JPS626697B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 4-oxo-2-(4-substituted phenyl)-2-cyclohexen-1-yl acetic acid represented by the following general formula []. However, R ¹ represents hydrogen or halogen. Among the compounds represented by the general formula [], compounds in which R ¹ is hydrogen are known from the literature (J.Chem.Soc.Perkin
, 1973, 1451), but compounds in which R ¹ is chlorine are unknown in the literature. The compound produced in the present invention is, for example, converted into a lower alkyl ester and then reacted with an iodinating agent to form the compound [], which can be easily led to the compound [] by hydrolyzing it with, for example, caustic alkali. be able to. However, R ¹ is the same as above, and R ² represents lower alkyl. Compound [] has excellent anti-inflammatory effect, analgesic effect, and platelet aggregation inhibitory effect, and is useful as a pharmaceutical. Therefore, the compound produced by the present invention is
It is useful as an intermediate in pharmaceutical synthesis. Among the compounds of the general formula [], compounds in which R ¹ is chlorine are described in the literature (J.Chem.Soc.Perkin
, 1973, 1451). In the conventional general formula []
Compounds in which R ¹ is hydrogen are produced using 3-(benzoyl)propionic acid as a starting material by the route shown below. ing. However, in the production of compounds in which R ¹ is chlorine, the formation of the Mannitz base in the first step does not proceed at all, which casts doubt on the wide applicability of the known method. As a result of various research aimed at establishing a simpler and generally applicable manufacturing method, the present inventors found that
A simple method in which the compound represented by the general formula [] is produced in one step by reacting 3-(4-substituted benzoyl)propionic acid ester represented by the general formula [] with methyl vinyl ketone in the presence of a base. They established this and completed the present invention. However, R ¹ and R ² are the same as above. The base used in the present invention may be one frequently used in ordinary organic synthesis reactions, but potassium tertiary nitoxide, DBU is preferably used, and the solvent is an inert solvent, preferably, Toluene and tertiary butanol are preferable. The preferred reaction temperature is 0°C to 110°C. 2-(4-substituted phenyl) represented by the general formula [] which is a product of the present invention
-2-Cyclohexen-1-yl acetic acid can be easily separated using conventional separation methods. By this method, known compounds represented by the general formula [], in which R ¹ is hydrogen, can be produced much more easily than with methods known in the literature. Therefore, the method of the present invention can be said to be the simplest method for producing the compound represented by the general formula []. Next, examples will be given to further clarify the present invention. Example 1 28.8 g of ethyl 3-(4-chlorobenzoyl)propionate and 15 g of methyl vinyl ketone were dissolved in 120 ml of tertiary butanol, and separately 5 g of metallic potassium was dissolved.
and 1/1 of the solution prepared from 100 ml of tertiary butanol.
0 amount was slowly added dropwise under ice-cooling and allowed to stand overnight at room temperature, and then an additional 9/10 amount was added dropwise to the reaction solution while stirring and refluxing, and the mixture was allowed to react for 3 hours. After cooling, tertiary butanol is distilled off under reduced pressure, and 10% hydrochloric acid is added to the residue to make it acidic. Extract with benzene and extract the benzene solution with aqueous sodium bicarbonate solution. The extract was acidified and the precipitated crystals were recrystallized from methanol to give 14.1 g of 4-oxo-2-(4-chlorophenyl)-2-cyclohexen-1-yl acetic acid, yield 41%, melting point.
Obtain 176-178°C. Elemental analysis value C ₁₄ H ₁₈ ClO ₃ Calculated value C: 63.52, H: 4.95, Cl: 13.39 Experimental value C: 63.70, H: 5.02, Cl: 13.27 Infrared absorption spectrum (KBr method) 3200-2600 (fine absorption) 1728 (-COOH), 1635 (C=C) 1607

[Formula] 827cm ^-1 nuclear magnetic absorption spectrum (CDCl ₃ ), δ, 2.2-2.7 (6H, m,

[Formula] and

[Formula]) 3.3 to 3.7 (1H, m,

[Formula]) 6.33 (1H, s,

[Formula]) 7.44 (4H, s,

[Formula]) 7.8-8.2 (1H, -COOH, disappears upon addition of _D2O ) Mass spectrum:
m/e 264 (M ⁺ , base peak) 219 (M ⁺ −
COOH), 204

[Formula] Example 2 2.4 g of ethyl 3-(4-chlorobenzoyl)propionate and 1.4 g of methyl vinyl ketone were dissolved in 10 ml of dry toluene, 1.6 g of DBU was added, and 2.
After stirring for an hour, the mixture was further stirred under reflux for 2 hours. The solvent was distilled off, and the residue was treated according to the post-treatment method of Example 1 to give 1.4% of 4-oxo-2-(4-chlorophenyl)-2-cyclohexen-1-yl acetic acid.
g, yield 45%. This completely matches the melting point and spectrum data obtained in Example 1. 4-oxo-2-phenyl-2-cyclohexen-1-yl acetic acid, melting point 139, known in a similar manner.
~142℃ (Literature value 136-137℃) [2,4-dinitrophenylhydrazone melting point 232-233℃ (Literature value 232
℃)] can be produced.

Claims (1)

[Claims] First-order general formula [] The following general formula [] is characterized by reacting a 3-(4-substituted benzoyl)propionic acid ester represented by with methyl vinyl ketone in the presence of a base. A method for producing 4-oxo-2-(4-substituted phenyl)-2-cyclohexen-1-yl acetic acid represented by However, R ¹ represents hydrogen or halogen, and R ² represents lower alkyl.