JPH0248533B2 - BENZENJUDOTAI - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention provides a novel (4-benzyloxy) compound useful as an intermediate for producing ω-(1-imidazolyl)pentyloxybenzene derivatives having excellent lipid-lowering and platelet aggregation inhibiting effects. It relates to phenyl (5-halogenopentyl) ether. (Solution Means of the Invention) More specifically, the present invention provides the general formula (In the formula, X represents a halogen atom. The same applies hereinafter.) (4-benzyloxy)phenyl (5
-halogenopentyl) ether. The halogen atom represented by X in the above general formula is, for example, a chlorine atom, a bromine atom, an iodine atom, or the like. (Prior Art) The compound () of the present invention is a compound characterized in its chemical structure in that it has a phenyl group having a benzyloxy group at the 4-position and a pentyl group having a halogen group at the 5-position. No known literature describing the compound has been found. (Manufacturing method) The compound of the present invention can be manufactured by the method shown by the following reaction formula. (In the formula, M represents a hydrogen atom or a sodium atom.) To produce the target compound of the present invention by this production method, sodium phenoxide (, M=Na)
and 1,5-dihalogenopentyl () by a conventional method in a benzene-dimethylformamide mixture, or by using phenol (, M=H) in place of phenoxide, methyl ethyl ketone,
The reaction is carried out in a solvent such as ethanol in the presence of an alkali (potassium carbonate, etc.). (Effect of the invention) The compound of the present invention is useful as a pharmaceutical ω-(1
-imidazolyl) is useful as a raw material for producing pentyloxybenzene derivatives. For example, the compound described in Japanese Patent Application No. 56-211058 has a lipid-lowering effect, particularly an excellent cholesterol- and triglyceride-lowering effect, and also has a platelet aggregation-inhibiting effect, and is effective against arteriosclerosis, cerebral infarction, and cancer. It is useful in the prevention and treatment of hyperischemic attack, angina pectoris, peripheral thrombosis and occlusion. In addition, the compounds of the present invention are disclosed in Japanese Patent Application No. 58-113988,
It is also useful as a raw material for producing the compounds described in No. 61-150078. The lipid-lowering effect of the compound of Reference Example 1 produced using the compound of the present invention as a raw material is shown below.

[Table] Lipid-lowering effect: Sprague-Dawley at 3 weeks old
Dawley male rats were fed a diet containing 1.5% cholesterol and 0.5% bile acids for 7 days, and for the last 4 days, the compound of the present invention suspended in a 0.5% methylcellulose aqueous solution was administered once a day by oral probe. After an overnight fast, blood was collected under ether anesthesia, and serum total cholesterol and HDL levels were measured.
Cholesterol measurement is performed by “Schettler, G.
Nu¨ssel; Arbeitsmed. Sozialmed. Pra¨ventivmed.
10, 25 (1975)” and
Measurement of HDL is performed by “TTIshikawaetal; Lipids, 11 ,
628 (1976)''. (Example) In order to explain the present invention more specifically, examples are listed below. In addition, using the compound of the present invention as a raw material, ω-(1 A specific example of producing a pentyloxybenzene derivative (-imidazolyl) is used as a reference example. Example 1 4-benzyloxyphenol sodium 22.0
g and 28.5 g of 1,5-dibromopentane in a benzene-dimethylformamide mixture (1:2 volume ratio).
Pour into a volume of 150 ml, heat to 80°C, and stir overnight to react. Pour this reaction solution into 500 ml of ice water, add 100 ml of benzene and stir, then separate the benzene layer, wash it sequentially with a 5% aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the remaining oil was subjected to silica gel column chromatography, the target product was eluted using n-hexane-benzene mixture (2:1 volume ratio) as the eluent, and the solvent was removed. The residue was then rectified under reduced pressure to obtain [4-benzyloxy]phenyl[5-bromopentyl]ether. Melting point 45-43℃ Reference example 1 Sodium hydride (60% suspension in mineral oil) 0.8g
After washing with dry benzene, 60 ml of dry dimethylformamide are added thereto, and an additional 1.36 g of imidazole is added while stirring at room temperature. After the intense foaming subsided, the suspension was heated to 80°C.
Heat and stir for 30 minutes, then cool to room temperature. A solution prepared by dissolving 6.33 g of [4-benzyloxy]phenyl[5-bromopentyl]ether obtained in Example 1 in 10 ml of dry dimethylformamide was added to the mixture, and the mixture was heated and stirred at 80 DEG C. for 4 hours. After evaporating the solvent from the reaction solution under reduced pressure, the residue was dissolved in methylene chloride, washed successively with a 5% aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a small amount of n was added to the remaining oil.
- Add hexane to crystallize and obtain the desired [4
-benzyloxy]phenyl[5-(1-imidazolyl)pentyl]ether was obtained. Melting point 63-64℃ Elemental analysis value (as C ₂₁ H ₂₄ N ₂ O ₂ ) C (%) H (%) N (%) Theoretical value 74.97 7.19 8.33 Experimental value 74.85 7.16 8.22 Reference example 2 [4-benzyloxy]phenyl[5-(1-
4 g of (imidazolyl)pentyl]ether was dissolved in 30 ml of ethyl acetate, 0.1 g of 10% palladium on carbon was added, and the mixture was reacted under normal pressure with stirring in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. After removing the palladium on carbon, the solvent is distilled off under reduced pressure to obtain the desired hydroquinone mono[5-(1-
(imidazolyl)pentyl]ether was obtained quantitatively. Melting point: 138-19°C Furthermore, this compound is mixed with a suitable acylating agent, alkylating agent, or isocyanate compound by a conventional method.
By reacting, various ω-(1-imidazolyl)pentyloxybenzene derivatives can be obtained (see Japanese Patent Application No. 56-211058).

Claims (1)

[Claims] 1. General formula (In the formula, X represents a halogen atom.) (4-benzyloxy)phenyl (5
-halogenopentyl) ether.