JPH045283A - Production of aminopropiophenone derivative or salt thereof - Google Patents

Abstract

PURPOSE:To obtain the title compound having antispasmodic action by a safe and simple operation in high yield by reacting a substituted propiophenone with a reaction product of a halogenomethyl alkyl ether and piperidine. CONSTITUTION:A 4'-substituted propiophenone shown by formula I (R<1> is 1-2C alkyl) is reacted with a reaction product of a halogenomethyl alkyl ether shown by the formula XCH2OR<2> (X is halogen; R<2> 1-4C alkyl) and piperidine to given the objective compound shown by formula II.

Description

[Detailed Description of the Invention] Skin Tojo Summer ■■ Min! The present invention relates to a novel method for producing aminopropiophenone derivatives such as 4'-substituted-2-methyl-3-piperidinoprobiophenone or salts thereof, which have excellent antispasmodic effects.

4',2-dimethyl-3-piperidinoprobiophenone, 4'-ethyl-2-methyl-3-piperidinoprobiophenone, which are already commercially available as excellent antispasmodics with few side effects. As a method for producing 4'-substituted-2-methyl-3-piperidinoprobiophenone, etc., the following (
Five methods a) to (e) are known.

(a) A method in which 4'-substituted propiophenone is reacted with piperidine or its inorganic salt and formaldehyde in an alcohol solvent alone or in the presence of a nitroalkane (Japanese Patent Publication No. 40-20390 and Japanese Patent Publication No. 55
-27914 (see reaction formula (A) below).

"" LL ・HCII (in the formula, R3 represents a halogen atom or a lower alkyl group,
) A method of reacting piperidine with a methacrylic acid derivative (described in JP-A No. 54-27571, the following reaction formula (
See B).

(In the formula, R3 represents the same meaning as above.) (C) A method of reacting substituted benzene with 2-methyl-3-piperidinopropionic acid halide under a Lewis acid catalyst (JP-A No. 5
4-30178, see reaction formula (C) below).

(In the formula, X is a halogen atom, and R3 has the same meaning as above.) (6) Method of reacting 4'-substituted-3-halogeno-2-methylpropiophenone with piperidine (JP-A-54
-32480, see reaction formula (D) below).

"" and L CHl CI (3 H3 F13 (in the formula, X has the same meaning as above, and R4 represents a lower alkyl group) (e) 4'-substituted-3-amino-2-methylpropiophenone A method of reacting 1,5-dihalogenopentane (described in JP-A-54-36274, the following reaction formula (E
)reference).

L (in the formula, X and R4 represent the same meanings as above), and the like.

＜”°　゛.

However, in method (a), the desired product cannot be obtained only in the alcohol solvent used in the usual Mannich reaction, or even if it is obtained, the yield is not satisfactory. Further, the formaldehyde vapor used at that time severely irritates mucous membranes, and is not desirable from a safety standpoint.

On the other hand, as shown in the above-mentioned reaction formula, the methods ([Y]) to (e) use a roundabout method as a whole, and have the disadvantage that the number of reaction stages is increased and the operation is complicated.

Therefore, it has been difficult to industrially advantageously produce aminopropiophenone derivatives or salts thereof.

The present invention has been made in view of the above circumstances, and is capable of producing aminopropiophenone derivatives and their salts by safe and simple operations.
Moreover, it is an object of the present invention to provide a method for producing aminopropiophenone derivatives and salts thereof that can be obtained with good yield.

In order to achieve the above object, the inventors of the present invention have made extensive studies and found the following general formula (I) (wherein R' represents a lower alkyl group having 1 or 2 carbon atoms). The following general formula (
IF)XCHgOR” (II)(
However, in the formula, X represents a halogen atom, and R2 represents a lower alkyl group having 1 to 4 carbon atoms. ) By reacting the reaction product of halogenomethyl alkyl ether with piperidine, aminopropyl ether represented by the following general formula (I[[) (wherein R1 represents the same meaning as above) can be obtained. The present inventors have discovered that phenone derivatives and their salts can be produced safely and easily with good yields, leading to the present invention.

That is, according to the present invention, a compound of formula (I) above, (n)
By reacting a compound of formula and piperidine, (
The target compound of formula III) is obtained; in this case, even if the three components are subjected to the reaction at the same time, the compound of formula (II) and piperidine react first, and then the compound of formula (I) reacts with it to obtain the target compound. When a compound is synthesized and the compound of formula (II) is reacted with piperidine, the reaction product is separated,
If the compound of formula (I) is added to the reaction mixture without purification, the target compound of formula (III) is synthesized. Therefore, the process of the present invention is very short, which is advantageous in terms of the reaction process, and the yield is also high, making it effective in industrial production.

Therefore, the present invention provides an aminopropiophenone derivative or A method for producing the salt is provided.

The present invention will be explained in more detail below.

In the method for producing an aminopropiophenone derivative or a salt thereof of the present invention, the 4'-substituted propiophenone as a starting material is represented by the following general formula (I), and the substituent R1 in the formula is
is a lower alkyl group having 1 or 2 carbon atoms,
Specifically, they are 4'-methylpropiophenone and 4'-ethylpropiophenone.

The 4'-substituted propiophenone of formula (I) can be easily obtained, for example, by a known method in which toluene or ethylbenzene is reacted with an acid chloride of propionic acid in the presence of a Lewis acid catalyst.

In addition, the following general formula (II)
However, in the formula, X is a halogen atom such as chlorine, bromine, or iodine, and R1 is a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, ethyl group, propyl group, butyl group, etc. ) As the halogenomethyl alkyl ether,
For example, chloromethyl methyl ether, chloromethyl ethyl ether, chloromethyl propyl ether, chloromethyl isobutyl ether, bromomethyl methyl ether, bromomethyl ethyl ether, bromomethyl propyl ether, iodomethyl methyl ether, iodomethyl ethyl ether, iodomethyl propyl ether Among them, chloromethyl methyl ether is particularly preferred from the economic point of view.

Therefore, the present invention provides the following general formula (In) (wherein , in which R1 has the same meaning as above) or a salt thereof is produced.

Here, when reacting the compound of formula (I) with the reaction product of the compound of formula (It) and piperidine, in advance (I[
) is preferably reacted with piperidine to obtain these reaction products, and then this reaction product is reacted with the compound of formula (I).
There is no problem even if the compound of formula IF) and piperidine are added and reacted at the same time. Note that the reaction product of the compound of formula (II) and piperidine does not need to be separated from the reaction mixture, and the compound of formula (I) can be directly added to the reaction mixture and reacted.

In this case, when a reaction product of a compound of formula ([) and piperidine is obtained and this is reacted with a compound of formula (I), a halogenomethylalkyl ether of formula (n) is added to piperidine at room temperature in a polar solvent. and then 4 of formula (I)
This can be carried out by adding a solution of the '-substituted propiophenone in a polar solvent and, if necessary, heating. By proceeding with the reaction in this way, the 4'-substituted-
3-piperidino-2-methylpropiophenone can be obtained.

In the present invention, the proportion of each compound to be used is not particularly limited, but the compound of formula (If) and piperidine are each equivalent to 2 times the mole of the compound of formula (I), particularly 1.1 times to 1.1 times the mole. It is appropriate to use it at a ratio of 3 times the mole,
If the amount is less than equimolar, the reaction may not proceed sufficiently and the yield may be low, and if more than twice the amount is used, it may be economically disadvantageous.

Further, as the reaction solvent, it is preferable to use one or more selected from alcoholic polar solvents such as methanol, ethanol, and isopropanol, and neutral polar solvents such as dimethyl sulfoxide and dimethylformamide. .

Incidentally, the reaction conditions can be adjusted as appropriate, but if piperidine and (I
When reacting with the compound of formula t), the reaction temperature is sufficient at room temperature, there is no particular need for heating, and the reaction time is several minutes to several tens of minutes, preferably about 30 minutes.

Further, when the compound of formula CI) is reacted with the reaction product of the compound of formula (It) and piperidine, the reaction temperature is room temperature to 120°C, preferably 80°C to 100°C, and the reaction time is 1 hour to 12 hours, preferably 2 hours to
It is 3 hours.

After the reaction is completed, the reaction solution is cooled, and the precipitated salt of the compound of the formula (I[[) is collected by filtration, or the solvent is removed under reduced pressure. After that, an excess of anhydrous potassium carbonate is added to the aqueous layer, and the separated oil is extracted with, for example, ether.
I) The hydrochloride salt of a compound of formula can be obtained.

As explained above, according to the production method of the present invention, (I
The aminopropiophenone derivative of the formula [[] and its salt can be obtained safely and easily with a high yield.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to examples, but the present invention is not limited to the following examples.

In addition, in the following examples, the melting point of the product is not corrected.

[Example 1] 1.7 g (0.02 mol) of piperidine was mixed with 5111.1 g (0.02 mol) of dimethylformamide. 5 ml of dimethylformamide in which 1.77 g (0,022 mol) of chloromethyl methyl ether had been dissolved was added dropwise while stirring.The reaction solution generated heat and the temperature rose from 20°C to 50°C. After rising, stir for 30 minutes, return to room temperature, and then stir for 4 minutes.
'-Methylpropiophenone 2.22g (0,015
A solution of 5 ml of dimethylformamide in which mol) was dissolved was added dropwise.

Thereafter, the reaction temperature was gradually increased to 90°C to 100°C for about 2
Stir for hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in water and extracted with ether.The ether layer was further extracted with dilute hydrochloric acid, combined with the aqueous layer, and a large excess of anhydrous potassium carbonate was added.

The separated oil was extracted with ether and dried, then dry hydrogen chloride gas was introduced and the precipitated crystals were collected by filtration. Recrystallize with isopropanol-acetone mixed solvent to obtain 2.4'-
Dimethyl-3-piperidinopropiophenone hydrochloride 3
．． Obtained 84 g (yield: 91%, melting point: 175-17
6°C).

The results of the infrared absorption spectrum and mass spectrum of the obtained compound are shown below.

Infrared absorption spectrum 1, R, Cv"' (cm -' ): 29
50.2650, 2550, 1680°1610.14
50,975,840 Mass spectrum Mass: M/e = 245 (MW = 245, basic substance) [Example, 2] 1.7 g (0.02 mol) of piperidine was dissolved in 5 ml of isopropanol, and this A solution of 5 vbi of isopropanol in which 1.77 g (0,022 mol) of chloromethyl methyl ether was dissolved was added dropwise with stirring. After the reaction solution generated heat and rose from 20°C to 50°C, it was stirred for 30 minutes, and after returning to room temperature, 2.22 g (0,015 mol) of 4'-methylpropiophenone was dissolved in isopropanol. 5 ml solution was added dropwise.

Thereafter, the mixture was stirred for about 12 hours while heating under reflux.

After the reaction was completed, the same treatment as in Example 1 was carried out to obtain 2.62% of the hydrochloride of 2.4'dimethyl-3-piperidinopropiophenone.
g (yield: 62%).

The obtained compound was confirmed to be the same as the compound obtained in Example 1 from the measurement results of melting point, infrared absorption spectrum, and mass spectrum.

[Example 3] 1.7 g (0.02 mol) of piperidine was dissolved in 5 ml of dimethylformamide, and while stirring, 1.77 g (0.022 mol) of chloromethyl methyl ether was dissolved in dimethylformamide 5. +cI! , The reaction solution into which the solution was added generated heat and rose from 20°C to 50°C, was stirred for 30 minutes, and after returning to room temperature was heated to 40°C.
'-Ethylpropiophenone 2.43g (0,015
A 5 val solution of dimethylformamide (mol) was added dropwise.

Thereafter, the reaction temperature was gradually raised and the mixture was stirred at 90°C-100°C for about 3 hours. After the reaction was completed, the same treatment as in Example 1 was carried out to obtain 3.77 g of hydrochloride of 4'-ethyl-2-methyl-3=piperidinopropiophenone (yield: 85%).
Melting point: 170-171°C).

The results of the infrared absorption spectrum and mass spectrum of the obtained compound are shown below.

Infrared absorption spectrum 1, R, (ν”' (cm −' )): 295
0,2750,2650.16751610,1230
．． 980,850 Mass spectrum Mass: M/e = 259 (MW = 259, basic substance) [Example 4] 1.66 g (0,0195 mol) of piperidine was dissolved in 5 ml of dimethyl sulfoxide, and the solution was dissolved in this while stirring. Chloromethyl methyl ether 1.69 g (0,0
21 mol) of dissolved dimethyl sulfoxide 5 van
The reaction solution that was added dropwise generated heat, and the temperature ranged from 20°C to 50°C.
After increasing to
015 mol) of dissolved dimethyl sulfoxide 5a+
f solution was added dropwise.

Thereafter, the reaction temperature was gradually raised and the mixture was stirred at 90°C to 100°C for about 3 hours. After the reaction was completed, it was treated in the same manner as in Example 1 to obtain 2.66 g of 4'-ethyl-2-methyl-3-biperidinopropiophenone hydrochloride (yield: 60%).
.

The obtained compound was confirmed to be the same as the compound obtained in Example 3 from the measurement results of melting point, infrared absorption spectrum, and mass spectrum.

Claims (1)

[Claims] 1. General formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, R^1 represents a lower alkyl group having 1 or 2 carbon atoms.) The following general formula (
II) XCH_2OR^2(II) (However, in the formula, X is a halogen atom, and R^2 is a lower alkyl group having 1 to 4 carbon atoms.) Reaction product between halogenomethyl alkyl ether and piperidine The following general formula (III), which is characterized by reacting substances ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (However, R^1 in the formula represents the same meaning as above.) A method for producing a piophenone derivative or a salt thereof.