JPS6045190B2 - Piprazine derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula '-HeY-B-''N■R1 [I] In the formula, A and B■Lower alkylene group: R1■Lower alkyl group, hydroxy lower alkyl group, aryl group, pyridyl group, aralkyl group, anyl group or pyridyl lower alkyl group; R2 ■ hydrogen atom, halogen atom, amino group, nitro group or hydroxyl group; and Y = amino group, lower alkylamino group, aralkylamino group, hydroxyl group , general formula R3CONH
- (wherein R° is a hydrogen atom, a lower alkyl group, an aryl group, or a pyridyl group) or a group represented by the general formula A℃0
The present invention relates to a novel piperazine derivative represented by the group J represented by 0- (R° is the same as defined above) and a salt thereof.

To explain the definition of each signal above more specifically, lower alkylene groups include methylene, ethylene, propylene, trimethylene, ethylidene, etc., lower alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, etc., and hydroxy lower alkyl Groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc. Halogen atoms include chlorine, bromine, fluorine, etc. Aryl groups include halogen atoms (same as above) and lower alkyl groups (same as above)
, a lower alkoxy group (methoxy, ethoxy, propoxy, butoxy, etc.), a trifluoromethyl group, etc. as a substituent, and a phenyl group with or without one or more in any combination; a pyridyl group is a 2- , 3- or 4-pyridyl group, aralkyl group includes benzyl, phenethyl, etc., pyridyl lower alkyl includes 2-, 3- or 4-pyridylmethyl, 2-, 3- or 4-pyridylethyl, etc. Lower alkylamino means methylamino, ethylamino, and propylamino means benzylamino with or without a halogen atom (as defined above) in the benzene ring, respectively.

According to the present invention, the piperazine derivative of general formula [1] is produced by the following method.

(a) It can be obtained by subjecting a compound represented by the general formula [wherein Z is a lower alkylene group (same meaning as above) and other symbols have the same meanings as above] to a reduction reaction.

The method for reducing the carbonyl group of the above compound [■] to a methylene group includes (1) reduction with zinc amalgam and pentahydrochloric acid, (Ii) reduction with dithioacetal and desulfurization with nickel, and (iii) reduction with hydrazone. Although methods such as reduction in the presence of a base are generally known, a method of reduction in the presence of a base using hydrazone, which is easy to handle in terms of reaction processing, is preferred.

That is, when the compound of the general formula [■] and hydrazine hydrate are reacted in primary butanol under heating under reflux, a hydrazone derivative represented by the general formula [wherein each symbol has the same meaning as above] is obtained. It will be done.

The compound of the general formula [■] is heated under reflux for 10 to 2 hours in a toluene solvent in the presence of potassium tertiary butyrate, or for 10 to 2 hours in the presence of caustic potassium in a solvent such as diethylene glycol or triethylene glycol.
By maintaining the temperature at 50 to 200°C, a compound of general formula [1] can be obtained. Furthermore, it can also be obtained by simultaneously adding and reacting the compound of the general formula [■], hydrazine hydrate, and caustic potassium in a diethylene glycol (or triethylene glycol) solvent. In the case of a reaction using caustic potassium in glycol, in the general formula [■], Y has a group of an acyl derivative [R3CONH-, R3COO- (R3 has the same meaning as above)]. X
represents an amino group or a hydroxyl group, and all other symbols have the same meanings as above]
The deacylated compound shown is often obtained.

J) In order to produce a compound in which Y is an acyl derivative in the general formula [1], the compound represented by the general formula [■] is treated with a suitable deoxidizing agent such as triethylamine, pyridine, etc., or sodium carbonate, carbonate, etc. By reacting an acylating agent such as acetic anhydride, acetyl chloride, benzoyl chloride, or nicotinic acid chloride in a solvent that does not inhibit the reaction, such as benzene, toluene, chloroform, or tetrahydrofuran in the presence of potassium or the like. can get.

-) In order to produce a compound in which Y is a lower alkylamino group or an aralkylamino group in the general formula [1], a compound in which x is an amino group in the general formula [■] and a compound in the general formula [in the formula , R4 and R5 are the same or different and represent a lower alkyl group (same as above), an aralkyl group (same as above), or an aryl group (same as above), and one of R4 and R5 may be a hydrogen atom. (This reduction reaction is carried out, for example, by treatment with a metal hydride complex compound such as sodium borohydride), or in the general formula [1], It can be obtained by reducing a compound in which Y is an acyl derivative with, for example, lithium aluminum hydride.

The compound of general formula [1] obtained by the above method can be converted into an acid addition salt by a conventional method.

The salt for forming the acid addition salt can be appropriately selected from, for example, hydrochloric acid, sulfuric acid, hydrogen bromide, fumaric acid, maleic acid, citric acid, and the like. General formula [1
] and its acid addition salts have pharmacological effects such as analgesic, anti-inflammatory, anti-competition, anti-avomorphine, antihypertensive, and peripheral vasodilatory effects, and are used as anti-inflammatory/analgesic agents, antipsychotics, and anxiolytics. It is useful as a medicine, such as a hypotensive agent, and as a synthetic intermediate thereof.

Next, the present invention will be specifically described with reference to Examples.

Example 1 4-(4-acetylaminomethylphenacyl-1-(2
-Methoxyphenyl)piperazine 31.5y1 10 mL of hydrazine hydrate is added to n-butanol 200e and heated under reflux for 6 hours.

After cooling, pour it into ice water to remove the crystals that precipitate. By taking, washing with water and drying, crude hydrazone 33.7y is obtained. Add this hydrazone 33.7 V and caustic strength 1 month 0 y to 100 ml of diethylene glycol, and heat at 180 to 200°C.
Heat for 2 hours. After cooling, water is added to the reaction solution, and the resulting oil is extracted with 200 ml of chloroform, washed with water, dehydrated and dried over anhydrous potassium carbonate, concentrated under reduced pressure, and crystallized when the oil is cooled. When this is recrystallized from isopropyl ether, 4-
[2-(4-aminomethylphenyl)ethyl]-1-(
19.0y of 2-methoxyphenyl)piperazine are obtained. Example 2 4-[2-(4-aminomethylphenyl)ethyl]-1
-(2-methoxyphenyl)piperazine 6.6V1 Nicotinic acid chloride hydrochloride 4.0y1 8ml of triethylamine is added to 100ml of chloroform and heated under reflux for 2 hours.

The reaction solution is concentrated under reduced pressure, ice water is added to the residue, and when it is left to stand, crystals begin to form. This was collected (2), washed with water, and then recrystallized from a mixed solvent of benzene-isopropyl ether to form colorless needle-shaped crystals of 4-[2-(4-nicotinoylaminomethylphenyl)ethyl]-1-(2) with a melting point of 126°C. -methoxyphenyl)piperazine 4.2y is obtained. Example 34
-[2-(4-aminomethylphenyl)ethyl]-1-
(2-methoxyphenyl)piperazine 4.0q. ．． P-
1.7y of fluorobenzaldehyde and 50m of alcohol
Add to L and heat on a water bath for 3 minutes.

It is then cooled on ice and reduced using sodium borohydride. Concentrate under reduced pressure, add water to the residue, extract with 100 mt of chloroform, wash with water, dry over magnesium sulfate, remove the solvent under reduced pressure, and add 2.5% HCl to the residue.
- Add isopropanol to make hydrochloride. When the resulting crystals are recrystallized from ethanol, 4-(2-[4-(4-fluorobenzylaminomethyl)phenyl]ethyl)-1-(2-
3.8y of methoxyphenyl)piperazine●dihydrochloride are obtained. Example 4 4-(4-acetylaminomethylphenacyl)-1-phenylpiperazine 20y1 hydrazine hydrate 5ml
was added to 200 mL of n-butanol and heated under reflux for 5 hours.

After cooling, the mixture is poured into ice water, and the precipitated crystals are collected, washed with water, and dried to obtain hydrazone 16y. This hydrazone 10f and potassium tert-butoxide 5f1 are added to 200 mL of toluene, and stirred and refluxed overnight. After washing with water, the oil obtained by concentrating under reduced pressure is cooled, and the resulting crystals are recrystallized from ethyl acetate. Then, the melting point of colorless scaly crystals is 1.
2.5y of 4-[2-(4-acetylaminomethylphenyl)ethyl]-1-phenylpiperazine at 45° C. is obtained. The following compounds can be synthesized in a similar manner.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A and B are lower alkylene groups, R^1 is lower alkyl group, hydroxy lower alkyl group, aryl group, pyridyl group , aralkyl group, thenyl group or pyridyl lower alkyl group, R^2 is a hydrogen atom, halogen atom, amino group, nitro group or hydroxyl group, Y is an amino group, lower alkylamino group, aralkylamino group, hydroxyl group, With the general formula R^3CONH- (wherein R^3 is a hydrogen atom, a lower alkyl group, an aryl group, or a group represented by a pyridyl group) or with the general formula R^3COO- (wherein R^3 has the same meaning as above) Piperazine derivatives and acid addition salts thereof represented by the following.