RU2320637C1 - Method for preparing4,4-dimethoxy-2,3,5-trichlorocyclopent-2-en-1-one - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 4,4-dimethoxy-2,3,5-trichlorocyclopent-2-en-1-one from hexachlorocyclopentadiene. Method involves carrying out two successive steps - interaction of hexachlorocyclopentadiene with potassium hydroxide in methanol medium in the ratio = 1:(8-10) at temperature 20-22°C for 24 h in a single reactor and acid hydrolysis of formed intermediate substance with 50% aqueous sulfuric acid without its isolation. The end substance is isolated by vacuum distillation with the yield 75-80% and purity 96-98%. Invention allows excluding the high cost and difficultly available reagents, simplifying the process and increasing yield of the end substance.

EFFECT: improved method of synthesis.

1 cl, 1 ex

Description

The invention relates to organic chemistry, specifically to a method for producing 4,4-dimethoxy-2,3,5-trichlorocyclopent-2-en-1-one of the formula (I),

which can be used as an intermediate in the synthesis of natural chlorine-containing cyclopentenones, in particular, a highly active antibiotic and cryptosporiopsin fungicide [1, 2], as well as chlorovulones and punaglandins, effective prostanoids of antiviral and anti-cancer action isolated from sea corals [3-5].

Known methods for producing compound (I) starting from hexachlorocyclopentadiene (HCCP) [6-10].

The two-stage method for the production of cyclopentenone (I), proposed by the authors of [6, 7], involves the photoreaction of HCCPD in a solution of ethyl acetate (EtOAc). With the conversion of 70-80% of HCCPD, the yield of the acetoxy derivative (II), isolated by chromatography from a complex mixture of products, is only 5-15% [6]. The second stage of this process is the mixing of 0.001 M of derivative (II) with a 5-fold excess of potassium hydroxide (KOH) in methanol (MeOH) (3 h, 20 ° С). Subsequent processing of the reaction mixture (evaporation, extraction with diethyl ether, concentration of the solution) and chromatographic purification on silica gel (SiO ₂ ) lead to the target compound (I) with a yield of 92% [7] and a total yield of 4–13% based on the initial HCLC.

The main disadvantage of this scheme is the extremely low selectivity and yield at the photochemical stage of the process. In addition, the disadvantages include the need to use special equipment and the chromatographic separation of both the target (I) and intermediate (II) compounds that complicate the process technology.

The second known way - 3-stage preparation (I) [8] is based on the interaction of the dimethoxy derivative (III) [9] with the sodium derivative of borneol. First, according to the method of [8], by the interaction of HCPCP with KOH (1: 2.6) in MeOH at 30-40 ° С (12 h), 5.5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene (III) (DMTCPPD) is obtained with a yield of 62% after vacuum distillation. Further, according to the synthesis scheme [8], a solution of DMTCPPD in DMSO is added to a sodium alcoholate obtained by acting on a solution of isobornoleol sodium hydride (NaH) in DMSO, stirred for 5 hours, decomposed with water and extracted with ethyl acetate. After washing the organic extract with a saturated solution of sodium chloride (NaCl), drying with magnesium sulfate (MgSO ₄ ), evaporation and chromatographic purification on SiO ₂ in 60% yield, vinyl ether (IV) was obtained. The latter decomposes slowly at room temperature (fragmentation stage, 30 days) with the formation of the target compound (I) in 80% yield and camphene, the separation of which from the target (I) is also carried out by chromatography. The yield of compound (I) based on dimethoxy derivative (III) is 48%, and on HCCP ~ 30%.

The disadvantages of this three-stage scheme include the use of expensive DMSO and NaH (and the use of inert gases such as nitrogen or argon associated with the use of this organometallic reagent), inaccessible borneol, the need for double chromatographic purification on a column with SiO ₂ (as an intermediate vinyl ether (IV), and target compound (I)). In addition, an important disadvantage of this approach is the long duration (~ 30 days) of the ether (IV) fragmentation stage and a low overall yield (~ 30% from HCCP).

The closest prototype of the present invention, the selected method of obtaining the target compound (I) from (DMTHCPD) (III) by the action of Na-derivatives of tertiary alcohols [10]. Prepared separately by dissolving metallic sodium (Na) in the corresponding alcohol (tert-butyl alcohol, 2-methyl-2-decanol, 1-vinylcyclohexan-1-ol), the Na-alcoholate is mixed with a solution of dimethoxy derivative (III) in DMSO (DMTCTCPD: RONa ratio = 1: 0.8) obtained by the interaction of HCPCP with KOH in MeOH (similar to that described above [8]), and the mass was stirred at room temperature for 24 hours. After processing the reaction mixture, including neutralization with 10% hydrochloric acid and extraction with chloroform (CHCl ₃₎ (3 × 300 ml), the title compound (I) is isolated from the mixture with the corresponding olefin by vacuum distillation (for sodium tert-butylate), or by chromatography on SiO ₂ (for high boiling alcohols) in yields of 70-80%. The total yield (I) of HCCPD is 40-50%.

R ¹ = R ² = CH ₃ , R ² = C ₈ H ₁₇ (a); R ¹ = R ² = R ³ = CH ₃ (b); R ¹ = R ² = cyclohexyl, R ³ = vinyl (c)

The disadvantages of the known two-stage method of the prototype are, firstly, the need for separate production of dimethoxy derivative (III) and sodium derivatives of tertiary alcohols; secondly, the use of an expensive solvent DMSO, metallic Na and tertiary alcohols and, thirdly, the preparation of the target compound (I) is accompanied by the formation simultaneously with the target (I) of the corresponding olefins, the dehydration products of the used alcohols, and the isolation of the target compound (I) requires carrying out complex technological methods, in particular, the need for chromatographic purification at the final stage (except for the use of tert-butanol).

The problem to which the invention is directed, is to simplify the process and increase the yield of the target compound (I).

According to the proposed two-stage "one-pot" method, a mixture of HCPCP and KOH in MeOH taken in a molar ratio of 1: (8-10) is stirred at 20-22 ° C for 24 hours and the intermediate compound (V) is hydrolyzed without isolation by adding 50 % aqueous solution of sulfuric acid (H ₂ SO ₄ ) to pH 1 and stirring at 20-22 ° C for 10 hours. Then MeOH is evaporated on a rotary evaporator, the product is extracted with EtOAc (3 × 100 ml). The combined organic extracts were washed with water, a saturated NaCl solution, dried with MgSO _4, and after distillation in vacuo, the target compound was isolated in 75-80% yields based on HCCP and 96-98% purity (according to gas-liquid chromatography).

The advantages of the proposed method, in comparison with the prototype, are, firstly, the exclusion of the inaccessible and expensive reagents, as well as organometallic reagents (Na, NaH) during the process, which eliminates the need for inert gases, and secondly, the possibility of implementation two consecutive stages in one reactor (flask) (“one-pot”), thirdly, in the technological simplicity of product purification (single vacuum distillation), fourthly, in a higher yield of the target product (75-80%).

The invention is confirmed by the following example.

Example. A mixture of 27.3 g (0.1 m) of HCCPD, 56.0 g (1.0 m) of KOH in 140 ml of MeOH is stirred at 20-22 ° C for 24 hours. Then the reaction mass is cooled to 0 ° C and a 50% aqueous solution is added dropwise with stirring. H ₂ SO ₄ to pH 1. The resulting mass was stirred at 20-22 ° C for 10 h, the precipitated salt (KCl) was filtered off, MeOH was evaporated on a rotary evaporator, and the product was extracted with EtOAc (3 × 100 ml). The combined organic extracts were washed with water, saturated NaCl. After drying the organic extract with MgSO _{4, the} solvent was evaporated on a rotary evaporator and the residue was distilled in vacuo. Get 18.4 g (75%) crystallized upon standing oily compound (I), so Kip. 100-103 ° C at 0.2 mm Hg

4,4-Dimethoxy-2,3,5 trichlorocyclopent-2-en-1-one (I). Colorless crystals with so pl. 52-54 ° C (R _f = 0.75, petroleum ether - ethyl acetate, 1: 1). IR spectrum, ν, cm ^-1 : 1596, 1620, 1636, 1696, 1752. ¹ H NMR spectrum, δ, ppm: 3.30 s (3H, OCH ₃ ), 3.50 s (3H, OCH ₃ ), 4.64 s (1H, C ⁵ H). ¹³ C NMR spectrum, δ, ppm: 52.03 (OCH ₃ ), 52.07 (OCH ₃ ), 62.19 (C ⁵ ), 100.49 (C ⁴ ), 133.77 (C ² ), 157.65 (C ³ ), 186.17 ( C ¹ ). Mass spectrum, m / z (I _Rel ,%): 249 (7.5), 247 (22.3), 245 (27.3) [M] ⁺ 218 (31.4), 216 (93.6), 214 (100) [M-OCH ₃ ] ⁺ , 212 (19.8), 210 (30.9) [M-Cl] ⁺ 190 (4.9), 188 (14.0), 186 (15.5) [M-CH ₃ O-CO] ⁺ 136 (6.1), 134 ( 13.8), 112 (2.5), 110 (9.7), 108 (13.3), 97 (31.9), 89 (7.4), 87 (22.8), 69 (11.9), 59 (17.7) [OSOSN ₃ ] ⁺ , 55 ( 11.1), 41 (8.0), 38 (5.5), 36 (14.8) [HCl] ⁺ 28 (23.9). Found,%: C 34.10; H, 2.82; Cl 43.40. C ₇ H ₇ Cl ₃ O ₃ . Calculated,%: C 34.25; H 2.87; Cl 43.60.

Literature

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Claims (1)

The method of obtaining 4,4-dimethoxy-2,3,5-trichlorocyclopent-2-en-1-one of the formula I

by reacting hexachlorocyclopentadiene with potassium hydroxide in methanol, characterized in that the process is carried out at a molar ratio of hexachlorocyclopentadiene: potassium hydroxide equal to 1: (8-10), at a temperature of 20-22 ° C for 24 hours, followed by acid hydrolysis of the resulting intermediate product without its selection and the selection of the target product by vacuum distillation.