JPS5910678B2 - Method for producing N-hydroxyalkyl-substituted phosphoramidate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N-hydroxyalkyl-substituted phosphoramidates.

More specifically, the present invention provides improvements for producing N-hydroxyalkyl-substituted phosphoramidates in high purity and yield by reacting phosphoric diester halides with hydroxyalkylamines in the presence of organic tertiary amines. The present invention relates to a manufacturing method. N-hydroxyalkyl-substituted phosphoroamidates are compounds useful as flame retardants and modifying agents for synthetic resins and fibers, lubricating oil additives, etc.
It is an extremely useful compound as a flame retardant for synthetic resins, especially soft and hard urethane foams.

Conventionally, a method for producing an N-hydroxyalkyl-substituted phosphoramidate by reacting a phosphoric acid diester halide with a hydroxyalkyl amine in the presence of an organic tertiary amine includes reacting phosphoric acid diisopropyl chloride with a monomer in the presence of triethylamine. A method for producing O-0-diisopropyl-N-(2-hydroxyethyl)phosphoramidate by reacting it with ethanolamine [Journal.
Tab the American Chemical Society (J.
Arn. Chem. SOc), Volume 75, No. 5757
Page 1953] is known.

However, this method only discloses triethylamine as the organic tertiary animine, phosphoric acid diisopropyl chloride as the phosphoric diester halide, and monoethanolamine as the hydroxyalkyl amine. The purity and yield of O.0-diisopropyl-N-(2-hydroxyethyl)phosphoramidate obtained by Conditions and Reaction 2 are not disclosed at all. When an acid chloride such as phosphoric acid diisopropyl chloride is reacted with an amine in the presence of triethylamine, the reaction is carried out using equimolar to slightly excess amounts of the amine and triethylamine relative to the acid chloride. It is a well-known method in the organic chemical industry to separate and remove the triethylamine hydrochloride obtained by filtration or washing with water to obtain the desired product. As a result of the above-mentioned conventional method, the present inventors repeated the conventional method according to a conventional method. In other words, in the presence of triethylamine, phosphoric acid diisopropyl chloride and monoethanolamine were reacted in a chloroform solvent, and the reaction was completed. The mixture was washed with water to separate and remove triethylamine hydrochloride, and then the organic layer was concentrated under reduced pressure to remove chloroform.
・0-diisopropyl-N-(2-hydroxyethyl)
Phosphoramidate has a purity of 88.07% and a yield of 73
．． It was 1%.

In addition, as a result of reacting various phosphoric diester halides with various hydroxyalkylamines in the presence of triethylamine in the same manner, various N-hydroxyalkyl substituted phosphoroamidates obtained had a purity of approximately 80 to 88%.
% and yield of about 60 to 75%, and the conventional method had low purity and yield. In the conventional method, triethylamine hydrochloride produced by the reaction is soluble in chloroform, the reaction solvent, and is also soluble in a small amount in N-hydroxyalkyl-substituted phosphoramidate, so it is difficult to separate and remove triethylamine hydrochloride. This is not sufficient, and even washing with water is not complete, resulting in the drawback that the purity of the resulting N-hydroxyalkyl-substituted phosphoroamidate is extremely low.

In addition, in the conventional method, since the N-hydroxyalkyl-substituted phosphoroamidate is extremely easily soluble in water, it is lost by dissolution in the washing water during washing, and the resulting N-hydroxyalkyl-substituted phosphoroamidate is lost. The disadvantage is that the rate is extremely low. Furthermore, when the target product is water-soluble, such as N-hydroxyalkyl-substituted phosphoroamidates, washing with a saturated inorganic salt aqueous solution such as saturated saline or saturated ammonium sulfate allows the target product to be added to the washing water. Preventing dissolution loss is a well-known method in the field of organic chemical industry, but in the conventional method, when washing with a saturated inorganic salt aqueous solution such as saturated saline or saturated ammonium sulfate, the organic layer and the saturated inorganic salt aqueous solution layer are separated. Since it is extremely difficult to separate the layers, the resulting N-hydroxyalkyl-substituted phosphoramidate has the disadvantage of low purity and low yield. As described above, it has been extremely difficult to produce N-hydroxyalkyl-substituted phosphoramidates with high purity and high yield using conventional methods.

An object of the present invention is to provide a method for producing N-hydroxyalkyl-substituted phosphoramidates with high purity and high yield by reacting a phosphoric diester halide with a hydroxyalkylamine in the presence of an organic tertiary amine. It is in.

The present inventors have improved the conventional method and achieved N2 with high purity and high yield.
- As a result of extensive research into methods for producing hydroxyalkyl-substituted phosphoroamidates, we have found that phosphoroamidates can be phosphoroamidates in the presence of organic tertiary amines, which have a larger dissociation constant than the hydroxyalkylamines used, in water-insoluble or sparingly soluble organic solvents. If an acid diester halide and a hydroxyalkylamine are reacted under substantially anhydrous conditions, and then an aqueous alkali metal hydroxide solution of 1.01 to 1.05 times the mole of the phosphoric acid diester halide is added and reacted, Surprisingly N-
After learning that hydrolysis of hydroxyalkyl-substituted phosphoroamidates does not occur, we conducted further research and separated the alkali metal halide produced by the reaction as a saturated aqueous alkali metal halide solution, making the organic tertiary amine water-insoluble. Alternatively, the inventors discovered that N-hydroxyalkyl-substituted phosphoroamidates can be obtained with high purity and high yield by separating them as a mixed solution together with poorly soluble organic solvents, and based on this knowledge, they have completed the present invention. .

That is, the present invention relates to the general formula (wherein R1 and R2 are the same or different from each other and each represents an alkyl group, an allyl group, an aralkyl group, or an aryl group which may be substituted with a halogen atom,
x represents a halogen atom.

) and the general formula (in the formula, R3 represents a lower alkylene group which may be substituted with a hydroxyl group, and R4 represents a hydrogen atom, a lower alkyl group or -R
Indicates a group represented by 3-0H. ) is reacted with a hydroxyalkylamine represented by the general formula (wherein R1,
R,, R3 and R4 have the same meanings as above.

) in a water-insoluble or sparingly soluble organic solvent in the presence of an organic tertiary amine having a larger dissociation constant than the hydroxyalkylamine used, phosphoric acid A diester halide and a hydroxyalkylamine are reacted under substantially anhydrous conditions, and then an aqueous alkali metal hydroxide solution of 1.01 to 1.05 times the molar amount to the phosphoric acid diester halide is added and reacted to produce an alkali. N, characterized in that metal halides are separated as a saturated aqueous alkali metal halide solution, and organic tertiary amines are separated as a mixed solution together with water-insoluble or sparingly soluble organic solvents.
- A method for producing a hydroxyalkyl-substituted phosphoroamidate.

The reaction formula of the method of the present invention is as follows.

(In the formula, R1, R2, R3, R4 and M
OH represents an alkali metal hydroxide. ) That is, the method of the present invention first uses a hydroxyalkylamine [], an organic tertiary amine [], and a water-insoluble or sparingly soluble organic solvent [V].
Phosphoric acid diester halide [1
] in a water-insoluble or sparingly soluble organic solvent [ ] in the presence of an organic tertiary amine [ ] whose dissociation constant is larger than that of the hydroxyalkylamine used [ ], the phosphoric acid diester halide [1] and the hydroxyalkyl An N-hydroxyalkyl-substituted phosphoramidate [], an organic tertiary amine hydrogen halide salt [], and a water-insoluble or sparingly soluble organic solvent [v] are obtained by reacting the amine [] under substantially anhydrous conditions. A reaction mixture (8) is obtained. Next, the above reaction mixture (B
) is reacted with an aqueous alkali metal hydroxide solution [ ] to form an N-hydroxyalkyl-substituted phosphoroamidate [ ]
, organic tertiary amine [ ], water-insoluble or sparingly soluble organic solvent [
v], an alkali metal...logenide [] and water (obtains 0).

The obtained reaction mixture (C) is subjected to a liquid separation treatment to convert the real alkali metal halide [] and water into alkali metal and water.
- Separate the chloride [] as a saturated aqueous solution to obtain a mixed solution O) consisting of an N-hydroxyalkyl-substituted phosphoramidate [], an organic tertiary amine [], and a water-insoluble or sparingly soluble organic solvent [V].

Then, by concentrating the resulting mixed liquid, the organic tertiary amine [] is converted into a water-insoluble or sparingly soluble organic solvent [V].
The target N-hydroxyalkyl-substituted phosphoramidate [] is isolated.

The reaction in the method of the present invention is carried out in a water-insoluble or sparingly soluble organic solvent [V]; This is preferable because by-products are generated and the purity and yield of the desired N-hydroxyalkyl-substituted phosphoroamidate [] are lowered, and furthermore, the isolation operation of the N-hydroxyalkyl-substituted phosphoroamidate [] after the reaction is preferable. This is not desirable because it becomes complicated.

In addition, the amount of water-insoluble or sparingly soluble organic solvent [V] used is 1.0 to 3.0 to phosphoric acid diester halide [1].
It is sufficient to use double the molar amount; however, if a large amount is used, the amount of solvent recovered increases and a lot of time is consumed in the recovery operation, which is not preferable. In the reaction in the method of the present invention, phosphoric diester halide [1] and hydroxyalkylamine [] are reacted in the presence of an organic tertiary amine [] whose dissociation constant is larger than that of the human oxyalkylamine [] used. , the hydroxyalkylamine used in this case []
If an organic tertiary amine with a smaller dissociation constant is used, the yield of the desired N-hydroxyalkyl-substituted phosphoroamidate [] will decrease because the hydroxyalkylamine [] also acts as a dehydrohalogenating agent. Therefore, it is not desirable.

Further, it is sufficient to use the organic tertiary amine [] in an equivalent molar amount to the phosphoric acid diester halide [1].

Water-insoluble or sparingly soluble organic solvent [V
] In the reaction between phosphoric diester halide [1] and hydroxyalkylamine [] in the presence of organic tertiary amine [], for example, hydroxyalkylamine [], organic tertiary amine [] and water-insoluble or poorly water-soluble organic solvent [v]
A method in which phosphoric acid diester halide [] is added dropwise to a mixed solution (A) of hydroxyalkylamine [] and an organic tertiary solution is added to a mixed solution of phosphoric diester halide [1] and a water-insoluble or sparingly soluble organic solvent [V]. This is carried out by dropping a mixture of amine [], but usually it is added to a mixture (4) of hydroxyalkylamine [], organic tertiary amine [], and water-insoluble or sparingly soluble organic solvent [V]. This is carried out by dropping phosphoric acid diester halide [1].

This reaction is carried out dropwise at a temperature of 50°C or lower, preferably 30°C or lower, and the reaction temperature after the dropwise addition is -10 to 60°C, preferably O
Reaction time at ~30°C 0.5-4 hours, preferably 0.5-4 hours
This is done by stirring for 2 hours. When this reaction is carried out in the presence of water, phosphoric acid diester lard [1
] to cause side reactions such as hydrolysis of the target N-
This is undesirable because the purity and yield of the hydroxyalkyl-substituted phosphoramidate [] will decrease, and it is preferable to carry out the reaction under substantially anhydrous conditions.

Further, it is sufficient that the amounts of hydroxyalkylamine [] and organic tertiary amine [] are used in equimolar amounts relative to phosphoric acid diester halide [1].

N-hydroxyalkyl-substituted phosphoramidate [],
Reaction mixture (8) consisting of an organic tertiary amine hydrogen halide salt [] and a water-insoluble or IIE-soluble organic solvent [V]
The reaction between the alkali metal hydroxide aqueous solution [] and the alkali metal hydroxide aqueous solution [] is added to the above reaction mixture (8) with stirring.
This is done by dripping.

Dropwise addition of the aqueous alkali metal hydroxide solution [] is carried out when the organic tertiary amine hydrogen halide salt [] is not present or when the reaction between the phosphoric acid diester halide [1], the hydroxyalkylamine [] and the organic tertiary amine [] is carried out. If this is carried out when the reaction is not completed, cleavage (hydrolysis) of the O-P bonds of the phosphoric acid ester groups RlO-P- and R2O-P- of N-hydroxyalkyl-substituted phosphoramidate []5 will occur, resulting in the target Since no N-hydroxyalkyl-substituted phosphoramidate [] is obtained, the above reaction mixture (B ) is preferably added dropwise.

This reaction is carried out at a temperature of 30° C. or lower, preferably 20° C. or lower, while dropping an aqueous alkali metal hydroxide solution. The reaction is almost complete when the aqueous alkali metal hydroxide solution [ ] is added dropwise. In this case, when the temperature is 30°C or higher, the phosphoric acid ester groups RlO-P- and R2O-P-
This is not preferred because the cleavage (hydrolysis) of the 1P bond tends to occur and the purity and yield of the desired N-hydroxyalkyl-substituted phosphoramidate decreases. The amount of alkali metal hydroxide aqueous solution [] to be used is preferably 1.01 to 1.05 times the mole of phosphoric acid diester halide [1], and if it is less than 1.01 times the mole, the target N
- The physical properties of the hydroxyalkyl-substituted phosphoramidate [] are poor, especially the acid value, and when the mole is 1.05 times or more, the phosphoric acid ester groups RlO-P- and R2O-P of the N-hydroxyalkyl-substituted phosphoroamidate [] are This is not preferred because the cleavage (hydrolysis) of the O-P bond of - tends to occur, resulting in a decrease in the purity and yield of the desired N-hydroxyalkyl-substituted phosphoroamidate.

When alkali metal hydroxide [] is used in the form of a crystal, the reaction is extremely slow, and the reaction is not uniform and cannot be carried out sufficiently. This is not preferred because the yield becomes extremely low.

In addition, alkaline earth metal hydroxides are undesirable because they are poorly soluble in water, making it difficult to use them in the form of aqueous solutions.
Furthermore, the reaction of alkali metal carbonates is slow even when used in aqueous solution, and the reaction produces alkali metal bicarbonate as a by-product, which improves the purity and yield of the target N-hydroxyalkyl-substituted phosphoroamidate This is not preferable because it reduces the

The above reaction mixture (B) and aqueous alkali metal hydroxide solution [
N-hydroxyalkyl-substituted phosphoroamidate obtained by reaction with [], an organic tertiary amine [], a water-insoluble or sparingly soluble organic solvent [v], an alkali metal...rogenide [], and water. The reaction mixture (0 is an alkali metal halide) is separated and removed as an alkali metal halide saturated aqueous solution.

In this case, to make the alkali metal halide [ ] into an alkali metal halide saturated aqueous solution, either add the amount of water required to prepare the saturated aqueous solution as an alkali metal hydroxide aqueous solution, or add an alkali metal hydroxide aqueous solution. After the addition, the alkali metal halide [ ] is dissolved by adding the amount necessary to prepare a saturated aqueous solution. In addition, the separation and removal of the alkali metal halide [ ] is usually carried out after the completion of the reaction by separating the alkali metal halide saturated aqueous solution, but the reaction mixture is concentrated and the organic tertiary amine [ ] is removed.
] and the water-insoluble or sparingly soluble organic solvent [V] and water are distilled off, and then water-insoluble or sparingly soluble organic solvent [V] and water are added to the obtained concentrate to obtain a saturated aqueous alkali metal halide solution. It can also be carried out by liquid separation.

From an N-hydroxyalkyl-substituted phosphoramidate [] obtained by separating and removing an alkali metal halide [] as an aqueous saturated alkali metal halide solution, an organic tertiary amine [], and a water-insoluble or sparingly soluble organic solvent [] The mixture I)) is concentrated under normal pressure or reduced pressure to remove the organic tertiary amine [] and the water-insoluble or sparingly soluble organic solvent [], and further contains 0.1 to 50 kg of Hg, preferably 0.1 to 50 kg. 5-1
Under reduced pressure of 0m7fLHg, 50-150℃, preferably 8
Highly purified N-hydroxyalkyl-substituted phosphoroamidate can be obtained in high yield by distilling off a very small amount of remaining water-insoluble or sparingly soluble organic solvent at 0 to 120°C.

At this time, the organic tertiary amine [] is recovered as a mixed solution with the water-insoluble or sparingly soluble organic solvent [V], and this mixed solution can be reused in the next reaction without purification.

Further, in this case, the recovery rates of the organic tertiary amine [] and the water-insoluble or sparingly soluble organic solvent [V] are quantitative. Examples of water-insoluble or sparingly soluble organic solvents used in the method of the present invention include chloroform, ethylene chloride, carbon tetrachloride, ethylidene chloride, 1,1,2-trichloroethane,
Trichlorethylene, 1,2-dichloropropane, 1.
Examples include halogenated hydrocarbons such as 2,3-trichloropropane, chlorobenzene, and chlorotoluene, and aromatic hydrocarbons such as benzene, toluene, and xylene.
- Logenated hydrocarbons are preferred, and it is not necessary to use a large amount; it is sufficient to use 1.0 to 3.0 times the mole of phosphoric acid diester halide [1].

The organic tertiary amine used in the method of the present invention has a larger dissociation constant than the hydroxyalkylamine used
] as trimethylamine, triethylamine,
-Propylamine, tri-n-butylamine, tri-i-butylamine, dimethylethylamine, methyldiethylamine, dimethyl-n-propylamine, dimethyl-1-
Aliphatic tertiary amines such as propylamine, dimethyl-n-butylamine, dimethyl-1-butylamine, dimethyl-Sec-butylamine, dimethyl-t-butylamine, N-methylpyrrolidine, N-n-butylpyrrolidine,
Examples include heterocyclic tertiary amines such as N-cyclohexylpyrrolidine, 1-ethylpiperidine, 1-n-butylpiperidine, 1-ethyl-2-methylpiperidine, and 1-n-butyl-2-methylpiperidine, and the amount used is It is not necessary to use a large amount, and it is sufficient to use the same mole to 1.05 times the mole, preferably the same mole, relative to the phosphoric acid diester halide [1].

The alkali metal hydroxide aqueous solution [] used in the method of the present invention includes a potassium hydroxide aqueous solution and a sodium hydroxide aqueous solution, and the amount used is 1.01 to 1.05 per phosphoric acid diester halide [1]. Use twice the mole.

The amount used is 1.
If it is less than 1.0 times the mole, the physical properties of the resulting N-hydroxyalkyl-substituted phosphoroamidate [] will deteriorate, so it is not preferable, and if it is more than 1.05 times the mole, the phosphoric acid ester of the N-hydroxyalkyl-substituted phosphoroamidate [] will become unfavorable. Cleavage of the O-P bond of the groups RlO-P- and R2O-P (
This is not preferable because it tends to cause hydrolysis (hydrolysis). Further, the concentration of the alkali metal hydroxide aqueous solution [] is not particularly limited, as long as the amount of water in the alkali metal hydroxide aqueous solution is equal to or less than the amount of water required to make the alkali metal halide a saturated aqueous solution.

The phosphoric acid diester lard [1] used in the method of the present invention includes R1 and R2 of the general formula []
The group represented by is a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, n-pentyl group, n-
Alkyl groups such as hexyl group, n-octyl group, 2-ethylhexynole group, lauryl group, 2-chloroethyl group,
-bromoethyl group, 2,3-dichloropropyl group, 2.
halogenated alkyl groups such as 3-dibromopropyl group, β-chloroisopropyl group, aralkyl group such as allyl group, 3-chloroallyl group, benzyl group, phenylethyl group, o-, m- or p-chlorobenzyl group, o- -, m
- or p-promobenzyl group, o-, m- or p-chlorophenylethynole group, o-, m- or p
- a halogenated aralkyl group such as a promophenylethyl group, a phenynon group, an o-, m- or p-tolyl group,
Aryl groups such as o-, m- or p-xylyl groups, 0
It is a halogenated aryl group such as m- or p-chlorophenyl group, o-, m- or p-promophenyl group, and the atom represented by X is a fluorine atom, a chlorine atom,
It is a compound that is a bromine atom or an iodine atom. Furthermore, the hydroxyalkylamine used in the method of the present invention [
] Examples include ethanolamine 2-methylaminoethanol, 2-ethylaminoethanol, 2-propylaminoethanol, 2-isopropylaminoethanol, 2-butylaminoethanol, diethanolamine, isopropanolamine, N-ethylisopropanolamine, diisopropanol Amine, 2-aminopropanol, 3-amino-1-propanol, 3-methylamino-1-propanol, 3-ethylamino-1-propanol, 3-propylamino-1-propanol,
3-butylamino-1 propanol 1-amino-2-
Butanol, 2-amino-1-butanol, 2-ethylamino-1-butanol, 2-propylamino-1-butanol, 3-amino-1-butanol, 1-amino-4
-butanol, 2-amino-3-butanol 1-amino-2-methyl-2-propanol, 2-amino-2-
Methyl-1-propanol, 2-ethylamino-2-methyl-1-propanol, 2-propylamino-2-methyl-1-propanol, 3-amino-1.2-propanediol, 3-methylamino-1. 2-propanediol, 3-ethylamino-1,2-propanediol 2
-amino-1,3-propanediol, 2-amino-2
-Methyl-1,3-propanediol and the like.

Next, the features and advantages of the method of the present invention will be explained in comparison with conventional methods.

The first feature of the method of the present invention is that N-hydroxyalkyl-substituted phosphoramidates can be obtained with high purity and high yield.

In the conventional method, in order to separate and remove the organic tertiary amine hydrogen halide salt produced by the reaction of phosphoric acid diester halide, hydroxyalkyl amine, and organic tertiary amine by washing with water, N-hydroxyalkyl Although the substituted phosphoramidate was lost in washing water and the yield was extremely low, the method of the present invention separates the organic tertiary amine hydrohalide salt as a free organic tertiary amine and a saturated aqueous solution of alkali metal halide. Since it is removed, N-
Hydroxyalkyl-substituted phosphoroamidates are obtained in high yields.

The second feature of the method of the present invention is that the organic tertiary amine and water-insoluble or sparingly soluble organic solvent used in the reaction can be quantitatively recovered.

In conventional methods, the organic tertiary amine used in the reaction is recovered by separating the organic tertiary amine hydrogen halide salt by washing with water, neutralizing it by adding an alkaline aqueous solution, and recovering the organic tertiary amine as a free organic tertiary amine. However, the recovery rate was low because the organic tertiary amine dissolves in water or azeotropes with water. However, the method of the present invention The organic tertiary amine is recovered as a mixed solution together with a water-insoluble or sparingly soluble organic solvent after converting the hydrogen salt into a free organic tertiary amine and alkali metal halide without separating it by washing with water. and water-insoluble or sparingly soluble organic solvents are quantitatively recovered.

The third feature of the method of the present invention is that the recovered mixture of organic tertiary amine and water-insoluble or sparingly soluble organic solvent can be reused in the next reaction without purification.

As mentioned above, the conventional method is to separate the organic tertiary amine hydrogen halide salt by washing with water, neutralize it by adding an aqueous alkali solution, and recover it as a free organic tertiary amine by distillation. However, since organic tertiary amines dissolve water or azeotrope with water, water cannot be reused in the next reaction unless water is separated and purified. However, the method of the present invention Since it contains almost no water by recovering the organic tertiary amine and the water-insoluble or sparingly soluble organic solvent as a mixed solution, the following process can be carried out without purifying the recovered organic tertiary amine and the water-insoluble or sparingly soluble organic solvent as a mixed solution. Can be reused for reactions.

Since the method of the present invention has the above-mentioned characteristics, by carrying out the method of the present invention, N-hydroxyalkyl-substituted phosphorus can be produced extremely economically on an industrial scale with high purity and high yield compared to conventional methods. This gives rise to the advantage that amidates can be produced.

Next, the method of the present invention will be specifically explained using Examples and Comparative Examples. Example 1 Production of 0.O-diisopropyl-N-N-bis(2-hydroxyethyl)phosphoramidate Thermometer, cooling tube,
In a 1t four-loop flask equipped with a dropping load, add 105.1y (1.0 mol) of diethanolamine, 101.2y (1.0 mol) of triethylamine, and 298 y of chloroform.
．． 5y (2.5 mol) was charged, and 200.6y (1.0 mol) of phosphoric acid diisopropyl chloride was added to this with stirring.
After dropping for 35 minutes at 5℃ or below, it was added for 20~20 minutes while stirring.
The reaction was carried out at 25°C for 0.5 hour.

Then, 84.2 f (1.01 mol) of a 48% aqueous sodium hydroxide solution was added dropwise to the reaction mixture at 20° C. or lower for 15 minutes while stirring. After the reaction was completed, 95 ml of water was added to the resulting reaction mixture and stirred for 15 minutes, and then a small amount of sodium chloride that remained undissolved in the water was filtered off. The layers were separated and separated.

The obtained organic layer was first concentrated under normal pressure and then under reduced pressure to remove triethylamine and chloroform and recover a mixed liquid.The obtained concentrated liquid was further heated at 100°C/0.5°C.
m7! A very small amount of light fraction was distilled off using LHg to obtain a pale yellow transparent viscous liquid of 0.O-diisopropyl-N-N-bis(2-
Hydroxyethyl) phosphoramidate 261.77 (
A yield of 97.2% based on phosphoric acid diisopropyl chloride was obtained. This material has a specific gravity of 1.118 and 2 at 25°C.
Refractive index at 5°C 1.4504, acid value 0.03K0H
~/y, hydroxyl value 413.9K0H immediately/y (theoretical value 41
6.7), and the hydroxyl value purity was 99.33%. Also,
The recovered triethylamine and chloroform were obtained as a mixed solution of 385.1 y, and as a result of analysis using a Karl Fischer moisture meter and gas chromatography, the water content was 0.93% (content 3.6 y) and the triethylamine content was 25.1 y. The chloroform content was 73.41% (content 282.77), and the triethylamine recovery rate was 97.6% and the chloroform recovery rate was 94.7%. Example 2 Production of 0.0-diisopropyl-N-N-bis(2-hydroxyethyl)phosphoramidate Triethylamine 101.2f7 (1.0 mol) used in Example 1 and chloroform 298.5y (2. 385.1f of the triethylamine-chloroform mixture recovered in Example 1 was used instead of 5 mol), and triethylamine,
By adding 2.4y and 15.8y of chloroform, the amount of triethylamine and chloroform charged was 10% each.
1.2y (1.0 mol) and 298.57 (2.5 mol), and then operated in the same manner as in Example 1 to obtain a pale yellow transparent viscous 0,0-diisopropyl-N.・N
-bis(2-hydroxyethyl)phosphoramidate 2
59.3V (phosphoric acid diisopropyl chloride standard yield 9
6.3%).

This product has a specific gravity of 1.118 at 25℃, a refractive index of 1.4503 at 25℃, and an acid value of 0.05K0Hη/y1.
Hydroxyl value 412.3K0H7ny/y (theoretical value 416
．． 7), the hydroxyl value purity was 98.94%. In addition, the recovered triethylamine-chloroform mixture was 37
6.17, moisture content 0.98% (content 3.7
y), triethylamine content 25.84% (content 9
7.2y) and chloroform content 73.17% (content 275.2y), triethylamine recovery rate 9
The recovery rate of chloroform was 92.2%.

Comparative Example 1 Conventional method Production of 0,0-diisopropyl-N-N-bis(2hydroxyethyl)phosphoramidate In a 2t four-bottle flask equipped with the same equipment as in Example 1, 1 liter of diethanolamine was added.
05.17 (1.0 mol), triethylamine 103.
2y (1.02 mol) and chloroform 596,9y
(5.0 mol), 200.67 (1.0 mol) of phosphoric acid diisopropyl chloride was added dropwise to this under stirring at 25°C or below for 1 hour.
The reaction was carried out at 40°C for 2 hours.

After the reaction was completed, 3001 n1 of water was added to the resulting reaction mixture to separate the triethylamine hydrochloride produced as a by-product from the reaction into an aqueous solution, which was then washed three times with 150 d of water.

The obtained organic layer was concentrated under reduced pressure to remove chloroform, and then the light fraction was further distilled from the obtained concentrated liquid at 100°C/1 hour of Hg to obtain O.0-diisopropyl as a yellow-brown transparent viscous liquid. -N-N-bis(2-hydroxyethyl)phosphoroamidate 196.87 (yield 73.1% based on diisopropyl chloride phosphate) was obtained. This one has a specific gravity of 1.117 at 25°C and a refractive index of 1.450 at 25°C.
0, acid value 3.10K0H Wa/V, hydroxyl value 367.0K
0H~/F7 (theoretical value 416.7), hydroxyl value purity 88
．． It was 0.7%. In addition, the triethylamine hydrochloride aqueous solution and washing water obtained by adding water to the reaction mixture and separating the layers were neutralized by adding a 10% aqueous sodium hydroxide solution, and then separated into an aqueous layer and a triethylamine layer at 25°C. Triethylamine 94.6V was obtained.

This product was analyzed using a Karl Fischer moisture meter and found to have a water content of 8.51% and a triethylamine recovery rate of 83.9%. In order to separate the dissolved water, the obtained triethylamine was repeatedly purified by distillation using a distillation apparatus equipped with a Widoma fractionator tube until the water content became 1% or less. As a result, triethylamine 76.4r was obtained.
was obtained, with a water content of 0.98% and a triethylamine recovery rate of 73.3%. Example 3 Production of O-0-bis(2,3-dichloropropyl)-N-(2-hydroxyethyl)phosphoramidate using various reaction solvents *Equipped with the same equipment as Example 1 30.57 (0.50 mol) of monoethanolamine was placed in a 500a four-necked flask.
50.6 t (0.50 mol) of triethylamine and 150 mj of various organic solvents were charged, and to this was added 169 t of bis(2,3-dichloropropyl) chloride phosphate with stirring.
2f1 (0.50 mol) was added dropwise at 25° C. or lower for 15 minutes, and then reacted with stirring at 20 to 25° C. for 0.5 hour.

Then, 130.37 (0.51 mol) of a 22% aqueous potassium hydroxide solution was added dropwise to the reaction mixture at 20° C. or lower for 15 minutes while stirring. After the reaction is complete, the resulting reaction mixture is filtered to remove a small amount of potassium chloride that remains undissolved in water. Method) The obtained solution ▲ was separated into an organic layer and a saturated potassium chloride aqueous solution layer.

In addition, when a water-soluble organic solvent and water were used as the reaction solvent (comparative example), the resulting ▲ solution was mixed with chloroform 3001.
! Ll was added to separate the organic layer and the potassium chloride saturated aqueous solution layer. The obtained organic layer was concentrated under reduced pressure to remove triethylamine and the solvent, and then heated at 100°C/1
The light fraction was distilled off at 111 Hg to obtain 0.0-bis(2.3-dichloropropyl) to N-(2-hydroxyethyl)phosphoroamidate. The results obtained are shown in Table-1.

(4) Theoretical value of hydroxyl value is 154.6K0Hη Example
4 O.0~di(n-) using various organic tertiary amines
octyl)-N-N-bis(2-hydroxyethyl)phosphoramidate.

O-0-di( n-octyl)-N-N-bis(
2-hydroxyethyl) phosphoroamidate was obtained.

The results obtained are shown in Table-2.

Example 5 0-0-diallyl-N − using various inorganic bases
Production of N-bis(2-hydroxyethyl)phosphoramidate 48% aqueous sodium hydroxide solution in Example 1★
(4) The theoretical value of hydroxyl value is 423.1K0'. The procedure of Example 1 was repeated using a predetermined amount of the intermediate inorganic base instead of 1.01 mol and phosphoric acid diallyl chloride instead of phosphoric acid diisopropyl chloride.
-O-diallyl-N-N-bis(2-hydroxyethyl)phosphoramidate was obtained.

The results obtained are shown in Table 3. It is ψ/7.

Example 6 0.0-di(n-propyl)-N-(n-butyl)-N
- Preparation of (2-hydroxyethyl) phosphoramidate Using phosphoric acid di-n-propyl chloride in place of phosphoric acid diisopropyl chloride in Example 1 and 2-butylaminoethanol in place of diethanolamine,
O-0-di(n-propyl)-N-(n-butyl)-N-(2- Hydroxyethyl) phosphoroamidate was obtained.

The results obtained are shown in Table 4.

Example 7 Production of various N-hydroxyalkyl-substituted phosphoroamidates [] Instead of phosphoric diisopropyl chloride in Example 1, various phosphoric diester halides [1] were used.
In addition, various N-hydroxyalkyl-substituted phosphoroamidates [] were obtained in the same manner as in Example 1 except that various hydroxyalkylamines [] were used instead of diethanolamine and the reaction temperature and reaction time were changed. Ta.

The results obtained are shown in Table-5.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. or aryl group, and X represents a halogen atom) and the general formula ▲ Numerical formula, chemical formula, table, etc. Indicates a group, R_4
represents a hydrogen atom, a lower alkyl group, or a group represented by -R_3-OH. ) is reacted with a hydroxyalkylamine represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, R_3 and R_4 have the same meanings as above.) N- In a method for producing a hydroxyalkyl-substituted phosphoramidate, a phosphoric diester halide and a hydroxyalkylamine are mixed in a water-insoluble or sparingly soluble organic solvent in the presence of an organic tertiary amine having a larger dissociation constant than the hydroxyalkylamine used. are reacted under substantially anhydrous conditions, and then an aqueous alkali metal hydroxide solution of 1.01 to 1.05 times the molar amount to the phosphoric acid diester halide is added and reacted, and the alkali metal halide produced is reacted with an alkali metal halide. The N-
A method for producing a hydroxyalkyl-substituted phosphoramidate.