JPS61246191A - Production of sodium carbamyl phosphate - Google Patents

Abstract

PURPOSE:To obtain the titled compound industrially advantageously, by reacting sodium dihydrogenphosphate with sodium cyanate in an aqueous solution to form sodium carbamyl phosphate and adding a basic agent of Na and ethanol successively in a specific constitution to it. CONSTITUTION:Sodium dihydrogenphosphate is reacted with sodium cyanate in an aqueous solution to form sodium carbamyl phosphate, a basic agent of sodium is added to the reaction solution, so unreacted sodium dihydrogenphosphate is made into sodium phosphate, precipitated and separated by filtration. The filtrate is blended with ethanol, unreacted sodium cyanate is processed into a solution of sodium cyanate in ethanol, divided into phases and separated. The residue solution is incorporated with a solvent (preferably methanol) miscible with water, sodium carbamyl phosphate is precipitated and separated from the mother liquor.

Description

[Detailed Description of the Invention] <Industrial Application Field> The present invention relates to a method for producing sodium carbamyl phosphate, and more specifically, to a novel method for producing sodium carbamyl phosphate with high purity industrially and efficiently. and an improved method.

It has long been known that carbamyl phosphate is synthesized from ammonia and carbon dioxide by carbamyl phosphate synthetase in vivo, and serves as a raw material for, for example, citrulline and N-carbamyl aspartic acid.

In recent years, techniques for using carbamyl phosphate industrially or as a diagnostic reagent have begun to be developed. For example, a carbamylating agent for antibiotics such as penicillin and cephorosborin, a raw material for the synthesis of sil-lucin, or the synthesis of azonesyntriphosphate (ATP), which plays an important role in many biochemical reactions as a bioenergy conductor. It is also used as a diagnostic reagent for measuring the activity value of ornithine carbamyl transferase.

Sodium carbamyl phosphate, which is the object of the present invention, can also be used in such technical fields.

<Prior Art> By the way, carbamyl phosphate is synthesized in vivo but is not accumulated, so it is necessary to synthesize it chemically to obtain it. However, there are few studies on the production of this substance, and J. Am. Chem. Soc.
77, 819 (1955) is the only known method. This conventional method generally consists of the following steps: i) reacting potassium phosphate and potassium cyanate in an aqueous solution to produce potassium carbamyl phosphate; ii) adding perchloric acid and water to the reaction solution; Lithium oxide is added, potassium is precipitated as potassium perchlorate, and unreacted potassium phosphate is precipitated as lithium phosphate (Li3PO4) and removed; Ethanol is mixed with the remaining reaction solution containing lithium carbamyl phosphate (converted from lithium to lithium) to precipitate only lithium carbamyl phosphate, which is then filtered and collected.

<Problems to be solved by the invention> However, this conventional method has the following drawbacks: ■ Expensive materials such as perchloric acid and lithium compounds are required; ■ Large amounts of potassium perchlorate, etc. Formed: ■The last precipitated lithium carbamyl phosphate becomes fine particles, so
Filtration, washing, drying, etc. become complicated.

As a result, this conventional method increases the manufacturing cost and results in an expensive product, so there is a problem that it can only be used in very limited fields.

SUMMARY OF THE INVENTION Therefore, the present invention has been made to solve the problems of the conventional methods as described above, and to provide a method that can efficiently produce high-quality carbamyl phosphate at low cost.

<Means for Solving the Problems> That is, the present invention is a method for producing highly pure sodium carbamyl phosphate, in which sodium dihydrogen phosphate and sodium cyanate are reacted in an aqueous solution to produce sodium carbamyl phosphate. After that, a basic agent of sodium is added to the reaction solution, and unreacted sodium dihydrogen phosphate is precipitated and filtered as aerium hydrogen phosphate. Ethanol is added to the filtrate and mixed, and unreacted sodium cyanate is separated from the ethanol. The method is characterized in that it is separated in portions as a solution, and then a water-miscible solvent is added to the residual solution to precipitate sodium carbamyl phosphate, which is then separated from the mother liquor.

The points that the present inventor particularly studied in the above-mentioned method of the present invention are that phosphate (sodium dihydrogen phosphate Na82PO4
) and cyanate (sodium cyanate) from the reaction solution, and the other method is to quickly separate the produced carbamyl phosphate from the aqueous reaction solution. In other words, carbamyl phosphate is produced by reacting phosphate with cyanate, which is a carbamylating agent, in water. Therefore, in order to obtain high-grade carbamyl phosphate, it is necessary to separate these unreacted phosphates and cyanates from the produced carbamyl phosphate.

In general, carbamyl phosphate is hydrolyzed, so
It is also necessary to generate and separate it from water quickly.

As a result of various studies on methods for removing unreacted phosphate from the reaction solution, the inventors of the present invention first investigated how to remove unreacted phosphate from the reaction solution. ) was found to be able to be effectively removed by precipitating it from the reaction solution and filtering it. That is, after reacting sodium dihydrogen phosphate and sodium cyanate in an aqueous solution, I)H is adjusted to the reaction solution with a basic agent of sodium, and at the same time, the reaction solution is cooled to remove unreacted phosphorus. Sodium dihydrogen phosphate may be precipitated using aerium phosphate dodecahydrate (precipitates as Na2HPO4''12H20 below room temperature) and then filtered.

Next, in order to separate the reaction product sodium carbamyl phosphate from the reaction solution from which unreacted sodium dihydrogen phosphate was removed, a method for removing unreacted sodium cyanate and water was studied. In the conventional method described above, when ethanol is mixed with a reaction solution containing lithium carbamyl phosphate, which is a reaction product, only lithium carbamyl phosphate is precipitated, and 1 q of lithium carbamyl phosphate is obtained by filtering this. However, in the method of the present invention, even if the reaction solution containing sodium carbamyl phosphate is subjected to the same operation as in the conventional method, some of the water in the reaction solution moves to ethanol, but sodium carbamyl phosphate does not precipitate and the aqueous solution remains. It was found that this amount was shared with ethanol. After further consideration, we found that
It has been found that carbamyl phosphate can be precipitated by adding a solvent completely miscible with water to the above aqueous solution containing sodium carbamyl phosphate obtained by fractional separation from ethanol. In other words, the water in the reaction solution can be reduced by the ethanol treatment in the first stage, and sodium carbamyl phosphate can be precipitated by the water-miscible solvent treatment in the latter stage.

Furthermore, it has been found that, preferably, unreacted sodium cyanate is transferred from the reaction solution into ethanol by the ethanol treatment in the first stage, and unreacted 1-lium cyanate can be efficiently removed from the reaction solution. Here, instead of ethanol, other solvents such as isopropanol.

When n-propanol, acetone, etc. are used, the proportion of sodium cyanate transferred to these solvents is small, and most of it remains in the reaction solution; furthermore, when methanol, acetonitrile, etc. are used, It was found that sodium cyanate could hardly be removed. Although it is unclear why ethanol is particularly effective in removing sodium cyanate, such an effect was completely unexpected. Accordingly, in the present invention,
Since the reaction product sodium carbamyl phosphate can be precipitated and isolated from the reaction solution from which unreacted sodium cyanate has been removed, high-grade sodium carbamyl phosphate can be produced.

Each step of the method of the present invention will be explained in detail below.

(1) Reaction of sodium dihydrogen phosphate and sodium cyanate The reaction of sodium dihydrogen phosphate and sodium cyanate to produce mono-lium carbamyl phosphate is almost entirely compatible with the reaction with potassium salt in the conventional method. There is no difference, and it is greatly affected by the pH of the reaction solution. If DH is too high, the reactivity with sodium cyanate will decrease and no reaction will occur. On the other hand, 1) If H is too low, sodium cyanate decomposes into carbon dioxide and ammonia. Therefore, the I)H of the reaction solution is adjusted to 4 to 8, preferably 5 to 1.5. By the way, I)I-( of the reaction solution gradually increases as the reaction progresses. Therefore, by adding acidic dihydrogen phosphate as it is or as an aqueous solution to an alkaline sodium cyanate aqueous solution, , it becomes easy to adjust the pH of the reaction solution.Although this reaction is an equimolar reaction of cyanic acid and phosphoric acid, taking into consideration that some cyanic acid will decompose to some extent during the reaction, sodium cyanate It is desirable to use a slight excess of.

Roughly speaking, the reaction solvent water is 1 to 2 parts of cyanate.
(on a weight basis; the same applies hereinafter) to 20 times, preferably 3 times
Increase the amount by 10 times to 10 times. If there is too much water, unreacted sodium dihydrogen phosphate may not be completely removed in the subsequent steps, or the amount of ethanol used to isolate sodium carbamyl phosphate will increase, which is economically disadvantageous.

On the other hand, the solubility of sodium cyanate in water is approximately 1
Since it is small at 2 g/100 mJ2 water, if the amount of water is less than 8 times the amount of sodium cyanate, the sodium cyanate will not be completely dissolved and will remain partially suspended, but the reaction with sodium dihydrogen phosphate will proceed. There is no problem as the suspended portion will dissolve over time. However, if the amount of water is too small, the reaction time will be prolonged and the reaction rate will also be reduced due to the small amount of dissolved sodium cyanate.

Also, since this reaction takes place in a short time, the reaction temperature is 10
The reaction is completed in 30 minutes to 2 hours at a temperature of 50°C to 50°C. If the reaction temperature is too high, the production of sodium carbamyl phosphate will be accelerated, but the hydrolysis of the produced sodium carbamyl phosphate will also be accelerated, resulting in a decrease in the yield of sodium carbamyl phosphate, so care must be taken.

(2) Removal of unreacted sodium dihydrogen phosphate Next, unreacted sodium dihydrogen phosphate is removed from the above reaction solution.

Among the sodium salts of phosphoric acid, dihydrogen phosphate is known to have extremely low solubility at low temperatures.

For example, the solubility at 0°C is 1.62(]/100 m
It is M. Therefore, 1) of the above reaction solution (pH is about 7-8)
H is adjusted to 8 to 12, preferably 9 to 10.5, with a thulium basic agent such as caustic soda or soda carbonate, and cooled. Since the lower the cooling temperature, the lower the solubility of dihydrogen phosphate, unreacted sodium dihydrogen phosphate can be removed. Generally, the temperature is preferably 5°C or less, preferably 0°C or less. By this, most of the unreacted sodium dihydrogen phosphate in the reaction solution was removed from Na2
HPO4” 12H20) can be distributed from house to house.

(3) Removal of Sodium Arashino Enokan In order to remove unreacted sodium cyanate from the reaction solution collected as the filtrate in the step (2) above, ethanol is mixed with the solution. As a result, some of the sodium cyanate and water are transferred to ethanol to create a homogeneous ethanol solution, while sodium carbamyl phosphate remains an aqueous solution (however, the amount of water decreases) and is divided into parts with the ethanol solution. Note that the amount of ethanol used is 0.2 to 4 times, preferably 0.4 to 2 times, the amount of the filtrate. If there is not enough ethanol, the removal of sodium cyanate will be insufficient, and if it is too much, the cost for regenerating ethanol for reusing it after treatment will increase, which is not economically desirable.

(4) Precipitation of sodium carbamyl phosphate 1 separation above (
The residual liquid from which the ethanol solution shared in step 3) was separated;
In other words, in an aqueous solution containing sodium carbamyl phosphate,
By adding an organic solvent that is completely miscible with water, sodium carbamyl phosphate is precipitated and separated. The precipitates separated from each other are dried under reduced pressure after washing the adhering water with a low boiling point solvent such as methanol. As solvents that are miscible with water, lower alcohols such as methanol, ethanol, isopropanol, and n-propanol, ethers such as tetrahydrofuran, dioxane, 2-methoxyethanol, and 2-ethoxyethanol, acetone, acetonitrile, etc. are used. However, the precipitation rate of sodium carbamyl phosphate,
It is preferable to use methanol from the viewpoint of the amount used and the ease of regeneration treatment for reuse. Particularly when methanol is used, sodium carbamyl phosphate precipitates quickly and relatively large particles with uniform particle size can be obtained, so that subsequent washing and drying can be carried out quickly and easily.

<Examples> Next, the present invention will be further explained with reference to Examples and Comparative Examples, but the present invention is not limited only to these Examples. In addition, "part" and 1 in each example and comparative example
%" indicates parts by weight and % by weight, respectively.

Example 1.

Mix 65 parts of sodium cyanate with 430 parts of water. Sodium cyanate was not completely dissolved and remained suspended in a small amount. Note that the aqueous solution temperature was 25°C. To this aqueous solution, 120 parts of sodium dihydrogen phosphate (NaN3 PO4) was added over 10 minutes for reaction. At this time, the pH of the reaction solution is maintained at 6.0 to 6.5. During this time, the temperature of the reaction solution became 30'C, and the reaction was continued in this state for approximately 30 minutes. Next, the reaction solution was cooled to -5°C, 10 parts of 48% caustic soda was added, and stirring was continued for 10 minutes, producing a large amount of precipitate. This is centrifuged and separated by filtration to obtain 428 parts of filtrate. 300 parts of ethanol is added to this filtrate, stirred and left to stand, and divided into an ethanol phase and an aqueous phase (209 parts). When the aqueous phase is separated and 120 parts of methanol is mixed therein, a precipitate is formed. This precipitate was separated using a centrifuge, and methanol 1
00 parts, filtered, and dried under reduced pressure for 1 day to obtain 106.5 parts of product.

The composition of the product thus obtained was 85% disodium carbamyl phosphate, 15% dihelium hydrogen phosphate,
and trace amounts of sodium cyanate. Further, the yield of milphosphate dibium for carle based on phosphoric acid (the same applies to each of the following examples) was 49%. These analyzes were performed using Methods of Enzym
oloay m, .

653 (Academic press, Nev.
York, 1957) and J. Chem, So.
The method described in J. C., 1944 (1962) was followed.

In addition, 178 parts of the above-mentioned precipitate generated when the reaction solution was cooled and caustic soda was added were obtained, and analysis of this by X-ray diffraction revealed that airtrium hydrogen phosphate dodecahydrate (N
a HPO4-12 Town O).

Example 2 78 parts of sodium cyanate are mixed with 400 parts of water, and 120 parts of sodium dihydrogen phosphate is added in two portions every 5 minutes. When sodium dihydrogen phosphate is added for the first time, intense foaming occurs. During this time, the reaction solution temperature was 35
°C, and the reaction is continued in this state for another 30 minutes. Next, the reaction temperature was cooled to -5°C, and the subsequent operations were carried out in the same manner as in Example 1 to obtain 126 parts of a product.

The composition of the resulting product was 89% disodium carbamyl phosphate, 11% airtrium hydrogen phosphate, and traces of sodium cyanate. Moreover, the yield was 61%.

Comparative Example 1 Product 114 was prepared in the same manner as in Example 1, except that acetone was used in place of ethanol used in Example 1.
get the part. The composition of the product obtained was 82% disodium carbamyl phosphate, 1 dihydrogen phosphate to 1 helium
4% and sodium cyanate 4%. This result shows that when acetone is used instead of ethanol to remove unreacted mono-lithium cyanate, sodium cyanate cannot be effectively removed and is contained in the product.

Comparative Example 2 Product 12 was produced in the same manner as in Example 1, except that methanol was used in place of the ethanol used in Example 1.
Take 0 copies by 1 q. The composition of the obtained product was 1% to 81% lithium carbamyl phosphate, 1% airtrium hydrogen phosphate.
4% and sodium cyanate 5%. This result shows that when methanol is used instead of ethanol to remove unreacted sodium cyanate, sodium cyanate cannot be effectively removed and ends up being contained in the product.

<Effects of the Invention> As can be seen from the above description, according to the method of the present invention, highly pure sodium carbamyl phosphate can be produced simply and quickly using inexpensive materials. Moreover, the organic solvent used can be easily recovered and recycled for reuse, and in addition, unreacted raw material phosphate and cyanate can be separated and recovered from the product carbamyl phosphate and reused. There is also the advantage of being able to do so.

Claims (1)

[Claims] 1. After reacting sodium dihydrogen phosphate and sodium cyanate in an aqueous solution to produce sodium carbamyl phosphate, add a sodium basic agent to the reaction solution and convert unreacted sodium dihydrogen phosphate into hydrogen phosphate ester. The atrium is precipitated and separated by filtration, ethanol is added to the filtrate and mixed, unreacted sodium cyanate is separated as an ethanol solution, and a water-miscible solvent is added to the residual solution to precipitate sodium carbamyl phosphate. A method for producing highly pure sodium carbamyl phosphate, which is characterized by separating the sodium carbamyl phosphate.