JPS5879993A - Preparation of 1,3,3,5,5,-pentaaziridino-1-thia-2,4,6-triaza-3,5- diphospholine-1-oxide - Google Patents

Abstract

PURPOSE:To prepare the titled compound exhibiting powerful carcinostatic action industrially and advantageously, by reacting ethyleneimine with a diphospholine oxide in a halogenated hydrocarbon organic solvent in the presence of a hydrogen chloride acceptor. CONSTITUTION:Ethyleneimine is reacted with a 1,3,3,5,5-pentahalo-1-thia-2,4,6- triaza-3,5-diphospholine-1-oxide in a halogenated hydrocarbon organic solvent, e.g. methylene chloride, chloroform or 1,1-dichloroethane, in the presence of a hydrogen chloride acceptor, preferably a tertiary amine such as triethylamine or N-methyl-pyrolidine, to prepare the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ethyleneimine and 1,5,3,5,5-pentam0-1-thia-2,4,6-)diaza-6,5-diphosphorine-1-oxide (hereinafter referred to as 1, 3.5.5.5-pentaaziridino-1- by reaction with
The present invention relates to a method for producing thia-2,4,6-)diaza-3,5-dibosphorin-1-oxide (hereinafter referred to as 5oAz).

j30Az is a known compound and has been reported to exhibit extremely strong anticancer effects.

(J, F, Labarr'e, Eur, J, 0anoe
r, 15.637 (1979) and J, O, Van
de Grampel et al.
nioaGhimic a AG ta's 53, L
'1115' (1981) #Sho). However, research into its manufacturing method had been carried out solely out of academic interest, and no research had been conducted with the aim of developing a large-scale synthesis method based on industrial knowledge.

However, the anticancer effect of 5OAz has been reported to be more disappointing (
J.F., Labarre et al., Oa'nc.
er Letter %12.245 (1981)), as the usefulness of 5OAz has come into the spotlight,
Research aimed at developing practical manufacturing methods is becoming more and more active.

The n6s used as a starting material for the production of 5OAZ is a known compound, for example the method reported by Grampel et al. (H,H, Baalman, H,P.

Velvis, J., 0. Vande glampe L＼
Re, 'I'rav.

Ohim, 91.935 (1972). However, according to the manufacturing method, 1.3.
5.5-tetrahalo1.6-cythia2.4. (S-
) Reazor 5-phosphorine-1,3-dioxide (hereinafter referred to as S2) is about 30 to 60% (mol%
) is known to occur as a by-product. S engineer and 82
If S is used as a mixture for the production of 5OAZ, the yield of 5OAZ decreases in the conventional method, so it is necessary to use a product separated from S, which necessitates complicated operations for purification. has been done.

The conventional general method for producing 5OAz is as follows: (1) As a solvent, ether organic solvents such as diethyl ether, dimethyl ether, and tetrahydrofuran, aliphatic hydrocarbon organic solvents such as hexane and heptane, benzene, toluene, nitrobenzene, etc. An aromatic hydrocarbon organic solvent or a nitrile organic solvent such as acetonitrile is used in an anhydrous state (as a phantom hydrogen chloride acceptor, an excess amount of ethyleneimine,
Using a tertiary amine, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, or alkaline earth metal hydroxide, (iii) the reaction temperature is set to about -100
Ethyleneimine and S are to be reacted within the range of ~10oOo, and 5OAz is obtained with a yield of about 60%.

Such conventional methods have the following problems, especially when implemented on a large scale (industrial scale).

(a) Solvents such as tetrahydrofuran and acetonitrile have good solubility in SO and 5OAz, but because they are solvents that mix with water and have high hygroscopicity, they are required to be kept in an anhydrous state compared to other solvents. Operation is complicated and difficult.

(b) Dimethyl ether, diethyl ether, etc. have low ignition points and are flammable, so they require special care when handling them in industrial applications and require special equipment for disaster prevention.

(a) For solvents that are immiscible with water such as diethyl ether, dimethyl ether, benzene, hexane, heptane, toluene, and nitrobenzene, the partition coefficient of 5OAZ in the organic solvent when water is added to create a water-organic solvent extraction system. is low and the extraction effect is poor. Therefore, S
When separating OAz from a hydrogen chloride acceptor/hydrogen chloride salt (for example, triethylamine/HO7 salt), a method using solvent extraction cannot be applied, and a very complicated operation is required.

(d) The solvents listed in (c) are
Due to its low solubility in the reaction, multiple electric currents are required for the reaction, making it uneconomical.

The reaction yield of (θ) 5OAz largely depends on the purity of the raw material S, and the yield will decrease if high purity S is not used.

The present invention was made in view of such conventional problems,
The purpose of the present invention is to provide an industrial method for manufacturing 77SOAZ that overcomes the problems of conventional methods.

That is, the present invention relates to a method for producing 5OAz, which is characterized in that the reaction between ethyleneimine and S is carried out in a halogenated hydrocarbon organic solvent in the presence of a hydrogen chloride acceptor.

Examples of the halogenated hydrocarbon organic solvent used in the present invention include methylene chloride, chloroform, 1,2-dichloroethane, 1.1-dichloroethane, 1.1.1.2
-tetrachloroethane, 1,1.2.2-tetrachloroethane, and the like are preferred.

The characteristics of the present invention obtained by using a halogenated hydrocarbon organic solvent are as follows:kf6゜(A) Halogenated hydrocarbon organic solvents generally have a low water content and have almost no hygroscopicity. Therefore, pretreatment such as distillation is not required before use.

(B) Halogenated hydrocarbon organic solvents are generally stable and nonflammable, so there is little risk when handling them in large quantities.
In addition, it can be easily recovered with a simple operation.

(0) The halogenated hydrocarbon organic solvent is
The solubility in OAZ is high (especially very high for 0H2012 or 0HO13), and the amount of solvent used during the reaction can be reduced, but the yield does not decrease even if the reaction solution becomes highly concentrated.

(D) The halogenated hydrocarbon organic solvent has a high distribution coefficient of 5OAz when used in a water-organic solvent extraction system. For example, in the methylene chloride-water extraction thread, 5OAZ is almost quantitatively extracted into the methylene chloride layer, and the hydrogen chloride acceptor/Hot
It becomes possible to easily separate it from water-soluble by-products such as salts. Therefore, the operation can be greatly simplified and it is suitable for mass production.

(In) The reaction yield hardly depends on the purity of the raw material, S, and even when using S with a purity as low as 50%, 5OAZ'E can be produced in good yield and with high purity without any special operations. You can wander around.

Next, preferred embodiments of the present invention will be described. That is, 1 to 2 equivalents of tertiary amine (as a hydrogen chloride acceptor) and 1 to 2 equivalents of ethyleneimine are added to a halogenated hydrocarbon organic solvent of approximately the same weight as Sl, based on the halogen content of S engineering. After dissolving and then cooling to about -100~60°0, preferably about -78~-60°0 and stirring vigorously, S (purity about 50~100%) was dissolved in a halogenated hydrocarbon organic solvent. Add the solution gradually. After completion of the dropwise addition, the reaction solution is about -60~60°o1, preferably about -10~
Continue stirring while maintaining the temperature at 0°0 for approximately 12-17 hours. After the reaction is completed, a 5-10% aqueous sulfuric acid solution is added to the reaction solution, stirred, and then allowed to stand to separate into two layers. By removing the aqueous layer, excess ethyleneimine, hydrogen chloride acceptor, hydrogen chloride acceptor/IIO! Salt etc. can be removed.

The organic layer is neutralized and dried by adding powdered sodium carbonate, and then concentrated under reduced pressure. The obtained residue can be purified by known purification methods such as recrystallization and column chromatography to obtain 5OAz with a yield of 65% or more and a purity of 99% or more.

The S-based compound used in the present invention includes those in which the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, but those in which the halogen atom is a chlorine atom are particularly preferred.

Further, as the hydrogen chloride acceptor used in the present invention, those used in conventional methods can be used, but especially
grade amines are preferred. Specific examples thereof include triethylamine, trimethylamine, tripropylamine, tributylamine, ethyl-diisopropylamine, N-methyl-pyrrolidine, N-methyl-piperidine, and N-methyl-morpholine.

Next, the manufacturing method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 In a 6 volume flask equipped with a mechanical stirrer, a calcium chloride tube and a dropping funnel, triethylamine 854+n1 (1.OF equivalent to S process) and ethyleneimine 378ml (1.2 times to S process) were added. equivalent)
and 400 ml of methylene chloride were added and stirred to form a homogeneous solution. Next, it was cooled to -60 to -70°0 in a dry ice-acetone bath, and S-processed (purity: 100%).
) A solution prepared by dissolving 400 g of methylene chloride in 400 mj of methylene chloride was added dropwise over 1 hour and 30 minutes. After the dropwise addition was completed, the reaction was continued for 17 hours while maintaining the reaction solution at about -5°O. After the reaction was completed, a 5% aqueous sulfuric acid solution (17) was gradually added to the reaction solution at -5°0, taking care not to exceed 15°a, and the pH was adjusted to -3 to 4. After standing still to separate an aqueous layer and an organic layer, the methylene chloride layer was separated, and then 50 g of sodium carbonate powder was added to neutralize and dry.

Next, sodium carbonate was removed by filtration, and the p solution was concentrated under reduced pressure to obtain 675 g of a residue. This residue was crystallized six times from ether-methylene chloride mixed solvent 41 to obtain 350 g of crystals of 5OA2 (yield: 80%).

The purity of the obtained 5OAz crystals was analyzed by high performance liquid chromatography and was found to be 99.7% or more.

Melting point: 105-105.5°0 Elemental analysis value: 010H2ON8”2SO (molecular weight 36
2.23) Theoretical value part): o33.15 N5
．． 56 N30.93 actual measurement value (2)): (133,
45N5.30 N31.1431P-NMR analysis value (solvent-〇DO13, external standard 285% phosphoric acid); 3
'5.91 ppm Example 2 Reaction after using a mixture of S and S2 at the weight ratio shown in Table 1 in place of S (purity = 100%) and adding a methylene chloride solution of S and S2 dropwise. An experiment was conducted in the same manner as in Example 1, except that the temperature was set as shown in Table 1.
A crystal of 5OAz was obtained. The yield (based on the amount of S used) and purity of the 5OAz obtained are shown in Table 1.

Table 1 As can be seen from Table 1, even if S was used as a raw material from which S was not separated, 5OAZ could be produced in a good yield of 70% or more and with a high purity of 99% or more. .

As described above, the present invention provides a method for producing 5OAZ that is simple and suitable for industrial mass production.

Claims (1)

[Scope of Claims] 1. The reaction between ethyleneimine and 1.3.5.5.5-pentahalo-1-thia-2,4,6-)diaza-6,5-diphosphorine-1-oxide is halogenated. 1, 3.3.5.5- characterized in that it is carried out in a hydrocarbon-based organic solvent in the presence of a hydrogen chloride acceptor.
Pentaaziridino-1-thia-2,4,6-)diaza-
Method for producing 6,5-diphosphorine-1-oxide. 2. The halogenated hydrocarbon organic solvent is methylene chloride, chloroform, 1,2-dichloroethane, 1,1-dichloroethane, 1.1.1.2-tetrachloroethane or 1.1.2.2-tetrachloroethane. A manufacturing method according to claim 1. 6. The production method according to claim 1 or 2, wherein the hydrogen chloride acceptor is a 6th class amine. 4. Claim 6, wherein the 6th class amine is triethylamine, trimethylamine, tripropylamine, tributylamine, ethyl-diisopropylamine, N-methyl-pyrrolidine, N-methyl-piperidine or N-methyl-morpholine. Manufacturing method described.