JP2001106676A - Production of n-acetylhomopiperazine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing N-acetylhomopiperazines in high yield by selectively acetylating one of amino groups in homopiperazines. SOLUTION: N-acetylhomopiperazines such as N-acetyl-1,4-diazacycloheptane and the like which are useful as intermediates for medicines are obtained by reacting homopiperazines with an acetylating agent in the presence of oxygen.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound useful as a pharmaceutical intermediate, N-acetylhomopiperazines such as N-acetyl-1,4-diazacycloheptane,
The present invention relates to a method for selectively producing a homopiperazine such as 4-diazacycloheptane in a high yield.

[0002]

2. Description of the Related Art Homopiperazines, for example, 1,4-diazacycloheptane (commonly called homopiperazine) are useful compounds as pharmaceutical intermediates. Homopiperazines have two amino groups, and N-acetylhomopiperazines such as N-acetyl-1,4-diazacycloheptane (commonly known as N-acetylhomopiperazine) having only one of them acetylated. Classes are also very important and useful pharmaceutical intermediates. However, it is difficult to selectively acetylate only one amino group of homopiperazines, and it is extremely difficult to avoid by-producing a large amount of diacetylhomopiperazines in which both amino groups are acetylated. Was.
Many studies have been made on the selective acetylation of piperazine. However, also in this case, it is difficult to selectively acetylate only one amino group, for example, see Richard Barturli et al., J. Am. Am. Chem.
Soc. 66, 263-267 (1944), reports that when piperazine was acetylated with acetic anhydride in acetic acid, the yield was only about 40%.

As described above, it is difficult to selectively acetylate one amino group of homopiperazines, and development of a method for producing N-acetylhomopiperazines in high yield has been desired.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing N-acetylhomopiperazines in high yield by selectively acetylating one amino group of homopiperazines in view of the above problems. Is to provide.

[0005]

Means for Solving the Problems As a result of intensive studies on the method for producing N-acetylhomopiperazines, the present inventors have found that by reacting homopiperazines with an acetylating agent in the presence of an acid, a high yield is obtained. The present inventors have found a novel fact that N-acetylhomopiperazines can be obtained, and have completed the present invention.

That is, the present invention is a method for producing N-acetylhomopiperazines, which comprises reacting homopiperazines with an acetylating agent in the presence of an acid.

[0007] In the method of the present invention, the homopiperazines which are the starting materials for the reaction include 1,4-diazacycloheptane (homopiperazine) having an amino group at the 1,4-position and the 1,4-position. And a homopiperazine derivative having a substituent bonded to a position other than the above. As the substituent,
Any acid can be used without limitation as long as it does not weaken the effect of the acid used in the method of the present invention. For example, methyl group, ethyl group, hydrocarbon groups such as propyl group,
Substituents having an electron-withdrawing property and an electron-donating property, such as a methoxy group, an ethoxy group or the like, which can be bonded to a homopiperazine, such as a substituent through oxygen or sulfur to a hydrocarbon, a carbonyl group, a carboxyl group, and a halogen. Among these, a substituent having an electron donating property is preferably used because the reactivity of the acetylation reaction is increased, but a bulky substituent or an electron-withdrawing group that causes steric hindrance during the acetylation reaction is used. Even if it is present, the selectivity of the reaction may be similarly increased, and it can be used. Also, as the number of substituents,
Not only one but also two or more is acceptable.

In the following description, a method for acetylating these homopiperazines, that is, homopiperazine and its derivatives, will be described using homopiperazine as a representative.

In the method of the present invention, homopiperazine is acetylated in the presence of an acid. As the acid used, either a strong acid or a weak acid may be used, but the use of a strong acid improves the yield of N-acetylhomopiperazine. More specific examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, formic acid, acetic acid, propionic acid, benzoic acid, phenol and benzenesulfonic acid. And organic acids such as toluenesulfonic acid. Further, among these, hydrochloric acid, sulfuric acid, and nitric acid are preferably used as inorganic acids, and formic acid, acetic acid, and phenol are preferably used as organic acids because they are inexpensive and easily available. These acids can be used alone or in combination of two or more as needed. It is difficult to limit the amount of the acid to be added because it varies depending on the type of the acid.
The range is preferably 0.1 to 1.9 mol, and more preferably 1.0 to 1.9 mol, in terms of reactivity. Outside of this range, if the amount is less than 0.1 mol, the effect of adding the acid may be significantly reduced,
If the amount exceeds 1.9 mol, the acetylation rate may be reduced. In the method of the present invention, the reaction mechanism is not necessarily clear, but the acid present during the acetylation reaction blocks one amino group of homopiperazine, whereby the acetylation reaction causes the other amino group. To selectively react with N-
It is presumed that high yield of acetylhomopiperazine is obtained.

In the method of the present invention, any acetylating agent can be used without particular limitation as long as it is generally known. However, acetyl halides such as acetic anhydride and acetyl chloride are generally used. And
It is industrially advantageous from the viewpoint of cost.

The amount of the acetylating agent is preferably in the range of 0.1 to 1.9 mol, more preferably 0.5 to 1.5 mol, particularly preferably 1.0 to 1.0 mol, per mol of homopiperazine. ~ 1.
A range of 5 moles is preferred.

[0012] If the amount deviates from this range and is less than 0.1 mol or more than 1.9 mol, the yield of N-acetylhomopiperazine may decrease.

The method of adding the acetylating agent is as follows.
Even if the whole amount is added to the reaction solution containing homopiperazine at once,
Although it may be added little by little, the yield of N-acetylhomopiperazine obtained by adding little by little increases.

In the method of the present invention, the acetylation reaction is preferably carried out at a temperature in the range of -40 to 100 ° C, more preferably at a temperature in the range of 0 to 100 ° C. −
Although the reaction proceeds even at a temperature lower than 40 ° C., the progress speed may be relatively slow, and there is little advantage in lowering the temperature. When the reaction is carried out at a temperature exceeding 100 ° C., the selectivity for N-acetylhomopiperazine may decrease.

In the method of the present invention, the acetylation reaction is generally carried out by dissolving homopiperazine in a solvent and adding an acetylating agent thereto, but the solvent used can dissolve homopiperazine. There are no restrictions on things. Solvents capable of dissolving homopiperazine include water, alcohols, carboxylic acids such as acetic acid, chloroform, and the like. However, it is preferable to use water from an economic viewpoint.

In the method of the present invention, after the acetylation reaction, N-acetylhomopiperazine can be purified by a generally known method, and the unreacted raw materials and solvent may be recovered and reused. . As an example of a method for purifying N-acetylhomopiperazine, caustic soda is added, a layer containing a large amount of N-acetylhomopiperazine and a layer containing a large amount of others are separated, and then N-acetylhomopiperazine is distilled or a poor solvent is distilled off. After the addition, a method of crystallization and recrystallization, a method of neutralizing N-acetylhomopiperazine salt in the reaction solution, and a method of separating and purifying by free distillation of N-acetylhomopiperazine are available. There is no harm in using the method.

As described above, N-acetylhomopiperazines can be produced from homopiperazines by the method of the present invention. Therefore, the structure of the homopiperazine as a reaction raw material is set according to the purpose of use, and one amino group is selectively acetylated by using the method of the present invention,
The corresponding N-acetylhomopiperazines are obtained and can be used in various applications as pharmaceutical intermediates.

[0018]

EXAMPLES Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited thereto.

The following abbreviations are used to simplify the notation.

HMP: Homopiperazine AHMP: N-acetylhomopiperazine Example 1 5 g of HMP (50 mm) was placed in a 50 ml glass flask.
ol), 25 g of water and hydrochloric acid (50 mmol), and the mixture was heated to 40 ° C. while stirring. 5.5 g of acetic anhydride (5
4 mmol) was added dropwise little by little. After completion of the dropwise addition, stirring was continued at 40 ° C. for 1.5 hours. Next, sodium hydroxide was added to neutralize the acid, and the reaction solution was analyzed by gas chromatography. As a result, the conversion of HMP was 89.6% and AHM
The yield of P was 69.8%.

Examples 2 to 4 The reaction was carried out in the same manner as in Example 1 except that the amount of acetic anhydride shown in Table 1 was added. Table 1 shows the results.

[0022]

[Table 1]

Examples 5 and 6 The reaction was carried out in the same manner as in Example 1 except that the reaction temperature was changed to the temperature shown in Table 2. Table 2 shows the results.

[0024]

[Table 2]

Examples 7 and 8 The reaction was carried out in the same manner as in Example 1 except that 50 mmol of the acid shown in Table 3 was used instead of hydrochloric acid. Table 3 shows the results.

[0026]

[Table 3]

Comparative Example A reaction was carried out in the same manner as in Example 1 except that hydrochloric acid was not added.
After neutralizing by-produced acetic acid with sodium hydroxide, the reaction solution was analyzed by gas chromatography. As a result, the conversion of HMP was 81.0%, and the yield of AHMP was 41.6%.

Comparison between Example 1 and Comparative Example shows that HMP is acetylated by allowing hydrochloric acid to be present in the reaction system to acetylate HMP.
It can be seen that the conversion of P is high and the yield of AHMP is also high.

In the examples, the conversion of HMP and A
It can be seen that the yield of HMP is high, and that the acid used is sufficiently high not only for hydrochloric acid but also for acetic acid and phenol.

[0030]

According to the present invention, one amino group of homopiperazines is selectively acetylated to give N-
Acetyl homopiperazines can be produced, which is an industrially useful method.

Claims (8)

[Claims] 1. A process for producing N-acetylhomopiperazines, which comprises reacting a homopiperazine with an acetylating agent in the presence of an acid. 2. The method of claim 1, wherein the homopiperazine is 1,4-diazacycloheptane and N-acetylhomopiperazine is N-acetyl.
The production method according to claim 1, wherein the production method is acetyl-1,4-diazacycloheptane. 3. The method according to claim 1, wherein the acetylating agent is acetic anhydride or acetyl halide. 4. The method according to claim 1, wherein the acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid and nitric acid.
The production method according to any one of the above. 5. The method according to claim 1, wherein the acid is at least one selected from the group consisting of formic acid, acetic acid and phenol. 6. The method according to claim 1, wherein the amount of the acid to be added is 0.1 to 1.9 mol per 1 mol of the homopiperazine. 7. The method of claim 1, wherein the amount of acetylating agent is homopiperazines 1
The production method according to any one of claims 1 to 6, wherein the amount is 0.1 to 1.9 mol per mol. 8. The process according to claim 1, wherein the reaction is carried out at -40 to 100.degree.