KR100376280B1 - Method for preparing cinnamaldehyde derivatives - Google Patents

Abstract

PURPOSE: Provided is a method for preparing cinnamaldehyde derivatives, which are useful as substituents at the position of C-5 in thiazolidin-4-one derivatives useful in the medical and agricultural chemical fields. CONSTITUTION: The method comprises the steps of: reacting a substituted benzaldehyde represented by formula (II) with a substituted cyanoacetic acid represented by formula (III) under reflux in the presence of a base to form a substituted cinnamonitrile represented by formula (IV); and reducing the cinnamonitrile represented by formula (IV) at -30 to -40 deg.C and treating with hydrochloric acid to form a cinnamaldehyde derivative represented by formula (I): wherein R1 is H, a C1-C4 alkyl, or a phenyl non-substituted or substituted with a halogen atom, a C1-C3 alkyl or a C1-C3 alkoxy; R2-R6 are the same or different H, a halogen atom, OH, nitro, a C1-C4 alkyl, a C1-C4 alkoxy or a C1-C3 haloalkyl.

Description

Method for preparing cinnamic aldehyde derivative

The present invention relates to a process for preparing cinnamic aldehyde derivatives, and more particularly, by reacting a compound represented by the following structural formulas (II) and (III) (E), (Z) -substituted represented by the following structural formula (IV) The present invention relates to a method for preparing cinnamonitrile, reducing and hydrochloric acid to prepare (E) -cinnamaldehyde derivatives represented by the following structural formula (I).

In the above formula,

R ¹ is a hydrogen atom, a C ₁ to C ₄ alkyl group, a phenyl group, or a halogen atom, a C ₁ to C ₃ alkyl group or a C ₁ to C ₃ alkoxy group substituted with a phenyl group;

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as or different from each other, and each hydrogen atom, halogen atom, hydroxy group, nitro group, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group or it represents a haloalkyl group of C ₁ ~ C _3.

Thiazolidin-4-one derivatives are induced by the dual action of platelet activating factor (PAF) receptor antagonists, 5-lipooxygenase inhibitors, or platelet activating factor receptor antagonists and 5-lipooxygenase inhibitors. Thiazoli, which is well-known for its usefulness in the prevention and treatment of diseases, allergic diseases, shock, circulatory diseases, myocardial infarction, asthma, pulmonary edema and respiratory diseases, also represented by the following structural formula A din-4-one derivative has been patented (Korean Patent Application No. 94-38,787).

Accordingly, the inventors of the present invention have studied the preparation method of cinnamic aldehyde derivatives used as substituents in the C-5 position in the thiazolidin-4-one derivative represented by the above structural formula (A). The present invention was completed by preparing cinnamic aldehyde derivative represented by the above formula (I) in high yield using substituted benzaldehyde represented by the formula (III) and substituted cyanoacetic acid represented by the above formula (III) as starting materials. .

Accordingly, an object of the present invention is to provide a process for preparing cinnamic aldehyde derivatives useful as C-5 position substituents of various thiazolidin-4-one derivatives industrially.

Hereinafter, the present invention will be described in detail.

The present invention provides a substituted cinnamonitrile represented by the following formula (IV) by refluxing the substituted benzaldehyde represented by the following formula (II) with the substituted cyanoacetic acid represented by the following formula (III) in the presence of an amine base. (cinnamonitrile); It is characterized by a method of producing a cinnamic aldehyde derivative represented by the following formula (I) by reducing the substituted cinnamononitrile represented by the formula (IV) at -30 ~ -40 ℃ and treated with aqueous hydrochloric acid solution.

Referring to the present invention in more detail as follows.

The present invention relates to a process for preparing cinnamic aldehyde derivatives useful as substituents of thiazolidin-4-one derivatives, which are well known as useful substances in medicine and pesticides. The manufacturing process of the present invention is briefly described as follows.

[Scheme]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, respectively.

First, 1 mole of substituted benzaldehyde represented by the structural formula (II) and 1.5 to 3.0 mole of substituted cyanoacetic acid represented by the structural formula (III) are refluxed in the presence of an amine base to be represented by the structural formula (IV). Substituted cinnamonitrile is prepared. In this case, as an amine base (secondary amine), for example, piperidine, pyrrolidine, dimethylamine, diethylamine or dipropylamine, etc. are used, the amount of which is represented by the structural formula (II) It is 1.0-5.0 mol with respect to 1 mol of substituted benzaldehydes. At this time, toluene, benzene, xylene or the like is used as the reaction solvent.

The substituted cinnamonitrile represented by the above formula (IV) prepared by the above preparation method is a stereoisomer, and the (E) -isomer and the (Z) -isomer are produced in a molar ratio of 70:30 to 80:20. . Each of these stereoisomers can be easily separated by a conventional separation method such as chromatography, recrystallization, etc. In the present invention, the stereoisomers of substituted cinnamonitriles represented by the above formula (IV) are separated or separated. It can be used for the next reaction in the mixture without.

When the substituted cinnamonitrile represented by Structural Formula (IV) is reduced at -30 to -40 ° C and treated with aqueous hydrochloric acid solution, cinnamic aldehyde derivative represented by Structural Formula (I) is prepared as (E) -isomer. In the reduction reaction, diisopropyl aluminum hydride, diisobutyl aluminum hydride, lithium diethoxy aluminum hydride or lithium triethoxy aluminum hydride is used as the reducing agent, and as reaction solvent, benzene, toluene, tetrahydro Furan and the like are used.

According to the production method of the present invention as described above (E)-cinnamic aldehyde derivative represented by the formula (I) is prepared in a high yield of 85% or more.

If the present invention will be described in more detail based on the following examples, the present invention is not limited thereto.

Example 1: Preparation of 3,5-dimethyl-4-hydroxycinnamonitrile (formula IV)

3,5-dimethyl-4-hydroxybenzaldehyde (5.0 g, 33.3 mmol) and cyanoacetic acid (10.0 g, 117 mmol) were dissolved in toluene (17 ml), followed by piperidine (13.7 g, 161 mmol). ) Was added. After refluxing for 2 hours, the mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and then washed twice with water and 1.0 N aqueous hydrochloric acid solution. After drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure, a yellow solid was obtained. The solid was recrystallized from ethyl acetate and hexane to give 5.55 g (96% yield) of the title compound.

(E) -isomer

Yield: 72%

(Z) -isomer

Yield: 24%

Example 2 Preparation of (E) -3,5-dimethyl-4-hydroxycinnamaldehyde (Formula I)

(E, Z) -3,5-dimethyl-4-hydroxycinnamonitrile (5.55 g, 32.0 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to -35 ° C, followed by diisobutylaluminum hydride ( 1.5 M toluene solution, 50 ml, 75.0 mmol) was added slowly. After addition, the mixture was stirred at -35 ° C for 30 minutes, and then 1.0N aqueous hydrochloric acid solution (200ml) was slowly added at room temperature, followed by stirring for 3 hours. The reaction solution was extracted with ethyl acetate (100 ml × 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized with ethyl acetate and hexane to obtain 5.36 g (yield 95%) of the title compound.

Cinnamic aldehyde derivatives were prepared as shown in Table 1 by the preparation method of Example 1 and Example 2.

Table 1

Claims (4)

Substituted benzaldehyde represented by the following structural formula (II) and the substituted cyanoacetic acid represented by the following structural formula (III) are refluxed in the presence of an amine base, and substituted cinnamonitrile represented by the following structural formula (IV) To prepare; Method for producing a cinnamic aldehyde derivative represented by the following formula (I), characterized in that the substituted cinnamononitrile represented by the formula (IV) is reduced at -30 ~ -40 ℃ and treated with hydrochloric acid. In the above formula, R ¹ is a hydrogen atom, a C ₁ to C ₄ alkyl group, a phenyl group, or a halogen atom, a C ₁ to C ₃ alkyl group or a C ₁ to C ₃ alkoxy group substituted with a phenyl group; ^{R 2, R 3, R 4} , R 5 and R ⁶ are the same or different as each a hydrogen atom, a halogen atom, hydroxyl group, nitro group, C ₁ ~ alkyl group of C _4, C ₁ ~ C ₄ alkoxy group or it represents a haloalkyl group of C ₁ ~ C _3. The method of claim 1, wherein piperidine, pyrrolidine, dimethylamine, diethylamine or dipropylamine is used as the amine base. [Claim 2] The preparation of cinnamic aldehyde derivatives according to claim 1, wherein diisopropyl aluminum hydride, diisobutyl aluminum hydride, lithium diethoxy aluminum hydride or lithium triethoxy aluminum hydride is used as the reducing agent. Way. The cinnamonitride derivative according to claim 1, wherein the cinnamonitrile represented by the structural formula (IV) is (E) -isomer, (Z) -isomer or (E), (Z) -isomer mixture. Way.