JPH04924B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1,3,3,5- represented by the following formula.
The present invention relates to an improved method for producing tetrachloro-1,5-dithia-2,4,6-triaza-3-phosphorine-1,5-dioxide (hereinafter referred to as _S2 ). 1,3,3,5,5-pentahalo-1-thia-2,4,6-triaza-3, represented by the following formula:
1,3,3,5,5-pentaaziridino-1-thia-2,4,6-triaza-3,5- in which the halogen atom of 5-diphosphorine-1-oxide (hereinafter referred to as S ₁ ) was replaced with ethyleneimine It has recently been discovered that diphosphorine-1-oxide has extremely high efficacy as an anticancer agent (JF
Labarre, Eur. J. Cancer, 15 , 637–643 (1979)
reference). Similar efficacy is expected for S 2 derivatives in which the halogen atom of S ₂ , which is a by-product during S ₁ synthesis, is replaced with ethyleneimine, and S _{1 and}
More and more studies are being conducted on the manufacturing method of _S2 . Conventionally, as a method for synthesizing _S2 , the method of Grampel et al. using phosphorus pentachloride, ammonium chloride and sulfamic acid is known (HH
Baalmann, HPVelvis and JCvan de
Grampel, Recl.Trav.Chim. 91 , 935 (1972)). The method of synthesizing S ₂ by the method of Grampel et al. can be roughly divided into five steps. That is, phosphorus pentachloride and ammonium chloride are reacted [Cl ₃ PNPCl ₃ ] [PCl ₆ ] (hereinafter referred to as P ₁ ).
The first step is to obtain P1, the second step is to react _P1 with sulfamic acid, the third step is to thermally decompose the reactant, the fourth step is distillation, and the fifth step is hydrolysis. . This method is the same as the method for synthesizing S ₁ ; S ₂ is obtained by crystallizing the hydrolysis reaction product from hexane, and S ₁ is obtained by purifying its mother liquor. The main reaction formulas in these steps are shown below.
In this reaction formula, A is a substance that is easily decomposed by water. (1st step) 3PCl ₅ +NH ₄ Cl → [PCl ₃ NPCl ₃ ] [PCl ₆ ] (P ₁ ) (Fourth step) NPCl ₂ +NSOCl→S ₁ +S ₂ +A (Fifth step) S ₁ +S ₂ +A→S ₁ +S _2This conventional method will first be described by citing one embodiment. The first step is the synthesis of _P1 , phosphorus pentachloride 2080
1,1,2, containing g and 175 g of ammonium chloride.
150ml of 2-tetrachloroethane and nitrobenzene
Pour 850ml of the mixed solvent under reduced pressure (10~20mm
Hg) between 75°C and 90°C for 6 hours. At this time, sublimed phosphorus pentachloride often clogs the solvent reflux tube. Next, the pressure was returned to normal pressure, the reaction temperature was maintained at 140°C for 15 minutes, and then the reaction vessel was cooled and left at -20°C overnight to separate the precipitated crystals, and 600ml of carbon tetrachloride and 600ml of carbon tetrachloride carbon 300ml
and n-pentane (300 ml), and finally, n-pentane (600 ml). the remaining crystals
Dry at 50°C for 3 hours under reduced pressure of 0.2 mmHg to obtain 1060 g of crude crystals of _P1 . The reaction with sulfamic acid in the second step is a solid-phase reaction, in which 194 g of sulfamic acid is added to the crystals formed earlier, mixed well, heated at 100℃,
The mixture is liquefied and heated until no hydrogen chloride gas is generated. After separating off unreacted materials, 950 g of product is obtained. The thermal decomposition reaction in the third step is carried out under high vacuum (at least 1 mmHg or less), and after removing phosphoryl trichloride at a heating temperature of around 100°C,
to 150°C to cause a thermal decomposition reaction. At this time, it is necessary to induce a thermal decomposition reaction by adding a small amount (several grams) of sulfamic acid. In this case, care must be taken to avoid clogging of the cooling pipe due to sublimation of unreacted phosphorus pentachloride. The thermal decomposition reaction is interrupted until the appearance of crystals that adhere to the cooling tube, or if nitrobenzene remains,
It is difficult to know the end point because the reflux of nitrobenzene makes it difficult to determine the appearance of crystals, and the end point is defined as the stop of distillation of phosphoryl trichloride. The fourth step of distillation is an even higher degree of vacuum (0.2~
0.6 mmHg) to a temperature of 160 to 200°C, which took a long time (about 7 hours) to obtain 320 g of a yellow fraction. In the fifth step of hydrolysis, the above fraction is cooled with ice water and stirred to decompose water-active substances. Separate the white precipitate and wash with cold water until the nitrobenzene odor disappears. Dry under reduced pressure in the presence of phosphorus pentoxide to obtain 225 g. This generates at the same time as S ₁
To obtain more S ₂ , heat and dissolve this mixture in 660 ml of n- _hexane and cool it to obtain 55 g of S ₂ (yield 10.6%, purity 85
%), and in order to further increase the purity, methods such as recrystallization with the above solvent or sublimation are used. The important point in the synthesis of S ₂ in such conventional methods is how smoothly the first step, that is, the synthesis of P ₁ by the reaction of phosphorus chloride and ammonium chloride, can be carried out smoothly, which affects the subsequent steps and ultimately the yield of S ₂ . will have a major impact on However, in this first step, the severe sublimation of phosphorus pentachloride during the reaction poses a problem in reaction operation, and especially in the case of depressurization operation, condensation crystallization occurs in the condenser, and the cooling tube is blocked by phosphorus pentachloride. There is a high risk of clogging and the reaction system is prone to overpressure of hydrochloric acid gas, making it unsuitable for industrial-scale synthesis. In addition, due to the loss of phosphorus pentachloride due to sublimation, the desired reaction cannot proceed sufficiently, and the final
The yield of S ₂ is as low as about 10%, and no improvements have been made to the S ₂ synthesis technology to date. The present invention was made in view of the above-mentioned problems, and provides an industrially advantageous production method that provides a high S ₂ yield by solving the problem of sublimation of phosphorus pentachloride in the conventional method and controlling the distillation time of hydrochloric acid gas. The purpose is to provide As a result of intensive studies on reaction conditions for increasing the reaction yield of S ₂ , the present inventors found that the amount of hydrochloric acid gas distilled out and the subsequent reaction in the reaction between phosphorus pentachloride and ammonium chloride in the first stage reaction. found a correlation between the yield of S ₂ produced in the process and completed the present invention. In the present invention, the amount of hydrochloric acid gas distilled out in the first stage reaction is used as a measure of the reaction change, preferably after the start of distillation of hydrochloric acid gas and before the amount of distillation per unit time reaches the maximum. By stopping the first stage reaction at 1/3 to 2/3 of the time from when the amount of hydrochloric acid gas distilled per unit time reaches its maximum, the yield of S ₂ is maximized. It was found that the yield of S ₂ decreased significantly as the heating reaction time increased. This reaction termination operation was determined by determining the temporal change in the amount of hydrochloric acid gas distilled from the relationship between temperature and time drawn by a temperature sensor installed at the base of the cooling tube. At this time, the molar ratio of phosphorus pentachloride and ammonium chloride is 3:1 to 1:
1, preferably in the case of 3:1 to 3:2, the yield of _S2 is high, and when using chlorobenzene alone, a higher yield _{of S2} can be obtained than when using a nitrobenzene-chlorobenzene mixed solvent. found. Chlorobenzene is 0.2 of the weight of phosphorus pentachloride
It is necessary to use more than 0.2 times the amount; if it is less than 0.2 times, phosphorus pentachloride will not be sufficiently dissolved, resulting in a non-uniform reaction system and a lower yield. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples. Example 1 5.4 kg of monochlorobenzene and 10 kg of phosphorus pentachloride
(48 mol) and 875 g (16 mol) of ammonium chloride were added, and it took 2 hours and 30 minutes to raise the temperature from 10°C to 100°C.
The mixture was further heated to 134°C for 2 hours, and then heated at 134°C for 1 hour and 25 minutes. The amount of hydrochloric acid gas distilled out per unit time that occurs at this time is determined from the temperature and time measured by a temperature sensor installed at the base of the cooling pipe that detects the temperature rise due to the reflux of hydrochloric acid gas. The reaction was stopped after the start of extraction but before the temperature at the base of the cooling tube reached its maximum, that is, usually within 30 minutes to 1 hour after the start of hydrochloric acid gas distillation. This corresponds to 1/3 to 2/3 of the time from the start of distillation to the maximum distillation. At this time, the internal temperature was 130 to 140°C. After the reaction was completed, the internal temperature was cooled to 120°C, the reaction solvent was distilled off under reduced pressure of 0.1 to 0.3 mmHg, and the mixture was thoroughly dried for about 4 hours. 1.24 kg (12.8 mol) of sulfamic acid and 2.0 kg (13 mol) of phosphoryl trichloride were added to the obtained crystals, and the mixture was heated at 109°C.
A liquefaction reaction was carried out nearby, and this reaction temperature was maintained for 9 hours until the generation of hydrochloric acid gas subsided. After cooling and filtering, 8.00 kg of viscous product was obtained. Next, this product was heated under a reduced pressure of 0.1 mmHg, and after distilling off the generated phosphoryl trichloride, 200 g of sulfamic acid was added.
was added to carry out a thermal decomposition reaction (3 hours and 30 minutes). The phosphoryl trichloride generated at this time is approximately
Distillation was carried out at 150-160°C. Next, this was distilled under a reduced pressure of 0.1 mmHg at an external temperature of 150 to 194°C to obtain 1.800 kg of yellow distillate. This was further hydrolyzed in ice water, the resulting white precipitate was filtered, and after drying,
g white crystals were obtained. This white crystal is mixed with hexane 4
After hot dissolution in the solution, it was cooled to precipitate S ₂ crystals, which were then dried separately. The weight of the obtained S ₂ is 640g
The yield was 25.9%. Note that the yield is based on the raw material phosphorus pentachloride, and the same applies hereinafter. Elemental analysis value (measured twice): N ₃ PS ₂ O ₂ Cl ₄ (molecular weight 310
) Theoretical value (%): N13.55 P10.00 S20.64 Cl45.48 Actual value (1) (%): N13.50 P9.98 S20.60 Cl45.40 Actual value (2) (%): N13.53 P10.01 S20.63 Cl45.47 IR (cm ^-1 , KBr) 400~1400cm ^-1 : 1310 (vs), 1180
(vs), 1130 (vs), 1020 (m), 835 (m), 720
(vs), 660 (m), 640 (vs), 560 (vs), 540 (vs)
,
485 (m), 435 (w) Mass spectrum: m/e 310 (m ⁺ ) Comparative Examples 1 and 2 Same as Example 1 except that the weight of ammonium chloride in Example 1 was changed to the amount shown in Table 1. We conducted an experiment and obtained the object S ₂ . The results obtained are shown in Table 1. Comparative Example 3 In place of chlorobenzene in Example 1,
The experiment was carried out in the same manner as in Example 1 except that nitrobenzene-chlorobenzene was used, and the target product _S2 was obtained. The results obtained are shown in Table 1. Examples 2 and 3 Experiments were conducted in the same manner as in Example 1, except that the first stage reaction was stopped 30 minutes and 1 hour and 30 minutes after the start of hydrochloric acid gas distillation. Got _S2 . The results obtained are shown in Table 1. Comparative Examples 4 and 5 The experiment was conducted in the same manner as in Example 1 except that the first stage reaction was stopped 2 hours and 3 hours after the start of hydrochloric acid gas distillation, and the target product was obtained.
Got _S2 . The results obtained are shown in Table 1. In Comparative Example 4, 2 hours later is the time at which the amount of hydrochloric acid gas distilled out per unit time is maximum. FIG. 1 shows a diagram of temperature changes at the base of the condenser as changes over time during distillation of hydrochloric acid gas in Example 1.

【table】

【table】 [Brief explanation of drawings]

FIG. 1 is a temperature change diagram at the base of the condenser showing changes over time in distillation of hydrochloric acid gas in Example 1.

Claims (1)

[Claims] 1 (a) A first step of reacting phosphorus pentachloride and ammonium chloride, (b) A second step of reacting the product of the first step with sulfamic acid, (c) A step of reacting the product of the second step with sulfamic acid. 1,3,3,5-tetrachloro-1,5 consisting of a third step of thermal decomposition, (d) a fourth step of distillation, and (e) a fifth step of hydrolysis.
- In the method for producing dithia-2,4,6-triaza-3-phosphorine-1,5-dioxide, in the first step, the reaction between phosphorus pentachloride and ammonium chloride, the molar ratio of phosphorus pentachloride and ammonium chloride is Using raw materials with a ratio of 3:1, the weight of phosphorus pentachloride
The process is carried out in chlorobenzene with a concentration of 0.2 times or more, and from the first half of the time from the start of distillation of hydrochloric acid gas until the distillation amount reaches its maximum per unit time.
1,3,3,5-tetrachloro-1, characterized in that the reaction is stopped at a time of 3 to 2/3, and the second step reaction is carried out in the presence of phosphoryl trichloride.
A method for producing 5-dithia-2,4,6-triaza-3-phosphorine-1,5-dioxide. 2. The manufacturing method according to claim 1, wherein the amount of chlorobenzene used is 0.5 to 1 times the weight of phosphorus pentachloride.