JPS5838437B2 - Dialkyl cyanophosphonate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing dialkyl cyanophosphonates.

In detail, the present invention relates to a method for producing dialkyl cyanophosphonates by reacting trialkyl phosphites with cyanogen chloride.

Conventionally, as a condensing agent for the production of peptide-type condensed compounds,
N・N-dichlorohexylcarbodiimide is well known, but these are used in large amounts relative to the raw materials.
There were problems in handling due to skin irritation, and the product had other disadvantages such as poor yield and high content of racemate.

According to JP-A-4880502, a unique condensation method is proposed in which an amino acid or peptide with a protected amino group is bonded to an amino acid ester or a peptide ester, and the condensation method does not contain a racemate. Dialkyl cyanophosphonates have been used with excellent results.

Therefore, dialkyl cyanophosphonates will be
It is becoming indispensable as a condensing agent for the synthesis of penicillins, cephalosporins, and other antibiotics.

The dialkyl cyanophosphonate has the general formula (wherein R1 and R2 are alkyl groups).

), and conventional methods for producing it include (1) a method of reacting cyanogen iodide with triethyl phosphite (J. Chem-Soc., 1948.
699) and (2) Method of reacting cyanogen bromide and triethyl phosphite "Pharmaceutical Journal 85.298 (
1965 )) is known. However, method (1) not only involves the contamination of innitrile compounds, but also has an extremely low yield, so it cannot be carried out industrially.

On the other hand, method (2) has a relatively high yield, but is expensive because it uses cyanogen bromide, and according to infrared spectroscopic analysis of the product, the yield is 2100-cm'. This is a practical problem as there is absorption in the isonitriles and contamination with isonitriles.

As a result of intensive research in an attempt to improve the various drawbacks of the conventional methods described above, the present inventors have discovered that by reacting trialkyl phosphite with cyanogen chloride, no isonitriles are produced at all, and dialkyl cyanophosphonates are extremely produced. They discovered scales that can be produced in high yield and completed the method of the present invention.

The raw material trialkyl phosphite according to the present invention is represented by the following general formula.

(However, in the formula, R1, R2 and R3 are an alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.

) Examples include trimethyl phosphite, triethyl phosphite, tri-n-propyl phosphite, tri-isopropyl phosphite, tri-n-butyl phosphite, tri-in-butyl phosphite, tri-Sec-butyl phosphite, Examples include tri-tert-butyl phosphite, tripentyl phosphite, and tridecyl phosphite.

As cyanogen chloride CICN, one produced by a conventional method can be used.

The amount used is 0.8 to 1.5 in molar ratio to the trialkyl phosphite, preferably 0.9 to 1.
It is 2.

The reaction between trialkyl phosphite and cyanogen chloride can be carried out without a solvent or in the presence of a solvent.

Since cyanogen chloride has a low boiling point, using a solvent results in less loss of cyanogen chloride and is easier to handle.

However, the reaction itself proceeds more quickly and produces better results when the amount of solvent is reduced or when no solvent is used.

Therefore, the amount of solvent used is from 0 to 50, preferably from 0 to 30, by weight relative to cyanogen chloride.

Any solvent can be used as long as it dissolves both trialkyl phosphite and cyanogen chloride and has a boiling point higher than the reaction temperature. Examples include benzene, toluene, xylene, and ether. , methanol, ethanol, isopropanol, butanol, etc.

The reaction temperature is usually 0 to 100°C, preferably 10°C.
~50°C.

The reaction time is 1 to 10 hours, preferably 2 to 5 hours.

The reaction can be carried out at normal pressure, reduced pressure or increased pressure, and can be carried out either batchwise or continuously.

After the reaction is complete, if a solvent is used, distill it off,
Further distillation under reduced pressure yields dialkyl cyanophosphonate in high yield.

As described above, since the method for producing dialkyl cyanophosphonates according to the present invention involves reacting trialkyl phosphite with cyanogen chloride, there is no contamination of isonitriles, which are produced as by-products when cyanogen iodide or cyanogen bromide is used. Moreover, it can be produced in extremely high yields.

Next, the method of the present invention will be explained in more detail with reference to examples of implementation.

Comparison row 1 500 m capacity with stirrer, thermometer and dropping funnel
Add triethyl phosphite to a three-necked flask.
．． 0P (0.35 mol) in dry ether 300
ml was supplied.

Next, cyanogen bromide 38.0'f! (0.35 mol) dissolved in 100 rrLl of dry ether was added dropwise over 3 hours while stirring and maintaining the temperature at 30-35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 1 hour.

The ether was then distilled off under reduced pressure.

After distilling off the ether, further vacuum distillation revealed that the boiling point was 80.
Diethylcyanophosphonate, a colorless transparent liquid with a temperature of ~83°C and 77mmHg} 4 5.6 ? (yield 8
0% changed.

When this material was analyzed by infrared spectroscopy, the wave number was 2100c.
There was absorption at m', and it was recognized that an isonitrile compound was contained.

Two days after distillation, the color changed to yellow, so when I redistilled it, it became clear and colorless, but the product was 42.8P (
Furthermore, when this product was further analyzed by infrared spectroscopy, as shown in Figure 1, the wave number was still 2.
There was absorption at 100 cm-1, and the isonitrile compound remained mixed without changing.

Example 1 Capacity 500 r with stirrer, thermometer and dropping funnel
Add triethyl filtrate to a three-necked rLl flask}5
8. OS' (0.35 mol) in dry ether 300m
It was supplied dissolved in 1 liter of water.

Then, a solution of 21.5 f (0.35 mol) of cyanogen chloride in 100 rrLl of dry ether was added dropwise over 3 hours while stirring and maintaining the temperature at 30 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 1 hour.

The ether was then distilled off under reduced pressure.

After distilling off the ether, further vacuum distillation revealed that the boiling point was 80.
Diethylcyanophosphonate, a colorless transparent liquid with a temperature of ~83°C/7mmHg} 4 8. 5 f? (yield 8
5.0%) changed.

When this product was analyzed by infrared spectroscopy, as shown in FIG. 2, no absorption was observed at a wave number of 2100 cm-, and no formation of isonitriles was observed.

Example 2 In the same reaction vessel as in Example 1, triethyl phosphite 5
8. OS' (0.35 mol) in dry benzene 300m
It was supplied dissolved in 1 liter of water.

Next, a solution of 21.5S' (0.35 mol) of cyanogen chloride in 100 ml of dry benzene was mixed with stirring for 3
The mixture was added dropwise over 3 hours while maintaining the temperature at 0 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 1 hour.

Then, benzene was distilled off under reduced pressure.

After distilling off the benzene, further vacuum distillation revealed a boiling point of 80.
Diethyl cyanophosphonate, a colorless transparent liquid with a temperature of ~83°C/7 mmHg} 4 7.3 f (yield 8
3%) changed.

This one has a wave number of 2100c, similar to that of Example 1.
No absorption at m' was observed, and no isonitrile formation was observed.

Example 3 In the same reaction vessel as in Example 1, triethyl phosphite 5
8.0P (0.35 mol) in 150ml of dry benzene
The solution was supplied as a solution.

Then, 21.51 (0.35 mol) of cyanogen chloride was added dropwise over 3 hours while stirring and maintaining the temperature at 30 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 1 hour.

Then, after distilling off benzene in the same manner as in Example 2, vacuum distillation was performed, and the boiling point was 80-83°C.
Colorless and transparent diethyl cyanophosphonate 56.0P (yield 98.2%) having πHg was obtained.

This one has a wave number of 2100c, similar to that of Example 1.
No absorption was observed in rrL-1, and no isonitrile formation was observed.

Example 4 Triethylphosphite}102S' (0.615 mol) was fed to a fourth flask with a capacity of 5001 rLl equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and to this was added cyanogen chloride 37.8S' (0.6 1 5 mol)
was added dropwise over 2 hours while stirring and maintaining the temperature at 30-35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 1 hour.

Then, when vacuum distillation was performed in the same manner as in Example 1,
Colorless and transparent diethyl cyanophosphonate 97.55' with a boiling point of 80-83°C/7vnHg (yield 97.2%)
) was changed.

Like the one in Example 1, this one has a wave number of 2100
No absorption was observed in -1, and no adverse effect on isonitrile was observed.

Example 5 After stirring, capacity 1007 with thermometer and dropping funnel
In a 71 liter three-necked flask, 12.5 f (0.05 mol) of tri-n-butylphosphite was added to 60 mol of dry benzene.
ml was supplied.

Then, 3.1 y' (0.05 mol) of cyanogen chloride
was dissolved in 15 ml of dry benzene and added dropwise over 1 hour while stirring and maintaining the temperature at 30 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 40 minutes.

Then, benzene was distilled off under reduced pressure.

After distilling off the benzene, further vacuum distillation resulted in a boiling point of 94.
Colorless and transparent di-n-butyl cyanophosphonate 10.3S' (yield 94.0%) was obtained at ~96°C/1 mmHg.

When this product was subjected to infrared spectroscopic analysis, as shown in FIG. 3, no formation of isonitriles was observed at a wave number of 2100'.

Example 6 In the same reaction vessel as in Example 5, trimethyl phosphite 1
A solution of 2.4P (0.1 mol) in 60 ml of dry benzene was supplied.

Next, a solution of 6.15P (0.1 mol) of cyanogen chloride in 15 ml of dry benzene was heated to 30 to 30% while stirring.
The mixture was added dropwise over 1 hour while maintaining the temperature at 5°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 40 minutes.

Then, benzene was distilled off under reduced pressure.

After distilling off the benzene, further vacuum distillation resulted in a boiling point of 56.
~57.5℃/3. Colorless and transparent dimethyl cyanophosphonate 11.8S' with 5 mmHg (yield 87
．． 4%) were changed.

When this product was analyzed by infrared spectroscopy, as shown in FIG. 4, no absorption was observed at a wave number of 2100 cm→, and no formation of isonitrile was observed.

Comparison row 2 500 m vessel equipped with stirrer, thermometer and dropping funnel
In a three-necked flask, add 24.
A solution of 8f (0.2 mol) in 1201 rLl of dry benzene was supplied.

Next, cyanogen bromide 2 1. 2P (0.2 mol) dissolved in Wotreichensen 2001rLl was added dropwise over 1 hour while stirring and maintaining the temperature at 30 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 40 minutes.

Then, after distilling off the benzene under reduced pressure, further vacuum distillation was performed to obtain dimethorcyanophosphonate 20, which is a colorless transparent liquid with a boiling point of 56-57.5°C/3.5 Hg.
．． 6? (yield 76.7%).

When this material was analyzed by infrared spectroscopy, the wave number was 210.
There was absorption at 0 cm', and it was confirmed that an isonitrile compound was contained.

(Two days after distillation, it turned yellow, so when I redistilled it, it became colorless and transparent, but the product was 19.3P.
(yield 71.5%), and when this product was further analyzed by infrared spectroscopy, as shown in Figure 5, there was still absorption at a wave number of 2100 cm'', indicating that the isonitrile compound remained unchanged and mixed. Ta.

) Comparative Example 3 500 m container equipped with stirrer, thermometer and dropping funnel
25.05' (0.1 mol) of tri-n-butyl phosphite was added to 120 liters of dry benzene in a three-necked flask.
It was supplied dissolved in rll.

Then, cyanogen bromide 2 1.2 9 (0.2 mol)
was dissolved in 200 ml of dry benzene and added dropwise over 1 hour while stirring and maintaining the temperature at 30 to 35°C.

After the dropwise addition was completed, stirring was performed at the same temperature for 40 minutes.

Then, benzene was distilled off under reduced pressure.

After distilling off the benzene, further vacuum distillation resulted in a boiling point of 94.
Di-
n-butylcyanophosphonate 16. oP (yield 73%
) was changed.

When this material was analyzed by infrared spectroscopy, the wave number was 2100c.
There was absorption at m', and it was recognized that an innitonyl form was contained.

(Figure 6).

[Brief explanation of the drawing]

Figure 1 shows the infrared absorption spectrum of diethyl cyanophosphonate obtained by reacting triethyl phosphite with cyanogen bromide, which was redistilled after being allowed to stand for 2 days.
The figure shows the infrared absorption spectrum of diethyl cyanophosphonate according to the present invention.
- infrared absorption spectrum of butyl cyanophosphonate,
Figure 4 shows the infrared absorption spectrum of dimethyl cyanophosphonate according to the present invention, Figure 5 shows the infrared absorption spectrum of methyl cyanophosphonate obtained by reacting trimethyl phosphite and cyanogen bromide, and Figure 6 shows the infrared absorption spectrum of dimethyl cyanophosphonate according to the present invention. - It is an infrared absorption spectrum of phosnate of di-n-phthyl cyanophosphonate obtained by reacting butyl phosphite and cyanogen bromide.

Claims (1)

[Claims] 1. A method for producing dialkyl cyanophosphonate, which comprises reacting trialkyl phosphite with cyanogen chloride.