RU2756658C1 - Method for producing cis-mirtanol acid - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a method for producing cis-myrtanol acid. The method consists in the oxidation of cis-myrtanol in acetic acid with a solution of CrO₃ in a mixture of acetic acid and water at a molar ratio of substrate: CrO₃ 1:1.5-3.0 by the reverse method for mixing reagents, by adding an oxidizer drop by drop into the solution of the initial compound, maintaining a reaction temperature of 13-20°С, followed by the release of acid through a water-soluble salt.

EFFECT: method makes it possible to increase the yield of the target product to 58-60%.

1 cl, 2 ex, 1 tbl

Description

The invention relates to the field of organic chemistry, namely to a method for producing cis- myrtanic acid, the derivatives of which, containing amide and acetylthiourea fragments, exhibit fungicidal activity against a number of 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].

The literature describes methods for the preparation of cis- myrtanic acid starting from myrtenol and myrtenic acid. Thus, myrtenol is hydrogenated over PtO ₂ and the resulting cis- mirtanol is oxidized with the KMnO ₄ -H ₂ SO _{4 system} , the acid yield is ~ 32% for the initial alcohol. In the second case, the hydrogenation of myrtenic acid is carried out in the presence of an Adams catalyst, the yield of cis- myrtanic acid is 90% [Eigenmann, GW; Arnold, RT Stereospecific Hydrogenation of α-Pinene Derivatives. J. Am. Chem. Soc. 1959, 81 (13), 3440-3442. doi: 10.1021 / ja01522a072], but the literature does not describe a highly efficient method for the synthesis of myrtenic acid, which requires at least three stages - the oxidation of α-pinene to myrtenal, the reduction of the aldehyde to myrtenol, and the oxidation of the latter to myrtenic acid.

It is much easier and more efficient to synthesize cis- myrtanic acid starting from cis- myrtanol. It is possible to carry out a two-stage “one-pot” process - hydroboration of β-pinene with a hydroboration reagent - borane-dimethyl sulfide from Aldrich (H ₃ B-SMe ₂ ), followed by oxidation of organoborane with pyridinium dichromate [Brown, HC; Kulkarni, SV; Khanna, VV; Patil, VD; Racherla, US Organoboranes for Synthesis. 14. Convenient Procedures for the Direct Oxidation of Organoboranes from Terminal Alkenes to Carboxylic Acids. J. Org. Chem. 1992, 57 (23), 6173-6177. doi: 10.1021 / jo00049a024]. The yield of cis- myrtanic acid was ~ 50%.

Authors of the work [Veeraiah, T .; Periasamy, M. A Simple Convenient Method for the Conversion of Primary Alcohols Into Carboxylic Acids Using NaBrO ₃ -HBr / CCl ₄ / T-BuOH System. Synthetic Communications 1989,19 (11-12), 2151-2157. https://doi.org/10.1080/00397918908052610] proposed a method for converting primary alcohols into the corresponding acids using a multicomponent oxidizing system - NaBrO ₃ -HBr-CCl ₄ - t -BuOH. An excess of tert- butyl alcohol is needed to prevent the formation of esters between the starting alcohol and the resulting aldehyde. Cis- myrtanic acid was obtained by the authors with a yield of about 64%.

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.], a rather laborious and complex method was proposed for the preparation of carboxylic acids using silver nanoparticles formed in situ (Ag ₂ CO ₃ -MnBr ₂ -KOH-polyvinylpyrrolidone PVP-mesitylene). The yield of products reaches 94%, but cis- mirtanol under these conditions is completely converted into thermodynamically more stable trans- mirtanic acid (yield 78%).

A known method of producing cis- myrtanic acid [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], chosen as a prototype, in which a solution of CrO ₃ in acetic acid was used for the synthesis of cis- myrtanic acid ( 1 ) at a substrate: oxidizer ratio of 1: 3 using a direct method of mixing reagents, that is, the substrate is gradually added to oxidizing agent. Myrtanol (0.2 mol) was dissolved in glacial acetic acid (200 ml) and the solution was slowly added to a solution of chromic anhydride (0.6 mol) in glacial acetic acid (250 ml) and water (50 ml). The mixture was stirred at room temperature. After 10 hours, the mixture was poured into water and the precipitate was filtered off. The resulting precipitate was dissolved in saturated aqueous sodium hydroxide solution, extracted with EtOAc (2 × 50 ml). The resulting aqueous phase was neutralized with 10% hydrochloric acid, extracted with EtOAc (3 × 50 ml). The resulting organic phase was washed with water (3 × 50 ml) and saturated NaCl solution (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give cis- myrtanic acid as a white solid. The preparative yield of cis- myrtanic acid 2 was 24.5%. Our experiments practically confirmed this result - on average, the yield of acid in the form of a crude product containing 8-10% of trans- myrtanic acid 3 as an impurity was 30-35%.

Scheme 1

The disadvantage of this method is the low yield of the target product associated with the formation of a significant amount of side compound - nopinone.

The proposed invention makes it possible to increase the yield of cis- myrtanic acid to 58-60% of the theoretically possible and significantly reduce the formation of the off-target product nopinone.

The technical result is achieved by the fact that the method for producing cis- myrtanic acid consists in the oxidation of cis- mirtanol in acetic acid with a solution of CrO ₃ and the isolation of the target product, characterized in that the oxidation is carried out in a mixture of acetic acid and water at a molar ratio of substrate: CrO ₃ - 1 : 1.5-3.0 by the reverse method of mixing the reagents, namely by adding the oxidizing agent dropwise to the solution of the starting compound, maintaining the reaction temperature at 13-20 ° C, followed by the separation of the acid through a water-soluble salt.

The starting compound is cis-myrtanol, which is formed in high yield (up to 96%) by hydroboration of β-pinene followed by the oxidation of organoborane H ₂ O ₂ in an alkaline medium. Chromium (VI) oxide CrO ₃ is used as an oxidizing agent, and acetic acid is used as a solvent.

The method is carried out as follows.

_{A solution of CrO 3} in a mixture of acetic acid with water (5: 1) is added dropwise to a solution of cis- mirtanol in acetic acid with stirring and cooling to 13-20 ° C. The reaction was monitored by TLC, after the disappearance of the spot of the starting alcohol 1, the reaction mixture was diluted with water, the reaction products were extracted with ether or ethyl acetate, the ether extracts were washed with water, saturated NaCl solution, and dried over MgSO ₄ . After removal of the solvent, the reaction mixture is analyzed by GLC. Next, the reaction products are treated with a 5% aqueous solution of NaHCO ₃ or 3% aqueous NaOH (KOH), neutral products are extracted with Et ₂ O or EtOAc, the aqueous layer is acidified with dilute H ₂ SO ₄ or HCl (5-10%), the acid is extracted with ether or ethyl acetate, washed with water until neutral and dried. When the solvent is distilled off, the acid crystallizes; further purification is carried out by crystallization from a mixture of hexane with ether. The results of the synthesis of cis- myrtanic acid are shown in Table 1.

Table 1

Like. corresponding
wearing
S: CrO ₃ ^* time, hour Tempe-
temperature, ° C mixing method GLC content ^** ,% a drug. output, % 2 3 1: 3 4-5 20-25 straight 42-50 3-4 30-35 (gen.)
8-10 ( 3 ) 1: 1.5 2 13-15 back 58 1.5 48 1: 2 2 13-15 back 60 2.0 48 1: 3 2 17-20 back 70 2.0 58 ^* - AcOH solvent
^** - conversion of cis- mirtanol 1 100% in all experiments

EXAMPLE 1 To a solution of 2 g (0.013 mol) of (-) - cis -mirtanola _{([α] D -16.4 (c} 1.4 EtOH)) in 20 ml of acetic acid was dropwise added a solution of 1.95 g (0.0195 mol) CrO ₃ in 18 ml of a mixture of acetic acid and water (5: 1), maintaining the temperature at 13-15 ° C. The reaction progress was monitored by TLC method until the disappearance of the starting compound (1.5 hours). Then the reaction mixture was diluted with water, the products were extracted with diethyl ether, washed with water, and dried over MgSO ₄ . After removal of the solvent, the mixture was treated with 40 ml of a 5% aqueous NaHCO ₃ solution, the neutral part was separated by extraction with diethyl ether, the aqueous part was acidified with 10% H ₂ SO _4, and the acid was isolated by extraction with diethyl ether, washed with water, and dried over MgSO ₄ . The yield of the crystalline product is 1.05 g (52% for the initial alcohol or 48% of the theoretically possible).

Example 2. To a solution of 2.9 g (0.019 mol) of (-) - cis- mirtanol ([α] _D -16.4 (with 1.4 EtOH)) in 25 ml of acetic acid with stirring, a solution of 5.6 g (0.056 mol) CrO ₃ in 30 ml of a mixture of acetic acid and water (5: 1), maintaining the temperature at 17-20 ° C. The reaction progress was monitored by TLC method until the disappearance of the starting compound (2 hours). Then the reaction mixture was diluted with water, the products were extracted with ethyl acetate, washed with water, dried over MgSO ₄ . After removal of the solvent, the mixture was treated with 40 ml of a 3% aqueous NaOH solution, the neutral portion was separated by extraction with ethyl acetate, the aqueous portion was acidified with 10% H ₂ SO _4, and the acid was isolated by extraction with ethyl acetate, washed with water, and dried over MgSO ₄ . The yield of the crystalline product is 1.82 g (63% for the starting alcohol or 58% of the theoretically possible).

Physicochemical characteristics and spectral data of cis- myrtanic acid (2). [α] _D -38.4 (c. 0.5 EtOH); T _pl 106-109 ° C; IR (ν, cm ^-1 ): 3064 (-OH), 2987, 2951, 2922, 2872 (CH), 1681 (C = O), 1475, 1458 (CH), 1413 (-OH), 1321 (CH) , 1255 (CO), 948 (OH); NMR ¹ H (300 MHz, CDCl ₃ ): 0.87 (s, 3H), 1.19 (d, J = 9.30 Hz, 1H), 1.21 (s, 3H), 1.77 - 1.91 (m, 1H), 1.91 (tq, J = 9.20, 4.60 Hz, 1H), 1.95 (qt, J = 12.00, 5.40 Hz, 2H), 2.27 (d, J = 12.00 Hz, 1H), 2.32 (dq, J = 12.00, 6.00 Hz, 1H), 2.49 (dt, J = 5.58, 4.90 Hz, 1H), 2.98 (dt, J = 10.42, 3.30 Hz, 1H). ¹³ C (75 MHz, CDCl ₃ ): 15.08 (CH2), 21.52 (CH3), 24.61 (CH2), 26.88 (CH3), 29.02 (CH2), 38.75 (C), 40.33 (CH), 42.97 (CH), 43.75 (CH), 183.07 (COOH). ESI-MS: m / z 167 [MH] ^- .

Claims (1)

A method for producing cis- myrtanic acid, which consists in the oxidation of cis- mirtanol in acetic acid with a solution of CrO ₃ and the isolation of the target product, characterized in that the oxidation is carried out in a mixture of acetic acid and water at a molar ratio of substrate: CrO ₃ 1: 1.5-3.0 in the reverse way mixing the reagents by adding the oxidizing agent dropwise to the solution of the starting compound, maintaining the reaction temperature at 13-20 ° C, followed by the separation of the acid through the water-soluble salt.