JP2003064060A - Method for producing 1-methyl-3-phenylpiperazine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method by which 1-methyl-3-phenylpiperazine can industrially readily be produced in good yield without requiring complicated operations. SOLUTION: This method for producing the 1-methyl-3-phenylpiperazine represented by formula (III) is characterized by chlorinating a diol compound represented by formula (I) and reacting the resultant dichloro compound represented by formula (II) without isolation thereof with ammonia.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 1-methyl-3-
It relates to a method for producing phenylpiperazine. More specifically, it relates to a method for producing 1-methyl-3-phenylpiperazine, which can be preferably used as an intermediate for producing mirtazapine useful as an antidepressant.

[0002]

BACKGROUND OF THE INVENTION Mirtazapine is a compound useful as an antidepressant. Conventionally, as a manufacturing intermediate of mirtazapine,
Piperazine derivatives are known. As a method for producing a piperazine derivative, a method of reacting 1-methyl-3-phenylpiperazine with 2-chloro-3-cyanopyridine in the presence of potassium fluoride is known (Japanese Patent Publication No. 59-42678). Gazette).

As a method for producing 1-methyl-3-phenylpiperazine, which is an important intermediate for producing the piperazine derivative, a method of reacting styrene oxide with N-methylethanolamine in water (Japanese Patent Publication No. 53-15).
520) and a method of methylating 2-phenylpiperazine with methyl iodide (US Pat. No. 4,772,705).

However, the former method has a drawback in terms of productivity since isomers are formed and a complicated process such as column separation is required, and the latter method has a disadvantage of 1
Since it is not possible to obtain -methyl-3-phenylpiperazine in high yield and a large amount of acetone is required, there is a drawback that industrial productivity is poor.

Therefore, as a method for solving such a drawback, N- (2-hydroxyethyl) -N-methyl-2-
Hydroxy-2-phenylethylamine was chlorinated to obtain N- (2-chloroethyl) -N-ethyl-
After salting 2-chloro-2-phenylethylamine,
Reacting the salt with ammonia, 1-methyl-3-
A method for producing phenylpiperazine has been proposed [WO 01/23345 pamphlet (2001)].

[0006] The above method is an excellent method capable of producing 1-methyl-3-phenylpiperazine in a high yield on an industrial scale. However, recently, 1-methyl-
It is desired to develop a method capable of producing 3-phenylpiperazine more easily.

[0007]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and 1-methyl-3-phenylpiperazine can be easily produced industrially with high yield without requiring complicated operations. It is an object of the present invention to provide a method that can be manufactured.

[0008]

The present invention provides the formula (I):

[0009]

[Chemical 4]

A diol compound represented by the formula (II) obtained by chlorination is obtained:

[0011]

[Chemical 5]

A dichloro compound represented by the formula (III) characterized by reacting with ammonia without isolation:

[0013]

[Chemical 6]

The present invention relates to a method for producing 1-methyl-3-phenylpiperazine represented by:

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the formula (I) used as a starting material:

[0016]

[Chemical 7]

The diol compound represented by (hereinafter referred to simply as "diol compound") is specifically N- (2
-Hydroxyethyl) -N-methyl-2-hydroxy-
It is 2-phenylethylamine.

The diol compound can be obtained, for example, from International Publication No. 0.
It can be easily produced by the method described in 1/23345, Pamphlet (2001).

Specifically, a diol compound can be obtained by reacting styrene oxide and N-methylethanolamine in an aprotic polar organic solvent.

The amount of N-methylethanolamine is not particularly limited, but in consideration of economical efficiency and treatment after the reaction,
Usually, 0.8-1.
It is preferably about 2 mol.

As the aprotic polar organic solvent, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, 1,3-dimethylimidazolidin-2-one, N-methyl-2-pyrrolidone and the like can be mentioned. They can be used alone or in combination of two or more. Among these, dimethylformamide and 1,3-dimethylimidazolidin-2-one are
It can be preferably used in the present invention.

The amount of the aprotic polar organic solvent is not particularly limited, but is usually preferably about 300 to 600 parts by volume with respect to 100 parts by volume of styrene oxide.

The reaction temperature is from the viewpoint of accelerating the reaction.
It is desirable that the temperature is 50 ° C. or higher, preferably 80 ° C. or higher, but if the temperature is too high, by-products will be generated, so 120 ° C. or lower, preferably 100.
It is desirable that the temperature is ℃ or less.

The atmosphere during the reaction is not particularly limited. Usually, it may be atmospheric air, for example, an inert gas such as nitrogen gas.

The reaction time is not particularly limited, but is usually 2
~ 5 hours. The end point of the reaction can be easily confirmed by, for example, gas chromatography.

Thus, a reaction solution containing a diol compound is obtained. The obtained diol compound may be subjected to chlorination in the next step after being isolated from the reaction solution, or the reaction may be carried out without isolation. The solution may be subjected to the next step of chlorination. The latter method is preferable from the viewpoint of obtaining a dichloro compound in good yield.

In the present invention, first, the diol compound is chlorinated. Chlorination of the diol compound can be carried out using a chlorinating agent such as thionyl chloride, phosphorus oxychloride, oxalyl chloride or phosgene. Although the amount of the chlorinating agent is not particularly limited, it is usually preferably about 2 to 3 equivalents per equivalent of the diol compound.

More specifically, for the chlorination of a diol compound using a chlorinating agent, for example, the chlorinating agent is dissolved in an organic solvent such as toluene, dimethylformamide or 1,3-dimethylimidazolidin-2-one. However, it can be easily carried out by mixing the organic solvent solution of the chlorinating agent with the reaction solution obtained above and appropriately stirring them. In this case, the amount of the organic solvent is usually preferably about 100 to 500 parts by weight with respect to 100 parts by weight of the chlorinating agent.

The temperature for chlorinating the diol compound is not particularly limited, but it is usually preferably about 20 to 50 ° C.

The time required for chlorinating the diol compound is not particularly limited, but is usually about 1 to 12 hours. Further, the end point of chlorination can be easily confirmed by, for example, gas chromatography.

Thus, by chlorinating the diol compound, the compound of formula (II):

[0032]

[Chemical 8]

A dichloro compound represented by the formula (hereinafter, simply referred to as "dichloro compound") is obtained. The dichloro compound is specifically N- (2-chloroethyl) -N-methyl-2-chloro-2-phenylethylamine.

The reaction solution containing the dichloro compound is subjected to the reaction with ammonia without isolating the dichloro compound from the reaction solution. However, before the reaction between the dichloro compound and ammonia, the impurities contained in the reaction solution are left in the organic layer, and the produced dichloro compound is contained in the aqueous layer, whereby the impurities can be removed from the dichloro compound, It is preferable from the viewpoint of obtaining a dichloro compound having high purity.

As a specific method thereof, for example, a method of adding a reaction solution containing a dichloro compound to water and then separating an organic layer and an aqueous layer can be mentioned.

In such a method, the amount of water is not particularly limited as long as the dichloro compound can be extracted. Usually, the reaction solution 100 containing the dichloro compound is taken into consideration in consideration of the amount of the hydrophobic organic solvent to be extracted. 20 to 20
It is desirable that the amount is 150 parts by volume, preferably 30 to 50 parts by volume. The water temperature is preferably 0 to 30 ° C from the viewpoint of preventing decomposition of the dichloro compound.

After adding the reaction solution to water, impurities remain in the organic layer, and the produced dichloro compound is transferred to the aqueous layer as a hydrochloride.

Next, it is preferable to add a hydrophobic organic solvent such as toluene or monochlorobenzene to the recovered aqueous layer in order to extract the dichloro compound as a free base. . From the viewpoint of sufficiently extracting the dichloro compound, the amount of the hydrophobic organic solvent is 1
It is desirable that the amount is 30 to 100 parts by weight, preferably 40 to 60 parts by weight, based on 00 parts by weight.

The pH of the aqueous layer is preferably adjusted to 3 to 7, preferably 4 to 5, from the viewpoint of sufficiently free-basing the dichloro compound and the hydrochloride to prevent decomposition of the dichloro compound. . The pH of the aqueous layer can be easily adjusted by adding an alkali to the aqueous layer. As the alkali, for example, a sodium hydroxide aqueous solution at 0 to 30 ° C. or the like can be used.

The organic layer out of the separated organic layer and aqueous layer is recovered, but in order to further increase the yield of the dichloro compound, a hydrophobic organic solvent such as toluene is added to the aqueous layer and left in the aqueous layer. It is preferable that the dichloro compound is extracted with a hydrophobic organic solvent and the organic layer is combined with the previously collected organic layer.

The organic layer is then subjected to a reaction with ammonia.

Ammonia may be blown into the reaction solution represented by the organic layer as it is, or may be added to the reaction solution as aqueous ammonia dissolved in water. When using ammonia as ammonia water, the ammonia concentration in the ammonia water is
Usually, it is preferably about 15 to 28%. The amount of ammonia is 5 to 50 with respect to 1 mol of the dichloro compound.
A molar amount, preferably 10 to 20 mol, is desirable from the viewpoint of reactivity and economy.

When the dichloro compound is reacted with ammonia, it is preferable to use a quaternary ammonium salt from the viewpoint of promoting the reaction by phase transfer. Examples of the quaternary ammonium salt include tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium bromide, tricaprylmethylammonium chloride,
Examples thereof include tetrabutylammonium iodide, and these can be used alone or in admixture of two or more. From the viewpoint of reactivity and economy, the amount of the quaternary ammonium salt is 200 mg to 30 g, preferably 1 to 2 with respect to 1 mol of the dichloro compound or the salt of the dichloro compound.
It is preferably 0 g.

The temperature at which the dichloro compound is reacted with ammonia is not particularly limited, but is usually 10 to 80.
It is desirable that the temperature is 0 ° C, preferably 20 to 50 ° C.

The reaction time is not particularly limited, but is usually 2
It is about 10 hours. The end point of the reaction is, for example,
It can be easily confirmed by high performance liquid chromatography, gas chromatography and the like.

Formula (III) thus obtained:

[0047]

[Chemical 9]

The reaction solution containing 1-methyl-3-phenylpiperazine represented by the formula (1) is extracted with, for example, ethyl acetate, toluene, ether and the like, and the organic solvent is removed by distillation or the like to give 1 -Methyl-
3-Phenylpiperazine can be isolated.

The 1-methyl-3-phenylpiperazine thus obtained is a useful compound as an intermediate for the production of mirtazapine.

[0050]

Example 1 503.9 g (4.19 mol) of styrene oxide was added to 951.4 g of N, N-dimethylformamide, and 8
286.4 g of N-methylethanolamine at 0 to 85 ° C
(3.81 mol) was added dropwise over 2 hours and 17 minutes. 81-
The mixture was stirred at 83 ° C. for 3 hours, the end point of the reaction was confirmed by gas chromatography, and the mixture was cooled to room temperature.

The diol compound contained in the obtained reaction solution was N- (2-hydroxyethyl) -N-methyl-
It was possible to confirm that it was 2-hydroxy-2-phenylethylamine by the following physical properties of the diol compound extracted from a part thereof.

¹ H-NMR (400 MHz, CDC
_{l 3) ppm: 7.26-7.37 (m} , 5H), 4.
73-4.77 (m, 1H), 3.66-3.67.
(M, 2H), 3.0-4.0 (m, 4H), 2.5-
2.7 (m, 4H), 2.37 (S, 3H)

Next, to a solution of thionyl chloride (368.8 g) dissolved in toluene (513.5 g), a solution (565.1 g) obtained by dividing the above reaction solution into three portions was dropped at 17 to 23 ° C. It was washed with 39 g and added to the above solution. It stirred at 50-53 degreeC for 2 hours. Next, the reaction solution was cooled to 18 to 23 ° C., and then dropped into a container separately containing 552 g of water to hydrolyze. The reaction vessel was washed with 58 g of toluene and added to the hydrolyzate.

The organic layer was separated, 600 g of toluene was added to the recovered aqueous layer, and the resulting mixed solution was added at 2 ° C. at 10 to 21 ° C.
395 g of a 5 wt% sodium hydroxide aqueous solution was added dropwise over about 20 minutes to adjust the pH of the aqueous layer to 1.0. Further 10-2
465 g of a 25 wt% aqueous sodium hydroxide solution at 5 ° C. was added dropwise to the mixed solution over about 30 minutes to adjust the pH of the aqueous layer to 4.6. The solution was allowed to stand still, the aqueous layer was extracted again with 393 g of toluene, and the layers were combined with the previous organic layer.

The fact that the dichloro compound contained in the obtained organic layer is N- (2-chloroethyl) -N-methyl-2-chloro-2-phenylethylamine means that part of the hydrochloride is measured by NMR. And confirmed. The measurement results are shown below.

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δppm: 7.397-7.766 (m, 5
H), 5.82 (bd, 1H), 3.41-4.1.
(M, 6H), 2.908 (s, 3H)

Next, N, N-dimethylformamide 66
2 g of tetrabutylammonium bromide and 2 g of 7 g
784 mL of 8% ammonia water was added, and the above organic layer was flown in at room temperature. A washing liquid obtained by washing the organic layer container with 27 g of toluene was added and mixed.

The resulting mixed solution was stirred at 45 to 50 ° C. for 1 hour, and N- (2-chloroethyl) -N-methyl-2-
It was confirmed that chloro-2-phenylethylamine had disappeared, 144 g of a 48% by weight aqueous sodium hydroxide solution was introduced into the mixed solution, and the mixture was stirred at 45 to 48 ° C. for 3 hours.

The mixture was allowed to stand still, and 234 g of toluene and 4 were added to the aqueous layer.
52 g of 8% by weight sodium hydroxide aqueous solution was introduced,
Stir for minutes. Then, the mixture was allowed to stand still again for liquid separation, and the organic layer was united with the previous organic layer. The mixture was allowed to stand still, and if there was a water layer in the lower layer, the layers were further separated.

The toluene layer was separated from the aqueous layer and the toluene layer and distilled under reduced pressure to obtain 98.2 g of 1-methyl-3-phenylpiperidine.

The boiling point of the obtained 1-methyl-3-phenylpiperidine is 105-116 ° C. (0.4-0.8 kP
a), the yield from N-methylethanolamine is 43.
It was 9%.

The NMR of the obtained 1-methyl-3-phenylpiperidine was as follows.

¹ H-NMR CDCl ₃ (400 MH
z): 1.8-1.9 (br, 1H), 1.95-2.
19 (m, 2H), 2.31 (s, 3H), 2.78-
3.15 (m, 4H), 3.84-3.89 (m, 1
H), 7.22-7.41 (m, 5H)

Comparative Example 1 25 g (0.2 mol) of styrene oxide was added to 50 ml of N, N-dimethylformamide, and N was added thereto at 80 ° C.
-Methylethanolamine 14.3 g (0.19 mol)
Was dripped. The mixture was stirred at 80 ° C. for 3 hours, the end point of the reaction was confirmed by gas chromatography, and the mixture was cooled.

Next, toluene 85 was added to the obtained reaction solution.
g was added, the mixture was cooled to 10 ° C., and 18.2 g of mesylic acid was added dropwise.

A part of the resulting solution was concentrated under reduced pressure and analyzed to confirm that it was N- (2-hydroxyethyl) -2-hydroxy-N-methyl-2-phenylethylamine mesylate. .

Next, 56.2 g (0.19 mol) of thionyl chloride was added dropwise to the obtained reaction solution at 0 to 30 ° C., and 2
The mixture was stirred at 0 to 30 ° C for 6 hours. After cooling, the reaction solution was mixed with water 1
Dropwise into 20 ml at a temperature of 18-24 ° C.

To the resulting solution, 225 g of 30% aqueous potassium hydroxide solution was added dropwise at a temperature of 20 to 25 ° C., the pH was adjusted to 4.4, the mixture was allowed to stand and the layers were separated.

6 g of anhydrous magnesium sulfate was added to the organic layer, stirred for 10 minutes, added with 6 g of activated clay, stirred for 15 minutes, filtered, and washed with 21.7 g of toluene.
To the toluene solution, 60 g (0.19 mol) of 11.6% hydrogen chloride ethyl acetate solution was added dropwise at 28 to 38 ° C., and 20 to 20
After stirring at 30 ° C. for 1 hour, filtration, washing with 87 g of toluene, drying at 45-60 ° C. and N- (2-chloroethyl) -N-methyl-2-chloro-2-phenylethylamine hydrochloride (dichloro 37.7 g of the compound hydrochloride was obtained (yield 73.7%).

132 g of 28% aqueous ammonia (2.
To 175 mol), 100 ml of ethyl acetate, 460 mg of tetrabutylammonium bromide and 20.1 g (0.075 mol) of the hydrochloride of the dichloro compound obtained above were added, and the mixture was stirred at 40 to 45 ° C for 3 hours.

The obtained reaction solution was separated, and the aqueous layer was washed with 40-
It was extracted twice with 30 ml of ethyl acetate at 45 ° C. and the organic layers were combined. Then, it was distilled under reduced pressure to obtain 7.1 g of 1-methyl-3-phenylpiperazine (yield from N-methylethanolamine: 39.6%).

From the above results, according to the method of Example 1, 1-methyl-3-phenylpiperidine can be produced by a simple operation and a high yield, as compared with the method of Comparative Example 1 of the related art. I know that I can do it.

[0073]

EFFECTS OF THE INVENTION According to the production method of the present invention, 1-methyl-3-phenylpiperazine, which is useful as an intermediate for the production of mirtazapine, can be easily produced industrially in high yield without the need for complicated operations. be able to.

Claims (5)

[Claims] 1. Formula (I): The diol compound represented by the formula (II) obtained by chlorination: A dichloro compound represented by the formula (III) characterized by reacting with ammonia without isolation: A method for producing 1-methyl-3-phenylpiperazine represented by: 2. A dichloro compound represented by the formula (II) is added to p.
Extraction into a hydrophobic organic solvent with H3 to 7 according to claim 1
-Method for producing methyl-3-phenylpiperazine. 3. The method for producing 1-methyl-3-phenylpiperazine according to claim 1, wherein the hydrophobic organic solvent is toluene or monochlorobenzene. 4. Styrene oxide and N-methylethanolamine are reacted in an aprotic polar organic solvent,
The method for producing 1-methyl-3-phenylpiperazine according to claim 1 or 2, wherein the obtained diol compound represented by the formula (I) is chlorinated. 5. A reaction between styrene oxide and N-methylethanolamine in an aprotic polar organic solvent, and then chlorinating the obtained diol compound represented by the formula (I) without isolation. 1-methyl-3 described in 4
-Method for producing phenylpiperazine.