. doi:10.1021/ja01522a072.], which includes three steps: 1) hydrogenation of myrtenic acid to cis -myrtanic acid; 2) synthesis of the methyl ester of cis -myrtanoic acid; 3) isomerization of the resulting ester into a trans -isomer, followed by hydrolysis of the ester into the target product.

The method is carried out as follows. A solution of myrtenic acid in acetic acid is hydrogenated in the presence of an Adams catalyst (PtO ₂ ) for 2 hours, the catalyst is separated by filtration, the filtrate is diluted with water, cooled and cis -myrtanoic acid is separated by filtration with a yield of 90%. Next, the solution of the resulting acid in diethyl ether is treated with an ethereal solution of diazomethane, after the completion of the reaction, the excess diazomethane is destroyed by adding acetic acid, the ethereal solution is washed with a saturated aqueous solution of NaHCO ₃ , dried and distilled. The yield of the methyl ester of cis -myrtanoic acid is 70%. The resulting ester is added to a solution of sodium methoxide obtained from sodium metal and anhydrous methyl alcohol, the mixture is boiled for 4 hours, then water is added and distilled until the temperature in the still reaches 95°C. The remaining aqueous solution is cooled, acidified with hydrochloric acid and extracted with benzene. After the UD isomer, it is 72%. The total yield of trans -myrtanoic acid per initial myrtenic acid is ~45%.

The disadvantages of this method are a rather complicated three-stage synthesis method, the absence of a highly efficient method for obtaining the starting compound - myrtenic acid, and, as a result, a low yield of the target product.

The objective of the present invention is to develop a one-stage method for the synthesis of trans -myrtanoic acid and increase its preparative yield to 58-74% of the theoretically possible.

The technical result is achieved by the fact that the method of obtaining trans -mirtanic acid consists in the oxidation of trans -mirtanol in acetic acid with a solution of CrO ₃ in a mixture of acetic acid and water at a molar ratio of the initial compounds (substrate): CrO ₃ - 1:2-3 direct (adding dropwise solution of the starting compound into a solution of an oxidizing agent) or reverse (dropwise addition of a solution of an oxidizing agent to a solution of the starting compound) by mixing the reagents at room temperature, followed by isolation of the acid through a water-soluble salt. The obtained trans -myrtanoic acid does not contain impurities of the cis isomer.

The starting compound is trans -mirtanol, which is formed in a fairly good yield by hydroboration of α-pinene or β-pinene, followed by organoborane isomerization at a temperature of 150-160°C and oxidation with hydrogen peroxide in an alkaline medium. Chromium oxide (VI) CrO ₃ is used as an oxidizing agent, and acetic acid is used as a solvent.

Scheme 1.

The method is carried out as follows:

a) Direct method of mixing reagents. To a solution of CrO ₃ in a mixture of acetic acid - water (5:1) with stirring, add dropwise a solution of trans -mirtanol in acetic acid, maintaining a temperature of ~18-20°C (room temperature). The reaction is monitored by TLC, after the disappearance of the starting alcohol spot, the reaction mixture is diluted with water, the products are extracted with diethyl ether or ethyl acetate, the ethereal extracts are washed with water, saturated NaCl solution, and dried with MgSO ₄ . After removal of the solvent, the mixture was analyzed by GLC. Next, the products are treated with 5% aqueous NaHCO ₃ solution or 3% NaOH(KOH) solution, neutral products are extracted with Et ₂ O or EtOAc, the aqueous layer is acidified with 5-10% H ₂ SO ₄ or HCl solution to pH 2-3, the released acid is extracted ether or ethyl acetate, washed until neutral, dried over MgSO ₄ . After removal of the solvent, a thick, pale yellow oil is obtained.

Example 1

To a solution of 1.95 g of CrO ₃ in 18 ml of a mixture of acetic acid and water (5:1), a solution of 1 g (0.0065 mol) of trans -mirtanol ([α] _D = -19.9° (c 0.9 EtOH)), maintaining the temperature at 18-20°C. The reaction progress was monitored by TLC until the starting compound disappeared (2 hours). Next, the reaction mixture was diluted with water, the products were extracted with EtOAc, washed with water, and dried over MgSO ₄ . After removal of the solvent, the mixture was treated with 30 ml of a 3% aqueous solution of NaOH, neutral products were separated by extraction with EtOAc. The aqueous part was acidified with 10% H ₂ SO ₄ solution to pH 2-3, the released acid was extracted with EtOAc, washed with water, dried over MgSO ₄ . The yield of trans -myrtanoic acid as a thick yellow oil was 0.629 g, 99% by GLC (63% of the starting alcohol or 58% of theoretically possible).

b) The reverse method of mixing the reagents. To a solution of trans -mirtanol in acetic acid is added dropwise a solution of CrO ₃ in a mixture of acetic acid - water (5:1) with stirring, maintaining a temperature of ~18-20°C (room). The reaction is monitored by TLC, after the disappearance of the starting alcohol spot, the reaction mixture is diluted with water, the products are extracted with diethyl ether or ethyl acetate, the ethereal extracts are washed with water, saturated NaCl solution, and dried with MgSO ₄ . After removal of the solvent, the mixture was analyzed by GLC. Next, the products are treated with 5% aqueous NaHCO ₃ solution or 3% NaOH(KOH) solution, neutral products are extracted with Et ₂ O or EtOAc, the aqueous layer is acidified with 5-10% H ₂ SO ₄ or HCl solution to pH 2-3, the released acid is extracted ether or ethyl acetate, washed until neutral, dried over MgSO ₄ . After removal of the solvent, a thick, pale yellow oil is obtained.

Example 2

To a solution of 0.75 g (0.0049 mol) of trans -mirtanol in 10 ml of acetic acid was added dropwise with stirring a solution of 1.5 g (0.015 mol) of CrO ₃ in 18 ml of a mixture of acetic acid and water (5:1), maintaining a temperature of 18-20°C. The reaction progress was monitored by TLC until the starting compound disappeared (2 hours). Next, the reaction mixture was diluted with water, the products were extracted with Et ₂ O, washed with water, and dried over MgSO ₄ . After removal of the solvent, the mixture was treated with 25 ml of 5% aqueous NaHCO ₃ solution, neutral products were separated by extraction with Et ₂ O. The aqueous part was acidified with 5% HCl solution to pH 2-3, the released acid was extracted with Et ₂ O, washed with water, dried over MgSO ₄ . The yield of trans -myrtanoic acid in the form of a thick pale yellow oil was 0.6 g, 98% by GLC (80% of the starting alcohol or 74% of theoretically possible).

Example 3

To a solution of 0.72 g (0.0047 mol) of trans -mirtanol in 10 ml of acetic acid was added dropwise with stirring a solution of 0.94 g (0.0094 mol) of CrO ₃ in 12 ml of a mixture of acetic acid and water (5:1 ), maintaining a temperature of 18-20°C. The reaction progress was monitored by TLC until the starting compound disappeared (2 hours). Next, the reaction mixture was diluted with water, the products were extracted with EtOAc, washed with water, and dried over MgSO ₄ . After removal of the solvent, the mixture was treated with 20 ml of 3% NaOH aqueous solution, neutral products were separated by extraction with EtOAc. The aqueous part was acidified with 10% H ₂ SO ₄ solution to pH 2-3, the released acid was extracted with EtOAc, washed with water, dried over MgSO ₄ . The yield of trans -myrtanoic acid as a thick pale yellow oil was 0.51 g, 99% by GLC (71% of the starting alcohol or 65% of theoretically possible).

Physicochemical characteristics and spectral data of trans -myrtanoic acid.

Oil, [α] _D = -2.4° (c 1.1 EtOH). R _f 0.28 (hexane:ether 1:1). IR: 2972, 2947, 2920, 2873, 2719, 2644, 2559, 1703 (C=O), 1458, 1415, 1386, 1367, 1298, 1238, 1209, 1143, 1074, 945, 779, ⁶⁸ 8.1H NMR (DMSO): 11.96 (1H, s, OH), 2.77 (1H, t, J=8.4Hz , C-1), 2.09 (2H, m, C-2, C-7'), 1.99 (1H, m , C-4'), 1.85 (1H, m, C-5), 1.79 (2H, m, C-3), 1.66 (1H, m, C-4”), 1.39 (1H, d, J=9.5 Hz, C-7”), 1.21 (3H, s, C-8), 0.85 (3H, s, C-9). ¹³ C NMR (DMSO-d6): 177.5 (C-10), 43.85 (C-2), 41.0 (C-1), 40.15 (C-5), 39.1 (C-6), 26.75 (C-8) , 24.35 (C-7), 24.0 (C-4), 20.55 (C-9), 16.7 (C-3). NOE: C-9↔C-2.

Claims (1)

The method of obtaining trans-mirtanol acid, which consists in the oxidation of trans-mirtanol in acetic acid with a solution of CrO ₃ in a mixture of acetic acid and water at a molar ratio of trans-mirtanol: CrO ₃ - 1: 2-3 by direct mixing of reagents by adding dropwise a solution of the original compounds into a solution of an oxidizing agent or in the opposite way - by adding dropwise a solution of an oxidizing agent to a solution of the starting compound, while the mixing of the reagents is carried out at room temperature, the isolation of trans-myrtanoic acid is carried out through a water-soluble salt.