JPS6025985A - Preparation of piperazine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug having high antiemetic action and antispasmodic action extremely in high purity, by reacting a piperazine derivative with benzhydrol. CONSTITUTION:A compound shown by the formula I (X is halogen; l and m are 1-4) or its reactive derivative at its hydroxyl group is reacted with a compound shown by the formula II(Y and Z are H, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, or methyleneoxy) or its reactive derivative at its hydroxyl group in a solvent such as toluene, ethylbenzene, etc. in the presence of a strong base (e.g., sodium amide, sodium hydride, metal sodium, etc.) under heating to give the desired compound shown by the formula III. Either of the compound shown by the formula I and the compound shown by the formula II is preferably used in the form of the reactive derivative, especially halide.

Description

Detailed Description of the Invention J i-1 produced by the present invention: the following general formula (1) (1) (where X is a halogen atom, Y and 2 are hydrogen atoms,
A halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group or a methyledioxy group, and t and m are integers from 1 to 4. Regarding standard manufacturing methods.

Piperazine derivatives of the general formula CI), especially 1-[2-
(4-methoxybenzhydryloxy)ethyl)-4-
43-(4-fluoropenozoyl)propylcopiperazine cimarate and the like are known to exhibit strong antiemetic and antispasmodic effects, and to have extremely excellent efficacy as therapeutic agents for diseases in humans and animals. West German Published Patent Application No. 2.719,246).

Conventionally, methods for producing these compounds include, for example, reacting γ-chlorovaler fluoroptylophenono and l-paramethoxybenozhydryloxyethylbiperazine in the presence of sodium iodide and sodium bicarbonate. A method is known (West German Published Patent Application No. 2719.246)
1. However, in this method, the target object, e.g. 1-[2
-(4-methoxybenozhydryloxynoethyl)-4
-[3-(4-fluorobenozoyl)propylcopiperazine simalate contains a large amount of the starting material 1-paramethoxybenzhydryloxyethylpiperazine and other impurities (see Figure 1), and these Since impurities are difficult to remove even through purification operations such as recrystallization, they inevitably get mixed into the product, making it unsuitable as a method for obtaining pharmaceuticals. The present invention has been completed as a result of various studies aimed at providing a method for obtaining the compound of formula 1) with high purity.

The method of the present invention is shown by the following reaction formula.

(n) Cm) (,V) (However, W represents a halide atom, and the other symbols have the same meanings as above.) In other words, a non-explosion [! Ij is alkylphenol 7(II)
was reacted with piperazinoalkanol (III) (
■) compound of formula and then this product i '7c (
tJ, a reactive derivative of benzhydrol (V) in its hydroxy group or anti-IL in its hydroxy group;
Reacting the 11d isomer to produce 4 piperazine ribs (1) tW
It is a method of building.

In order to obtain all of Compound (IV) from Compounds (II) and (■), (II) and (II) may be heated under reflux in a suitable solvent in the presence of an acid-reducing agent. As a solvent, dissolve both,
Anything that does not adversely affect the reaction may be used, such as alcoholic solvents such as methanol, ethanol, and propatool, acetone, and alcoholic solvents. Examples of deoxidizing agents include sodium carbonate and carbonic acid. potassium hydrogen,
Carbon n2 sodium, potassium carbonate, etc. are used.

The compound of formula (IV) thus obtained is subjected to a reaction with a compound of formula (CV);
) or (V) is preferably used in the form of a reactive derivative. Reactive derivatives of these hydroxy groups include halides and tosyl esters, with halides being particularly preferred.The reaction between (IV) and (V) is carried out by humidifying both in an appropriate solvent in the presence of a strong base. do it. The solvent should be one that dissolves the two and does not inhibit the reaction, such as toluene, ethylbenzene, xylene, etc., and strong bases such as sodium amide, sodium hydride, metallic sodium, etc. is used.

The compound of formula (1) obtained in this way has extremely high purity (see Figure 1), and contains almost no impurities unlike conventional methods. This can be converted into a salt by a conventional method, and the salt is preferably an organic salt such as maleic acid or fumaric acid.

Next, Examples, Comparative Examples, and Test Examples will be explained.

Example 1 1-('2-(4-methoxybenzhydryloxy)ethyl)-4-[3-(4-fluorobenzoyl)
Production of propylcopiperazine (sima)/ite (1) 1-(2-human r?xylethyl)-4-[3-
Production of (4-fluorobenzoyl)propylcopiperazine; γ-chlorop-fluorobutyrophenone 23.2y,
1~Piperazinoethanol: 1.5.1! 100 m7 of ethanol containing i' and 1467 potassium bicarbonate!
The solution was refluxed overnight with stirring. After cooling, insoluble matter is passed through LF! was contracted under reduced pressure. The residue was dissolved in dilute hydrochloric acid, washed with dichloroform, made alkaline with dilute sodium chloride solution, extracted with ethyl acetate, washed with 8 waters, dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized as 1-(2-hydroxyethyl)-4-[3
-(11-Furuko Robe/Zoil) Solo Bilko Piperazino 2! j, 6f (yield: 87 h) were obtained.

Melting point 96-975℃ 11 too; cm-' 3400+29 40.282
0.1+j75°1590.1218,1150,10
50゜1ooo, sa.

(2) 1'7 (2-chloroethyl)-4-43-(
Production of 4-fluorobenzoyl)propylcopiperazine Thionyl chloride 8- was cooled with aqueous salt to produce 1-(2-hydroxyethyl)-4-43-(4-fluorobenzoyl).
After gradually adding propylcopiperazine 12 and adding fC9,
After stirring at room temperature for 4 hours, thionyl chloride was distilled off under reduced pressure. Water was added to the residual liquid, made alkaline with dilute sodium hydroxide, and then extracted with 1]-hexane. After washing with water, drying the sodium sulfate and removing the solvent under reduced pressure, 1-(2-chloroethyl)-4-4
3-(4-fluorobenzoyl)propyl]piperazi 7
900 m'j (yield 85%) was obtained.

Melting point 38-39°C IR; cJrt-' 2940.2810,167
0.1590°1228.1153,1000,850
゜15 (3) 1. - Preparation of [2-(4-methoxybenzhydryloxy)ethyl]-4-43-(4-fluorobenzoyl)but[1-pyl]piperazine cimarate; ; no zkl-luene 5 nrA with sodium amide 67
mg to b'l Shu, then Ku1 Tensui Toluene 2.5
4-Methochloride/Zuhydrol 350 in response to ml
After slowly adding T4, the mixture was refluxed for 1 hour. After cooling,
1-(2-chloroethyl)-4-43-(4-fluorobenzoyl)propyl]piperazine b1o+ns+@ dissolved in 2.5 me of anhydrous toluene was added, and the mixture was further refluxed for 3 hours. After cooling, water was added and the toluene layer was separated. Further, extract with benzene, combine the 41 layers, dry with a sniper salt, condense under reduced pressure, and develop the 8 residue with a silica gel column chromatography. 'Jingyu Acetone:Chloroform=I:2) Q trowel sheathed 1-(2-(4-methoxybenzhydryloxy)
ethyl)-4,-C50-(4-fluorobenzoyl)propylcopiperazino 670y+C yield: 83, yield).

Oily substance 2925, 2800, 1678, 15
90゜1500.1240I 830 6707 ng of 1-(2-(4-methoxybenzhydryloxy)ethyl)-4-('3-(4-fluorobenzoyl)propylcopiperazine) obtained above was dissolved in methanol 1
350 mf of maleic acid dissolved in 0 mA and 5 ml of methanol was added, and the precipitated crystals were collected. After washing with methanol and drying, 1-,C2-(4-methoxybenzhydryloxy)ethyl]-#-C3-C4-fluorobenzoyl)propylcopiperazine simalate 90
0yn! (yield 91%).

Melting point 159-161℃ II also rainbow crrr-' 3500-3350.275
0~2100°1688.1570,1510,146
0°1360.1250, 1100.870 Comparative Example (i) 1-c2-(4-methoxybenzhydryloxy)ethylcopiperazine: Anhydrous piperazine 67 and toluene, 227n1. A mixture of toluene, 8meK1-CC4-methquine, benzhydryl)oxyph-2-chloroethane, and 4.82
Slowly add 9 drops of the dissolved solution. Then, after refluxing for 15 hours, cooling to around 70°C (2 times, adding water and washing with water (2 times)
times). Extract with 10% acetic acid, wash with toluene, make alkaline with dilute sodium hydroxide, and extract with toluene. After washing with water, drying with Glauber's salt and distilling off the toluene under reduced pressure, the title compound of oily substance 4.84f! get.

(ii) 1-[2-(4-methoxybenzhydryloxy]ethyl)-4-(3,-(4-fluorobenzoyl)propyl]biperanone cimarate: 1-[2((4-methoxybenzhydryl)oxy) ]
ethyl]piperazi 747, γ-chlorop-fluorobutyrophenone 27g, sodium bicarbonate 19g', potassium iodide 0132 and methyl ethyl ketone 401r
Reflux the mixture of RL for 616 hours. Add cooled water and separate the layers. Further, the aqueous layer was extracted with methyl ethyl ketone, the organic layers were combined and dried with mirabilite, and the solvent was distilled off under reduced pressure to obtain an oily substance 5.22.

The obtained oil was dissolved in methanol bO-, and a solution of 32 m of maleic acid in 20 mi of methanol was added.
Collect the precipitated crystals. After washing this with methanol,
Drying under reduced pressure yields the title compound 6.67.

Trial test example 1 - (2-(4-methoxybenzhydryloxy)ethyl,]-4[3=[4-fluorobenozoyl]propyl]piperazine base (-1 in the figure), maleic acid (-2 in the figure) ), 10 each of the product obtained in Example 3 (-3 in the figure) and the product obtained in Comparative Example (11) (-4 in the figure)
of this solution in 5 tJ of methanol.
was spotted on a thin layer plate, and thin layer chromatography was performed under the following conditions.

Developing solvent: Isopropanol-ethyl acetate-water-ammonia water (3:1:1:1) Thin layer plate: Kieselgel 6011' 254 thickness 0.2
Mn (Merck & Co. 'A) 201m x 20 r1n
Deployment distance ¥11; approx. 10 cm Detection method: Ultraviolet irradiation (main wavelength 245 + 1210) The results are as shown in Figure 1: However, it was found that the product obtained by the present invention does not contain impurities.4)

[Brief explanation of drawings]

FIG. 1 shows thin layer chromatograms of the products obtained by the method of the present invention and the conventional method. IJi “margin”

Claims (2)

[Claims] (1) A compound represented by the general formula (wherein, , halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group,
21.4 group or methidi/dioxy group) or its reactive derivative at the hydroxy group (wherein X, Y, Z, L, Ill are as above) (having the same meaning) or a method for producing a piperazine derivative or a salt thereof. (2) General formula (where W is a halogen atom, X is a halogen atom), Rogge/atom,
t represents an integer from 1 to 4) A compound represented by the general formula, (where m represents an integer from 1 to 4) is reacted with the compound represented by the general formula, (where X, t, m has the same meaning as above), and then this product or its reactive derivative at the hydroxy group has the general formula, (However, Y and Z are hydrogen atoms, halogen atoms, lower alkyl groups, lower alkoxy group, trifluoromethyl group,
(representing a nitro group or a methylene dioxy group) or a reactive derivative of its hydroxy group (wherein X, Y, Z, L, m are (having the same meaning as above) A method for producing a piperazine derivative or a salt thereof.