JPH0355403B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1, 3, 3, 5,
This invention relates to an improved method for producing 5-pentachloro-1-thia-2,4,6-triaza-3,5-diphosphorine-1-oxide (hereinafter referred to as _S1 ). 1,3,3,5,5-pentaaziridino-1-thia-2,4,6-triaza-3,5-diphosphorin-1-oxide, in which the halogen atom of S ₁ is substituted with ethyleneimine, is extremely effective as an anticancer agent. Recently discovered to have efficacy (JF
Labarre, Eur. J. Cancer, 15 , 637–643 (1979)
reference). As a result, S ₁ has begun to attract attention as a precursor for the synthesis of anticancer substances, and at the same time, the method for producing it has also begun to be reconsidered. As a conventional method for synthesizing S ₁ , the method of Granbell et al. using phosphorus pentachloride, ammonium chloride, and sulfamic acid is known (JCvande et al.
Grampel, Recl.Trav.Chim., 91 , 935–941.
(1972); HH Baalmann, JC van de Grampel,
Recl.Trav.Chim, 92 , 1237–1239 (1973) and
JBvan den Berg, B.de Ruiter, JCvan de
Grampel, Z. Naturforsch 31 , 1216–1218 (1976)
reference). The synthesis method of S ₁ by the method of Granbell et al. can be roughly divided into the following five steps. In other words, the first step is to react phosphorus pentachloride with ammonium chloride.
The second step is to react the product of the first step with sulfamic acid, the third step is to thermally decompose the reaction product, the fourth step is distillation, and the fifth step is hydrolysis. The main reaction formulas in these steps are shown below. In this reaction formula, S ₂ is 1, 3,
5,5-tetrachloro-1,5-dithia-2,
It is 4,6-triaza-3-phosphorine-1,5-dioxide, and A is a substance that is easily decomposed by water. (1st step) 3PCl ₅ +NH ₄ Cl→ [PCl ₃ NPCl ₃ ] [PCl ₆ ] (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 [PCl ₃ NPCl ₃ ] [PCl ₆ ], using a mixed solvent consisting of 1,150 ml of 1,1,2,2-tetrachloroethane and 850 ml of nitrobenzene containing 280 g of phosphorus pentachloride and 175 g of ammonium chloride. 75℃ to 90℃ under reduced pressure (10-20mmHg)
Heat for 6 hours between. 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℃ for 15 minutes, the reaction vessel was then cooled and left overnight at -20℃, and after separating the precipitated crystals, 600ml of carbon tetrachloride, Washing is carried out in the following order: a mixed solvent of 300 ml of carbon and 300 ml of n-pentane, and finally 600 ml of n-pentane. The remaining crystals were heated at 50°C under a reduced pressure of 0.2 mmHg.
The first step product, crude crystals, was dried for 3 hours.
Obtain 1060g. The second step, the reaction with sulfamic acid, is a solid-phase reaction, in which 194 g of sulfamic acid is added to the previously formed crystals, mixed well, and then liquefied by heating at 100°C 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 continues until the appearance of crystals that adhere to the cooling tube, but if nitrobenzene remains, it is difficult to know the end point because the nitrobenzene reflux makes it difficult to determine the appearance of crystals. The end point is the stop of the output. The fourth step, distillation, is performed at an even higher vacuum level (0.2 to 0.6 mm).
Hg) to a temperature of 160 to 200℃ for a long time (about 7
320 g of yellow fraction was obtained.
In the fifth step of hydrolysis, the above fraction is cooled with ice water.
Stir to break down water-active substances. Collect the white precipitate and wash with ice water until the nitrobenzene odor disappears. Dry under reduced pressure in the presence of phosphorus pentoxide to obtain 225 g of crude crystals. This is a mixture of S ₁ and S ₂ as a by-product, and the absorption intensity in the IR spectrum chart of the crude crystal (S ₁ = 750 cm ^-1 , S ₁ = 725 cm ^-1 )
Therefore, the content ratio of S ₁ and S ₂ is analyzed to be 1/2.
After heating and dissolving this mixture in 660 ml of n-hexane,
Cool and decompose 55 g of _S2 as crystals. After concentrating the remaining mother liquor and removing hexane, the residue was dissolved in 30 ml of ethyl ether and cooled to -20°C to crystallize, giving 45 g of S ₁ with a dullness of 90% (8% yield).
It can be grown. In order to further increase the purity, recrystallization or sublimation using the solvent (hexane) may be performed. The important point in the synthesis of S ₁ in this conventional method is how smoothly the first step, the synthesis of [PCl ₃ NPCl ₃ ] [PCl ₆ ] by the reaction of phosphorus pentachloride and ammonium chloride, can be carried out. This will have a significant impact on subsequent steps and even the yield of _S1 . However, in this first stage reaction, the severe sublimation of phosphorus pentachloride during the reaction poses a problem in reaction operation, and especially in the case of reduced pressure operation, condensation crystallization occurs in the condenser, and the cooling pipe There is a high risk of blockage due to the hydrogen chloride gas in the reaction system, and it is not suitable for industrial-scale synthesis. Furthermore, due to the loss of phosphorus pentachloride due to sublimation, the desired reaction cannot proceed sufficiently, and the final yield of S ₁ obtained is usually extremely low at several percent (10% or less). The present invention was made in view of the above problems, and as a result of intensive studies regarding the selection of a mixed solvent in the first step of the reaction between phosphorus pentachloride and ammonium chloride, 1,1,2,2-tetra By using the chlorobenzene-nitrobenzene system instead of the chloroethane-nitrobenzene system, the sublimation of phosphorus pentachloride is suppressed, and finally S ₁ is obtained in a higher yield.
The present invention was completed based on the discovery that this can be achieved. According to the present invention, it has been found that the yield of the target product S ₁ can be changed by changing the ratio of chlorobenzene and nitrobenzene in the mixed solvent in the first step, and the weight ratio of chlorobenzene and nitrobenzene can be changed. In the case of 1:0.2 to 1:1.5, preferably in the range of 1:0.5 to 1:0.8
S ₁ was obtained in a higher yield, and the yield of S ₁ decreased when the weight ratio of nitrobenzene was less than 0.2 or greater than 1.5. This is considered to be because the polarity of the mixed solvent in the above ratio provides optimal reaction conditions. The appropriate amount of the mixed solvent to be used is 1 or more, preferably 1 to 2 times the weight of phosphorus pentachloride. In addition, as a result of changing the reaction molar ratio (R) of phosphorus pentachloride and ammonium chloride in the reaction of the first step and examining the reaction yield of the target product S ₁ (yield based on phosphorus pentachloride), 18 at a molar ratio of 3:1
%, 16% for 3:2 and 13% for 3:3. When the above yield is compared with the yield of the conventional method (8% or less), a remarkable improvement can be seen. Furthermore, in the second step, the reaction between [PCl ₃ NPCl ₃ ] and [PCl ₆ ] and sulfamic acid is a solid-phase reaction in the conventional method, and the reaction time is extremely long (although it liquefies by heating to 100°C). In the present invention, 0.1 of the weight of phosphorus pentachloride used in the first step is phosphoryl trichloride.
It was confirmed that by adding at least twice the amount, preferably 0.15 to 0.2 times, the reaction time in the second step was shortened to 6 to 7 hours, and there was no adverse effect on the production of _S1 . 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 6 kg of monochlorobenzene and 4.8 kg of nitrobenzene
10 Kg (48 moles) of phosphorus pentachloride and 848 Kg (16 moles) of ammonium chloride are added to a mixed solvent consisting of Kg and heated under normal pressure. It took about 30 minutes to raise the temperature from 25°C to 100°C, and the temperature was further maintained at 100°C to 140°C for 1 hour. Hydrogen chloride gas generated at this time was removed under normal pressure. After heating, bring to room temperature (25℃) for about 4 hours.
After cooling to 100%, the mixture was allowed to stand for an additional day. The obtained product was washed the first time, the second time with a mixed solvent consisting of 3 kg of carbon tetrachloride and 2.4 kg of hexane, and the third time with 5 kg of hexane. The washed product is approx.
The mixture was dried under reduced pressure for 2 hours under heating at 55°C, and the washing solvent was distilled off to obtain pale yellowish white crystals of [PCl ₃ NPCl ₃ ] [PCl ₆ ]. Thus obtained [PCl ₃ NPCl ₃ ]
[PCl ₆ ] is directly used in the next step without being purified. Obtained as described above [PCl ₃ NPCl ₃ ]
1.24Kg (12.8mol) of sulfamic acid in [PCl ₆ ]
and 2.0 kg (13 mol) of phosphoryl trichloride were added, and a liquefaction reaction was carried out at an internal temperature of 100 to 110°C, and this reaction temperature was maintained until the generation of hydrogen chloride gas subsided. After the reaction was completed, the mixture was quickly cooled and filtered to obtain 6.8 kg of a product. Next, this product was heated for 1 hour and 12 minutes from an external temperature of 100°C to 139°C under a reduced pressure of 0.1 mmHg.
After distilling off the generated phosphoryl trichloride, 80 g of sulfamic acid was added and thermal decomposition was carried out at around 150° C. for 1 hour and 40 minutes under reduced pressure of 0.16 to 0.22 mmHg.
Phosphoryl trichloride generated at this time was distilled off under the same reduced pressure. At this time, in order to prevent loss of product due to distillation, the mixture was passed through a 0°C condenser. By completely distilling off phosphoryl trichloride from the reaction product,
3.22Kg of product was obtained. Further increase this by 0.07~0.5mm
Distilled under reduced pressure of Hg at an external temperature of 140-200℃, 2.37Kg
A yellow distillate of was obtained. Add this to 5 methylene chloride
After dissolving in water, add ice and stir for 5 to 15 minutes.
Hydrolysis was carried out at a temperature of °C. By dissolving the yellow fraction in methylene chloride, hydrolysis can easily proceed by stirring with ice water and separating the liquid. After decomposing and concentrating the methylene chloride layer, it was dissolved in hexane 3 while hot, and then cooled to precipitate 321 g of S ₂ (yield: 12.9
%) was removed by filtration, the liquid was concentrated, and the resulting residue was dissolved by adding 1 part of ethyl ether to -20
By leaving it to cool at ℃, it becomes the desired object.
478 g (yield 18%) of S ₁ was obtained. Note that the yield is based on the raw material phosphorus pentachloride, and the same applies hereinafter. Elemental analysis value: N ₃ P ₂ S ₁ Cl ₅ O (as molecular weight 329) Theoretical value (%): N12.76 P18.84 S9.72 Cl53.50 Actual value (%): N12.70 P18.88 S9. 70 Cl53.50 Actual value (%): N12.75 P18.90 S9.74 Cl53.48 IR (cm ^-1 , KBr) 400 to 1400 cm ^-1 : 1320 (VS), 1220 (VS), 1140 (VS) , 1087 (m),
870 (W), 750 (m), 665 (W). 620 (VS), 540
(VS), 445 (W) Mass spectrum: m/e 329 (m ⁺ ) ³¹ P NMR: δ 26.5 ppm (CDCl ₃ , 85% phosphoric acid standard) Example 2 Monochlorobenzene 6 kg and nitrobenzene 4.8
10 kg (48 mol) of phosphorus pentachloride and 1750 g (33 mol) of ammonium chloride are added to a mixed solvent consisting of 1.0 kg and heated under normal pressure. It took about 30 minutes to raise the temperature from 25°C to 100°C, and the temperature was further maintained at 100°C to 134°C for 1 hour. Hydrogen chloride gas generated at this time was removed under normal pressure. After heating, the mixture was cooled down to 30° C. over about 2 hours, and then left for another day. The obtained product was washed with a solvent. That is, the first and second cleanings were performed using a mixed solvent consisting of 4 kg of carbon tetrachloride and 3.2 kg of hexane, and the third cleaning was performed using 6 kg of hexane. Thereafter, by drying under reduced pressure for 2 hours under heating at 50°C to 55°C, [PCl ₃ NPCl ₃ ] [PCl ₆ ]
Pale yellow crystals were obtained. This includes 1.24Kg (12.8mol) of sulfamic acid and 2.0Kg of phosphoryl trichloride.
(13 mol) and caused a liquefaction reaction at 100-115℃,
This reaction temperature was maintained until the evolution of hydrogen chloride gas subsided. After cooling, filter the product
Obtained 6.37Kg. This product was heated under a reduced pressure of 0.1 mmHg from an external temperature of 104°C to 157°C for about 1 hour, and after distilling off the generated phosphoryl trichloride, 80 g of sulfamic acid was added and under a reduced pressure of 0.08 to 0.17 mmHg for 1 hour.
Thermal decomposition reaction was carried out for 50 minutes at an external temperature of around 150°C. Phosphoryl trichloride generated at this time was distilled off at an external temperature of 143 to 152°C under reduced pressure of 0.1 mmHg. At this time, in order to prevent loss of product due to distillation, the mixture was passed through a 0°C condenser. Phosphoryl trichloride was completely distilled off from the reaction product to obtain 3.389 kg of product. This is further reduced to 0.08 to 0.2 mmHg at an external temperature of 180.
Distilled at ~200°C to obtain 1.808Kg of yellow distillate.
This was hydrolyzed with ice water and the white precipitate formed was separated and dried in the presence of phosphorus pentoxide to obtain 1.808 kg of product. This was recrystallized using hexane.
Only 206 g of S ₂ (yield 8.3%) was precipitated and then removed by filtration, and the target product was removed from the liquid.
428 g (yield 16%) of S ₁ was obtained. Example 3 6 kg of monochlorobenzene and 4.8 kg of nitrobenzene
10 Kg (48 moles) of phosphorus pentachloride and 2.566 Kg (48 moles) of ammonium chloride are added to a mixed solvent consisting of Kg and heated under normal pressure. It took about 30 minutes to raise the temperature from 25°C to 100°C, and the temperature was further maintained at 100°C to 130°C for 1 hour. Hydrogen chloride gas generated at this time was removed under normal pressure. After standing for one day, the obtained product was washed with a solvent. That is, for the first and second times, a mixed solvent consisting of 2 kg of carbon tetrachloride and 1.6 kg of hexane,
The third cleaning was performed using 4 kg of hexane.
Thereafter, by drying under reduced pressure for 2 hours and 30 minutes under heating at 50°C to 55°C, pale yellowish white crystals of [PCl ₃ NPCl ₃ ] [PCl ₆ ] were obtained. In this, sulfamic acid
1.24Kg (12.8mol) and phosphoryl trichloride 2.0Kg (13
mol) was added, a liquefaction reaction was carried out at 100 to 105°C, and this reaction temperature was maintained until the generation of hydrogen chloride gas subsided. After cooling, filter the product
Obtained 7.331Kg. This product was heated under a reduced pressure of 0.1 mmHg from an external temperature of 99°C to 144°C for about 1 hour and 15 minutes, and after distilling off the generated phosphoryl trichloride, 80 g of sulfamic acid was added and the mixture was heated under a reduced pressure of 0.057 to 0.1 mmHg. 2
Thermal decomposition was carried out for 30 minutes at an external temperature of around 150°C. Phosphoryl trichloride generated at this time was distilled off at an external temperature of 145 to 150°C under reduced pressure of 0.1 mmHg. At this time, in order to prevent loss of product due to distillation, the mixture was passed through a 0°C condenser. Phosphoryl trichloride was completely distilled off from the reaction product to obtain 4.593 kg of product. This is further reduced to 0.18~0.2mmHg at an external temperature of 150℃.
Distilled at ~190°C to obtain 2.0359Kg of yellow distillate.
This was hydrolyzed with ice water, and after separating the white precipitate produced, it was dried in the presence of phosphorus pentoxide to obtain 951.2 g of a product. This was recrystallized using hexane.
Only 160 g of S ₂ (yield 6.5%) was precipitated and then removed by filtration, and the target product was removed from the liquid.
345 g (yield 13%) of S ₁ was obtained. Examples 4 and 5 Experiments were conducted in the same manner as in Example 1, except that the weight composition of chlorobenzene and nitrobenzene was changed to the amounts shown in Table 1, and S ₂ and the target product were
Got S ₁ . The results obtained are shown in Table 1.

[Table] FIG. 1 shows the IR spectrum chart of S ₁ obtained in the above example, and FIG. 2 shows the ³¹ P NMR spectrum chart.

[Brief explanation of drawings]

FIG. 1 is an IR spectrum chart of S ₁ , and FIG. 2 is a ³¹ P NMR spectrum chart of S 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. 1,3,3,5,5-pentachloro-1 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 thia-2,4,6-triaza-3,5-diphosphorine-1-oxide, the first step, the reaction between phosphorus pentachloride and ammonium chloride, is carried out in a mixed solvent of chlorobenzene and nitrobenzene. , 1,3,3,5,5-pentachloro-1-thia-, wherein the reaction in the second step is carried out in the presence of phosphoryl trichloride.
2,4,6-triaza-3,5-diphosphorine-
Method for producing 1-oxide. 2. The manufacturing method according to claim 1, wherein the mixing ratio of the mixed solvent is 0.2 to 1.5 parts of nitrobenzene to 1 part of chlorobenzene by weight.