JPS5936668A - Preparation of piperazine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound, economically, by reacting the piperazinocarbonyl chloride corresponding to the objective compound with a glycine derivative under specific condition, separating the reaction liquid into two phases, and precipitating the compound from the aqueous phase with an acid, wherein said processes are carried out at specific reaction temperature and acid precipitation temperature. CONSTITUTION:4-Ethyl-2,3-dioxopiperazinocarbonyl chloride is made to react with p-hydroxyphenyl glycine in the presence of a base in a mixture of an organic solvent and water at relatively low temperature, i.e. -10-+15 deg.C, preferably -5-+10 deg.C. The reaction mixture if separated into the aqueous phase and the oily phase, and the recovered aqueous phase is made acidic to precipitate the piperazine derivative of formula at 15-80 deg.C, preferably 20-60 deg.C. The objective derivative is useful as an intermediate of antibiotic substance, and is obtained as flowable crystals extremely suitable for the operations such as filtration, washing, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a piperazine derivative, and more particularly to a method for producing a piperazine derivative represented by the following structural formula.

Piperazine derivatives with the forepaw structural formula are useful, for example, as intermediates for antibiotics, and are usually
3-dioxopiperazinocarbonyl chloride (hereinafter referred to as F
! (abbreviated as DPO) and p-hydroxyphenylglycyl (hereinafter abbreviated as HPG) are reacted in a mixture of an organic solvent and water in the presence of a base, and then the resulting mixture is mixed into an aqueous phase and an oil phase. It is produced by separating the aqueous phase into two phases and precipitating the recovered aqueous phase with acid. (For example, Tokuko Shoj!-1
．． T? (Refer to Publication No. F) In this method, KDPO and HPG
If the temperature is too high during the reaction, the desired piperazine derivative cannot be obtained in good yield. It is desirable to carry out the reaction with 'C at a relatively low temperature. However, when the reaction is carried out at such a low temperature, the subsequent liquid separation step and acid precipitation step for the reaction mixture are also carried out at a low temperature comparable to the reaction temperature.

When acid precipitation is carried out in the temperature range of -10-/j℃,
The crystals of the target compound obtained do not become smooth and tend to form a gummy substance that looks like a solidified oil. In this way, if a gum-like substance is formed, stir the crystals and filtrate.
This makes cleaning and other operations extremely difficult.

In view of the above-mentioned circumstances, the present inventors have conducted various studies on methods for recovering smooth crystals in the acid precipitation step when the reaction between FiDPO and HPG is carried out at a temperature of -10 to 15°C. The present invention was completed based on the discovery that the object of the present invention can be achieved by conducting the analysis at a specific temperature.

That is, the gist of the present invention is to react IDPO and HPG in the presence of a base in a mixture with an organic solvent and water,
Next, in a method for producing a piperazine derivative having a forefoot structural formula by separating an aqueous phase and an oil phase and precipitating crystals from the resulting aqueous phase under acidic conditions, the reaction is carried out at -io℃~/
It is carried out at a temperature of less than J℃, and the precipitation of crystals is 7! r
- A method for producing a piperazine derivative, characterized in that the process is carried out at a temperature of 0°C.

The present invention will be explained in detail below.

In the present invention, KDPO and HPG are reacted in the presence of a base, and F! DPOs are usually
/-Ethyl-cotton 3-dioxopiperazine can be easily obtained by reacting with trimethylchlorosilane in the presence of a tertiary amine and then reacting the resulting product with phosgene. On the other hand, for HPG, a normal Ichisaka product can be used. BDPO,! :The amount of HPG used is usually 0.7 to 7.3 mol per 1 mol of 1fDPO.

The reaction between 1npc and HP() produces hydrogen chloride as a by-product, but in the present invention, the reaction is carried out in the presence of a base in order to neutralize this hydrogen chloride. The type of base typically includes alkali metal hydroxides, carbonates, bicarbonates or organic bases such as triethylamine, N-methylpiperidine, diethylamine, and the like. The amount of base used is usually such that the pH within the reaction system is maintained at 7 to 1/2.

The reaction of the present invention is carried out in an aqueous medium, and the amount of aqueous medium used is usually between λ and I for the mixture of EDPO and HPG.
O weight times. However, in the case of the reaction of the present invention, mnpc as a raw material is used as a solution in an organic solvent, so the reaction is carried out in a mixture of organic solvent and water.

In this case, the ratio of organic solvent to water is usually O, S-
It is in the range of 1 times the weight. The organic solvent for dissolving the raw material 1rDpa usually includes ethylene dichloride, methylene chloride,
Water-insoluble organic solvents such as toluene and ethyl acetate.

The reaction temperature is 0°C to less than 10°C, preferably -5 to 10°C; if this temperature is too high, the reaction between PDPO and HPG will not proceed well and the objective will not be achieved. It is not possible to obtain a piperazine derivative with a high yield, and if the yield is too low, the aqueous medium will freeze, which is not preferable.

The reaction time is about 5 hours at the above temperature.

The above reaction can be carried out batchwise or continuously. For example, when carrying out batchwise, for example, an aqueous medium in which a predetermined amount of HPG is suspended is charged into a reactor, and the aqueous medium is heated to a constant temperature. Hold and stir, 1! This can be carried out by dropping a solution of IDPO in an organic solvent and an alkali.

The mixture after the reaction consists of an aqueous phase in which the alkali salt of the desired piperazine derivative is dissolved and an oil phase consisting of an organic solvent.
Then, crystals of the target compound are recovered by acid precipitation of the aqueous phase.

The acid used for acid precipitation usually includes mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, and the amount used is usually added until the pH in the system becomes 2 or less. In this acid precipitation, crystals do not precipitate immediately due to the addition of acid, so it is usually necessary to ripen for /-& hours after addition of acid, and crystals gradually precipitate due to this ripening.

In the present invention, the temperature at which crystals precipitate is set at 13 to
It is an essential requirement to maintain the temperature at goC, preferably 20 to AOC.

If this temperature is lower than the above temperature range, a gummy substance like solidified oil will be produced, and if it is higher than the above temperature range, the solubility of the desired piperazine derivative in water will be reduced. This is not preferable because the crystal size increases and the recovery rate of crystals decreases. When crystal precipitation is performed in the above temperature range, 0
Crystals can be obtained with almost the same recovery as when carried out at lower temperatures of ~10°C.

The mixture after acid precipitation can be recovered by filtering and separating the crystals according to a conventional method, washing the crystals with water as necessary, and then drying.

71 In the present invention, KDPO and HPG are reacted at a relatively low temperature of -70 to less than /S °C, and the crystal precipitation temperature is /,
! By conducting the reaction at -gO°C higher than the reaction temperature, the crystals that precipitate under acidic conditions do not become gummy and good smooth crystals can be obtained. This is an extremely preferable method in terms of operations.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Examples 1 to 3 and Comparative Examples
Water containing ttr, 2f (/mo/l/)/r004
and triethylamine 2Ai, 3 f! -, adjust the temperature in the system to θ℃, and then add K at the same temperature.
DPO20I1. /, y-(1 mol) of ethylene dichloride 100θd and triethylamine-〇&,!
f was added dropwise to the reaction system over 2 hours with stirring while maintaining the pi in the reaction system at 3, and the reaction was continued with further stirring for 7 to 8 hours. Then, the aqueous phase and oil phase were separated.

The aqueous phase obtained as described above was transferred to a stirring vessel equipped with a temperature controller, and the temperature was adjusted to the temperature shown in Table 1. Hydrochloric acid, 23% I, was gradually added under stirring to adjust the pH in the system. Acid precipitation was carried out by holding the solution for 3 hours.

The state of the crystals of the piperazine derivative having the forefoot structural formula precipitated by this acid precipitation was observed, and the results shown in Table 1 were obtained.

Table 1 9 - Crystals of the desired product were collected by washing with a glass filter for P weeks, but the acid precipitation mixture obtained in Comparative Examples 1 to 1 was a gummy substance that was completely lumped into a glass filter. The mother liquor was purged by decantation, and crystals of the desired product were collected. Gum-like substances cannot be washed as they are, and require a complicated crushing process in advance. For these crystals,
When the recovery rates of the target products were measured, they were almost the same and there was no difference.

Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase - (1 other person) 1 10-

Claims (1)

[Claims] +11 41-Ethyl-3-dioxopiperazinocarbonyl chloride and p-hydroxyphenylglycine are reacted in the presence of a base in a mixture of an organic solvent and water, and then the aqueous phase and oil phase are separated. In a method for producing a piperazine derivative represented by the following structural formula by precipitating crystals from the resulting aqueous phase under acidic conditions, the reaction is carried out at a temperature of -lθ°C to less than /j°C, and the crystals are precipitated under acidic conditions. A method for producing a piperazine derivative, characterized in that the precipitation is carried out at a temperature of 13 to 10°C.