KR790001648B1 - Process for the preparation of trimethoxy benzyl piperazino ethanol deriyatives - Google Patents

Abstract

Title compds. (I; A = CH2CH(X)OH, -CH2CHCH2O(X = H, lower alkyl, oxymethyl, phenyl, or phen- oxymethyl)) were prepd. by the reaction of II with epoxy. Thus, 34g II. HC1 was soluted in 500ml C2H5OH contg. 5.0g metal Na and C2H5OH removed under reduced presure and then 15g β-bromo hydrine and 15g CaCO3 were added to said residue in 150ml DMF and stirred at 80-90≰C for 3hr to give I.

Description

Method for preparing trimethoxy benzyl piperazino ethanol derivative

The present invention relates to a method for preparing trimethoxybenzylpiperazino ethanol derivative represented by the following general formula (I).

혹은

(Where A is

or

X is hydrogen, lower alkyl group, oxymethyl group, phenyl group or phenoxy methyl group)

The compound of the present invention is a novel substance in the literature, and exhibits useful pharmacological action against the circulatory system such as coronary vasodilation and cardiomotor inhibition.

As an example of these pharmacological actions, the cardiovascular activity by the Langendorff method in the molar extract heart and LD ₅₀ values for mice are shown in the first table.

[Table 1]

Compounds included in the present invention can be synthesized by any of a variety of methods, but the most common and convenient is represented by the following chemical formula (II)

It can synthesize | combine by making various epoxy compounds react with trimetadiazine.

In addition, the N-alkylation method which makes a halohydrin act on a compound of formula (II), or the method of performing trimethoxy benzylation on piperazino ethanol is also advantageous. In addition to the above method, the piperazine cyclization method using ethanol amines and the structural formula (II) compound can be synthesized by first reacting with the α-halocarbonyl compound and then reducing.

It will be described in more detail by the following examples.

Example 1 (A: -CH ₂ CH ₂ OH)

34 g of hydrochloride (melting point 215-222 ° C.) of compound (II) was dissolved in 500 ml of ethanol in which 5.0 g of metallic sodium was dissolved. The residue was dissolved in 150 ml of DMF, 15 g of β-bromohydrin was added thereto, and 15 g of anhydrous potassium carbonate was added thereto, followed by warming and stirring at 80-90 ° C. for 3 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. Recrystallize with.

Melting point 220-225 ° C., yield 27.8 g

Example 2 (A: -CH ₂ CH ₂ OH)

10 g of hydrochloride of compound (II) was added to 50 ml of ethanol containing 7.5 g of triethylamine, and the mixture was stirred under reflux for 30 minutes. After cooling, 34 ml of ethanol containing 2.0 g of atylene oxide was added dropwise in 10 minutes under ice-cooling stirring, and 3 at room temperature. Stir for time.

Ethanol was distilled off under reduced pressure, and the residue was treated in the same manner as in Example 1 to obtain 8.8 g of hydrochloride of the target substance.

Example 3 (A: -CH ₂ CH ₂ OH)

45 g of 2,3,4-trimethoxy benzaldehyde and 30 g of N-β-hydroxyethyl piperazine are heated and stirred in 200 ml of ethanol for 30 minutes, and 5.0 g of sodium borohydride is added for 2 hours while cooling, followed by reduction.

41 g of the hydrochloride salt of the target substance was obtained by following the same procedure as in Example 1.

Example 4 (A: -CH ₂ CH ₂ OH)

19.6 g of 2,3,4-trimethoxybenzaldehyde and 19.5 g of N-β-hydroxy ethyl piperazine are refluxed for 6 hours by adding 10 ml of formic acid under reflux in 100 ml of ethanol. Treatment is carried out according to the conventional method below to obtain 17.0 g of hydrochloride of the desired substance.

Example 5 (A: -CH ₂ CH ₂ OH)

4.33 g of 2,3,4-trimethoxybenzyl chloride and 3.0 g of N-β-hydroxyethyl piperazine are added to 50 ml of ethanol, 2.0 g of potassium carbonate is added, stirred for 6 hours, and refluxed. The procedure is followed according to the conventional method to obtain 3.3 g of hydrochloride of the target substance.

Example 6 (A: -CH ₂ CH ₂ OH)

50 g of N, N-bis-β-chloroethyl-2,3,4-trimethoxybenzylamine hydrochloride (melting point 127-131 ° C) and 50 g of monoethanolamine were heated to reflux for 1 hour 30 minutes in 150 ml of ethanol. Treated according to the conventional method below to obtain 32 g of hydrochloride of the target substance.

Example 7

1.33 g of metallic sodium is dissolved in 100 ml of ethanol, and 10 g of hydrochloride of compound (II) is added and stirred for 30 minutes. Thereafter, 2.5 g of propylene oxide was added dropwise in 5 minutes, and the mixture was heated to reflux for 1 hour.

Treated according to the conventional method, the resulting oily reaction product is treated with hydrochloric acid in ethanol to be hydrochloride and recrystallized from isopropanol.

Melting point 212-215 ° C., yield 6.5 g

Example 8

1.36 g of metallic sodium is dissolved in 100 ml of ethanol, and 10 g of hydrochloride of compound (II) is added thereto, followed by stirring for 30 minutes. Thereafter, 3.26 g of glycidyl (2,3-epoxy-1-propanol) was added dropwise in 5 minutes, followed by heating to reflux for 2 hours.

Treated according to the conventional method, the basic material is extracted with n-butanol, the extract is treated with ethanol hydrochloric acid to be hydrochloride and recrystallized from ethanol.

Melting point 215-218 ° C., yield 6.8 g

Example 9

10 g of hydrochloride and 7.43 g of triethylamine of Compound (II) are heated to reflux for 30 minutes in 50 ml of ethanol. After cooling, 5.25 g of styrene oxide was added dropwise in 5 minutes, and heated to reflux for 2 minutes. The product obtained by treatment according to the conventional method is purified by silica gel chromatography, hydrochloride and recrystallized from isopropanol.

Melting Point 170-173 ° C, Yield 3.5g

Among the reaction products, the material represented by the following chemical formula (III) as a side reaction product is also obtained at the same time.

Melting point (hydrochloride) 177-182 ° C, yield 0.7g

Example 10

0.14 g of metallic sodium is dissolved in 10 ml of ethanol, 2.0 g of compound (II) hydrochloride is added and stirred for 30 minutes. Then, 1.2 g of potassium carbonate and 1.7 g of penacylbromide are added, and the mixture is stirred and refluxed for 1 hour. By the following conventional method, 2.3g of oily reaction products are obtained.

2.3 g of the N-phenacyl agent thus obtained is reduced by adding 300 mg of sodium borohydride in 20 ml of methanol as it is. After stirring for 1 hour at room temperature, the solution was treated according to a conventional method, and the mixture was recrystallized from isopropanol as hydrochloride.

Melting Point 171-173 ° C, Yield 1.5g

Example 11

6.0 g of compound (II) hydrochloride are dissolved in 100 ml of ethanol, 5.0 g of triethylamine is added, and the mixture is stirred for 30 minutes. 3.75 g of phenylglycidyl ethers are added to this and heated to reflux for 15 minutes. The solution is treated according to the conventional method to obtain hydrochloride, and recrystallized from isopropanol. Melting Point 180-185 ° C, Yield 5.1g

Example 12

After dissolving 3.4 g of compound (II) hydrochloride in 20 ml of alcohol, 1.2 g of caustic soda and 1 g of epichlorohydrin were added and refluxed for 1 hour, the solid was filtered off. Alcohol is distilled off and the residue is distilled under high pressure. Yield 2.5 g

Claims (1)

A process for preparing the trimethoxybenzyl piperazino ethanol derivative of the following formula (I) characterized by reacting the trimethadizine of the following formula (II) with an epoxy compound.

(Where A is

X is hydrogen, lower alkyl group, oxymethyl group, phenyl group or phenoxy methyl group).