JPS59164781A - Preparation of 2,3-dioxo-1-piperazinocarbonyl chlorides - Google Patents

Abstract

PURPOSE:In preparing the titled compound useful as an intermediate for synthetic penicillin, etc, by reacting a 2,3-dioxopiperazine with phosgene, to improve its yield at normal temperature with suppressing side reactions, by making phosgene exist in excess during the reaction. CONSTITUTION:A 2,3-dioxopiperazine shown by the formula I (R is H, or alkyl; A is alkyl, alkenyl, alkadienyl, cycloalkyl, benzyl, or aryl; R' is alkyl) is reacted with phosgene in a molar ratio of phosgene to the compound shown by the formula I of >=1.1, preferably 1.2-1.3 in an organic solvent such as chloroform, etc, at about normal temperature at -25-50 deg.C, preferably 0-30 deg.C, to give the desired compound shown by the formula II. The starting raw material shown by the formula I , for example, is synthesized by reacting a compound shown by the formula III with trimethylsilyl chloride in a solvent in the presence of a deoxidizer such as triethylamine, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2,3-dioxo-1-piperazinocarbonyl chlorides. In more detail,
2. A process for producing 3-dioquine-1-piperazinocarbonyl chlorides with improved yields.

2.8-Dione-1-piperazinoyl chlorides are extremely useful compounds as intermediates for synthetic penicillins and synthetic cephalosporin thread compounds.

As a method for producing 2.3-dioxo-1-piperazinocarbonyl chlorides, 2.3-dioxo-1-piperazinocarbonyl chlorides are prepared by reacting 2.3-dioxopiperazines with phosgene 7i Lr; The manufacturing method is known from Japanese Patent Publication No. 55-49580. As is clear from the examples, the reaction between 2,3-dioquine piperazines and phosgene disclosed in the Japanese Patent Application Publication No. 2003-110012 involves using an excess of 2,3-dioxopiperazines relative to phosgene in the reaction medium. reacting under the conditions that exist. However, when the present inventors tried this method again, the yield was about 90% even at a reaction temperature of 125°C with phosgene, and when the reaction temperature got higher, the yield was remarkable. It decreases to 81% at 25°C.

In response to these circumstances, the present inventors conducted an ω1 study to find a method to further increase the yield when the reaction temperature is around room temperature, and found that when carrying out the reaction while maintaining an excess of phosgene, the It has been discovered that the reaction can be prevented and, as a result, the yield can be improved, and the present invention has been completed.

That is, the present invention relates to the general formula 0 group or aryl group, R/ represents an alkyl group] and phosgene to react the 2,3-dioxopiperazines represented by the general formula 1'1l-3 [wherein R3 and A are ] In the method for producing 2,8-dioxo-1-piperazinocarbonyl chloride represented by Provided is a method for producing 2,3-dioxo-1-piperazinocarbonyl chloride, which is carried out under conditions where

In the present invention, A in formula [I] is methyl, ethyl, propyl, or isopropyl.

Alkyl groups such as butyl, amyl, hexyl, heptyl, ocnal, dodecyl; vinyl.

Artenyl groups such as propenyl and butenyl; cycloalkyl groups such as cyclopentyl, cyclohexyl and cycloheptyl; phenyl.

These A represent aryl groups such as naphthyl and benzyl groups, and these A are, for example, halogen atoms, hydroxyl groups, alkyl groups, alkoxy groups, alkylthio groups, nitro groups, cyan groups, carboxyl groups, acetoxy groups, acyl groups, alkylamino groups, and ring groups. It may be further substituted with a substituent such as an amino group. A is especially methyl.

Alkyl groups such as ethyl, propyl, butyl are preferred.

61CI) In the formula, k is hydrogen or a methyl group,
Examples include alkyl groups such as ethyl group, propyl group, and butyl J^. Particularly preferred is hydrogen.

[■] In the formula, '' includes alkyl groups such as methyl, ethyl, propyl, and butyl groups. Although k' does not have to have the same number of carbon atoms, it is more economical to use compounds with the same number of carbon atoms. Specifically, the 02,8-dioxopiperazines, which are particularly preferably methyl groups, include l
-Methyl-4-trimethylsilyl-2,8-dioxopiperazine, l-ethyl-4-trimethylsilyl-2,3
-dioxopiperazine, l-propyl-4-trimethylsilyl-2,3-dioxopiperazine, l-butyl-4
-trimethylsilyl-2,8-dioxopiperazine, ■
-pentyl-4-trimethylsilyl-2,8-dioxopiperazine, l-hexyl-4-trimethylsilyl-2
, 8-dioxopiperazine, l-hebutyl-4-trimethylsilyl-2,3-dioxopiperazine, l-octyl-4-trimethylsilyl-2,8-dioxopiperazine, l-isopropyl-4-trimethylsilyl-2° 8
-dioquinpiperazine, ■-aryl-4-trimethylsilyl-2,8-dioxopiperazine, 1-(2-acetyloxyethyl)-4-trimethylsilyl-2,8-dioxopiperazine, l-phenyl-4-trimethylsilyl- 2,3-dioquinepiperazine, 1-(2-chloroethyl)-4-)limethylsilyl-2,3-dioxopiperazine, l-ethyl-4-trimethylsilyl-5-methyl-2,8-dioxopiperazine, ■- Examples include 2,8-dioxopiperazines such as methyl-4-trimethylsilyl-5-methyl-2,8-dioxopiperazine.

Special ICl-methyl-4-trimethylsilyl-2,8-dioxopiperazine, l-ethyl-4-trimethylsilyl-2,8-dioquine piperazine, l-propyl-4-trimethylsilyl-2,8-dioxopiperazine, l -Butyl-4-trimethylsilyl-2,8-dioxopiperazine is preferably used.

These 2,3-dioxopiperazines, which are the raw materials of the present invention, can be prepared by combining, for example, a compound represented by the general formula [wherein RE and A have the meanings described in 1] with methylene chloride, chloroform,
Triethylamine, tributylamine, In the presence of a deoxidizing agent such as N-methylpiperidine, N-methylmorpholine, pyridine, or diazabicycloundecene, trimethylsilyl chloride is generally treated at a reaction temperature of -25°C to 50°C for 80 minutes to 5 hours. It can be produced by reacting the trimethylsilyl chloride and the deoxidizing agent with respect to the starting materials, generally using a molar ratio of 1.0 to 1.5, respectively.

In carrying out the method of the present invention, 2,8-dioxopiperazines are reacted under conditions in which phosbone is present in excess with respect to 2,8-dioquinpiperazines during the reaction. As a method for making phosgene present in excess of 2.8-dioxopiperazines during the reaction, for example, 2.8-dioquine piperazines are added continuously or intermittently to an inert organic solvent in which excess phosgene is dissolved. 2.8-dioxopiperazide with an inert organic solvent in which phosgene is dissolved
10- This can be achieved by adding it to the container. What is important here is that there is always an excess of phosgene relative to the 2,3-dioxopiperazines, and if the 2,3-dioxopiperazines are present in excess, the yield will be greatly reduced. This is not desirable as it becomes lighter in weight. 2. of phosgene during the reaction.
The molar ratio to 3-dioxopiperazines is at least 1.
．． 1 L or more (preferably kept at 1.2 or more; the higher side is not particularly limited, but is determined in consideration of the economic efficiency of recovery operations, etc.).

The amount of phosgene required for completing the reaction is generally 1.1 to 1.6 molar, preferably 1.2 to 1.3 molar based on the 2,3-dioxopiperazine.

The reaction temperature is generally -25°C to 50°C, preferably 0°C to 3°C.
The reaction is carried out at 0°C, and the reaction time is usually 30 minutes to 4 hours.

Examples of the organic solvent include methylene chloride, chloroform, l,2-dichloroethane, tetrahydrofuran,
One or more mixed melts of dioquinane, acetonide +)/L, methyl acetate, acetone, methyl ethyl ketone, 1,2-dimethoxyethane, and benzene are used.

During the reaction, it is preferable to sufficiently stir the reaction mixture so that the amount of 2,3-dioquine piperazine does not locally become excessive compared to the amount of phosgene.

There is no difference in setting the anti-[r5 pressure separately whether it is pressurized or depressurized,
It is usually carried out at around normal pressure.

The phosgenation reaction can be carried out continuously, semi-continuously, or batchwise.

The crude reaction product is degassed as necessary by applying a vacuum, passing an inert gas such as nitrogen, distilling off the solvent, or a combination thereof to remove unreacted phosgene. except for.

The desired product can then be easily isolated by processing the crude reaction product or the crude reaction product after degassing using conventional means such as distillation of the solvent and filtration.

The 2,8-dioxo-1-piperazinocarbonyl chloride thus obtained can be used as it is, after further purification treatment such as recrystallization as necessary, or isolated (
This bath solution is used as an intermediate material for synthetic penicillin and synthetic cephalosporin compounds.

Hereinafter, the method of the present invention will be explained in detail with reference to Examples, but the method of the present invention is not limited thereto.

Example 1 14.2 F of 1-ethyl-2,8-dioxopiperazine was dissolved in 1282 F of 1,2-dichloroethane, 12.14 F of triethylamine was added, 18 F of trimethylsilyl chloride was added dropwise at 10°C, and 1 F was dissolved at the same temperature. Allowed time to react. The reaction solution was then filtered to remove triethylamine hydrochloride, and the quenching solution was mixed with phosgene 12.9F and 1.2-
One drop of 18 was added dropwise to a mixed solution of 1702 dichloroethane while maintaining the temperature at 10° C. over 1 hour and 30 minutes, and stirring was continued for another 1 hour at the same temperature. After the reaction, the solvent was distilled off under reduced pressure to obtain 19.4f (95%) of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride.

In the above reaction, the reaction temperature was -25°C.

The reaction was carried out in the same manner as above except that the temperature was 25°C and 40°C. The results were as shown in Table 1.

Table 14 - Example 2 Dissolve 14.2 f of 1-ethyl-2,8-dioxopiperazine in 1281 of 1,2-dichloroethane, add 18 of trimethylsilyl chloride, and add 2.1 f of triethylamine at 25°C. was added dropwise, and the mixture was reacted with IW at the same temperature for 1 hour. The reaction mixture was then added over a period of 1 hour and 80 minutes to a mixed solution of 12.99 g of phosgene and 170 g of 1,2-dichloroethane kept at 10 DEG C., and stirring was continued at the same temperature for an additional 1 hour. After the reaction, triethylamine hydrochloride was purified and the solvent was distilled off under reduced pressure, resulting in 4-
19.4f (95%) of ethyl-2,8-dioxo-1-piperazinocarbonyl chloride was obtained.

Example 8 1-Methyl-2,8-dioxopiperazine 12.8F was dissolved in 1,2-dichloroethane 128F, and triethylamine l 2. l? In addition, trimethylsilyl chloride 18.Of was added dropwise at 10°C, and then 18.
Allowed time to react. The reaction solution was then clarified to remove triethylamine hydrochloride, and the quenched solution was poured into a mixed solution of phosgene 12.9r and 1,2-dichloroethane 170f at 10°C.
The mixture was added dropwise over 1 hour and 80 minutes while maintaining the same temperature, and stirring was continued for another 1 hour at the same temperature. After the reaction, the solvent was removed under reduced pressure to obtain 17.9 r (94%) of 4-methyl-2,8-dioxo-1-piperazinocarbonyl chloride.

For comparison, in the above reaction, 2.8-
When the reaction was carried out at a molar ratio of 1.0 to the dioxopiperazines, the yield was 72%.

Example 4 1-propyl-2,8-dioxopiperazine 15.6F
was dissolved in 128 t of 1.2-dichloroethane, trimethylsilyl chloride 1B and Of were added, and triethylamine 1 was added at 25C. After dropping l f, 1 at the same temperature.
Allowed time to react. The reaction solution was then clarified to remove triethylamine hydrochloride, and the quench solution was treated with phosgene 12.9F.
25 into a mixed solution of 1,2-dichloroethane and 1702
The mixture was added dropwise over 1 hour and 80 minutes while maintaining the temperature at 0.degree. C., and stirring was continued for 1 hour at the same temperature. After the reaction, the solvent was removed under reduced pressure, and 20.85' (95%) of 4-propyl-2,8-dioxo-1-piperazinocarbonyl chloride was obtained.
was gotten.

Comparative Example 1 14.2f of 1-ethyl-2,8-dioxopiperazine was dissolved in 1282 of 1,2-dichloroethane, 12.1f of triethylamine was added thereto, trimethylsilyl chloride 1B and Of were added dropwise at 10°C, and the mixture was heated at the same temperature. Let it react for 1 hour. Then, a mixed solution of 12.9 f of phosgene and 170 t of 1,2-dichloroethane was added dropwise at -25°C over 1 hour and 80 minutes, and stirring was continued for another 1 hour at the same temperature. After the reaction, triethylamine hydrochloride was removed and the solvent was distilled off under reduced pressure to obtain 18.4f (90%) of 4-ethyl-2°8-dioxo-1-piperazinocarbonyl chloride.

Comparative Examples 2 to B The same procedure as Comparative Example 1 was conducted except for the reaction temperature with phosgene. The yields of 4-ethyl-2,8-dioxopiperazinocarbonyl chloride were 68% and 81% at reaction temperatures lθ°C and 25°C, respectively.

118 completed-

Claims (3)

[Claims] (1), General formula [Equation] [In the formula, k is a hydrogen IQ atom or an alkyl group, and A is an alkyl group with or without a substituent, an alkenyl group, an alkagenyl group, a cycloalkyl group, a benzyl group, or An aryl group, R/ is an alkyl group, is reacted with 2,3-dioxopiperazines and phosgene to form a compound of the general formula α] [where k and A have the meanings described above. ] In the method for producing 2,8-dioxo-1-piperazinocarbonyl chloride represented by 1. Production of 2,8-dioxo-1-piperazinocarbonyl chlorides, characterized in that reaction E is carried out under conditions in which phosgene is present in excess relative to 2,8-dioxopiperazines during the reaction. Method. (2) The reaction is carried out under conditions in which phosgene is present in a molar ratio of 1.1 or more to the 2,8-dioxopiperazines. A method for producing the described 2.8-dioxo-1-piperazinocarbonyl chlorides. (3) A method for producing 2,8-dioxo-1-piperazinocarbonyl chloride according to claim 1 or 2, characterized in that the reaction temperature is 125°C to 50°C.