JPH0251910B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a cyanuric halide derivative, and more specifically, a cyanuric halide is reacted with a polyoxyalkylene glycol or a derivative thereof to produce a polyalkylene glycol of cyanuric halide. - It relates to a method for producing a monosubstituted product.

Polyalkylene glycol monosubstituted cyanuric halides (hereinafter abbreviated as HCPA) react extremely easily with hydroxyl groups, amino groups, etc., so they are widely used as fiber modifiers, proteins, or enzymes modifiers. There is.

For example, in JP-A-50-42087, polypeptides are treated with 2-0-methoxypolyethylene glycol-4,6-dichloro-s-triazine (HCPA).
It has been stated that the immunity of polypeptides can be eliminated by reacting them with.

The production of HCPA is usually performed by reacting a cyanuric halide with a polyalkylene glycol derivative in an inert organic solvent from which water has been excluded, such as anhydrous benzene, in the presence of an acid acceptor such as sodium carbonate or sodium bicarbonate. and purifying the resulting reaction mixture by reprecipitation.

At that time, polyalkylene glycol as a raw material, HCPA as a product, and high molecular weight impurities other than HCPA as a by-product have different properties such as affinity with various solvents, which differ only in the structure of one end of the high molecular weight substance. There is almost no difference between the two, and the substances removed by the reprecipitation operation are limited to unreacted cyanuric halides and other low molecular weight by-products.

Therefore, high molecular weight impurities other than the target substance HCPA, such as unreacted polyalkylene glycol and its derivatives, polyalkylene glycol disubstituted cyanuric halides, or
Compounds in which one or two of the two halogens of HCPA undergo hydrolysis and change to hydroxyl groups are obtained without being removed. If HCPA containing a large amount of such impurities is used, it will lead to a decrease in efficiency during modification reactions of fibers, proteins, enzymes, etc., and fluctuations in quality after modification. It is essential to increase the reaction rate and adopt conditions that allow the reaction to occur stably.

In order to avoid hydrolysis of the halogen group of HCPA,
Conventionally, in this type of reaction, efforts have been made to eliminate as much water as possible from the reaction solvent used. For example, Abuchowski et al. (A.Abuchowski, T.vanEs,
NCPalczuk.FFDavis, J.Biol.Chem., 252(11)
3578 (1977)) uses anhydrous benzene when synthesizing 2-0-methoxypolyalkylene glycol-4,6-dichloro-S-triazine.

The present inventors have repeatedly studied various reaction conditions for obtaining HCPA stably and in high yield, and have found that in a solvent that excludes water, the reaction is extremely slow and the yield is low. The present inventors have discovered the completely unexpected fact that when a solvent to which water is added, both the reaction rate and the yield increase dramatically.

That is, the present invention provides a cyanuric halide derivative represented by the general formula () by reacting a cyanuric halide with a polyalkylene glycol represented by the general formula () or a derivative thereof in an inert organic solvent in the presence of an acid acceptor. In the method of manufacturing,
A method for producing a halogenated cyanuric derivative, characterized in that water is contained in the reaction solvent at a ratio of 50 to 10,000 ppm.

General formula (): RO [(CH ₂ ) nO] mH General formula (): [In the above general formulas () and (), R represents hydrogen, an alkyl group, an aromatic group, an alkylcarbonyl group, an aromatic carbonyl group, an alkylaminocarbonyl group, or an aromatic aminocarbonyl group, and X represents fluorine and Indicates a member selected from the group consisting of chlorine, m indicates a number of 30 or more on average,
n represents an integer of 2 to 4. ] Although the details of this reason are not clear,
This is thought to be due to the increase in polarity of the reaction system.

The cyanuric halide used in the method of the present invention may be either cyanuric chloride or cyanuric fluoride, and depending on the purpose, both may be used as a mixture in an appropriate ratio.

The structure of polyalkylene glycols and their derivatives is shown by the general formula (), and both ends are hydroxyl groups, which are inert to the reaction with ordinary polyalkylene glycols and cyanuric halides such as ester bonds, ether bonds, and urethane bonds at one end. Any polyalkylene glycol derivative blocked with a group may be used.

General formula ():RO[( _CH2 )nO]mH (R represents hydrogen, an alkyl group, an aromatic group, an alkylcarbonyl group, an aromatic carbonyl group, an alkylaminocarbonyl group, or an aromatic aminocarbonyl group.n represents an integer of 2 to 4, and m represents an average number of 30 or more.) The group R used for blocking is a group bonded to one end of the polyalkylene glycol with an ester bond, an ether bond, a urethane bond, etc., and Those having no reactivity with cyanuric halides are used, and their structures may be saturated, unsaturated, linear, branched, or cyclic. The size of the group used for blocking is not particularly limited, but
It is preferably within a range that does not affect the physical properties of the polyalkylene glycol main chain.

Examples of polyalkylene glycols include polyethylene glycol, polypropylene glycol,
Examples include polybutylene glycol. The average number m of repeating units in the main chain of polyalkylene glycol and its derivatives is 30 or more, and the reaction rate generally decreases as the molecular weight increases, but the effect of water addition in the method of the present invention is exhibited no matter how large the molecular weight. be done.

The polyalkylene glycols and derivatives thereof used in the method of the present invention may be used in any combination as long as they are defined by the general formula (), and different types may be appropriately mixed and used depending on the purpose. It does not impair the effectiveness of For example, polyalkylene glycols are usually a mixture of different molecular weights, but in the method of the present invention, they can be used as long as they have an average number of repeating units of 30 or more.

The organic solvent used as the reaction solvent may be any organic solvent as long as it can dissolve polyalkylene glycol and cyanuric halide without reacting with cyanuric halides and HCPA. Examples include aromatic solvents such as benzene, toluene, and xylene. Hydrocarbon compounds, tetrahydrofuran, chloroform,
Examples include chlorinated hydrocarbons such as dichloroethane, sulfur compounds such as dimethyl sulfoxide, and phosphorus compounds such as hexamethylphosphoric triamide.

The acid acceptor may be any base that binds to insoluble or soluble hydrochloric acid in the reaction system. Examples of insoluble bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide,
Alkali and alkaline earth metal hydroxides such as calcium hydroxide, sodium carbonate, potassium carbonate,
Alkali and alkaline earth metal carbonates such as calcium carbonate and barium carbonate, sodium hydrogen carbonate,
Examples include alkali metal hydrogen carbonates such as potassium hydrogen carbonate. Examples of the soluble base include pyridine derivatives such as γ-collidine 2,6-lutidine and 2-methylquinoline.

Similar to the reaction solvent, the solvent used during reprecipitation purification is a solvent that does not react with HCPA and can dissolve HCPA.

Nonsolvents used in reprecipitation purification include
The solvent used is one that has no reactivity with HCPA, is miscible with the solvent used to dissolve HCPA, and does not dissolve HCPA. Examples include hydrocarbons such as hexane, heptane, petroleum ether, and cyclohexane.

In the method of the present invention, it is essential to include water in the reaction solvent, and the amount of water used is 50 to 10,000 ppm, preferably 500 to 10,000 ppm, based on the reaction solvent. If the water content is less than 50 ppm, the effect of the present invention will not be sufficient, and if the water content exceeds 10,000 ppm, the hydrolysis effect will be strong and the yield will decrease.

To describe the specific procedure for HCPA synthesis in the method of the present invention, polyalkylene glycol and its derivatives are charged and dissolved in a reaction vessel containing water, a reaction solvent, and an acid acceptor, and then the cyanuric halide is added as a solid or is added as a solution dissolved in an inert solvent, and after stirring for more than 10 hours, the insoluble matter is filtered out. It is carried out by an extremely simple operation of repeating reprecipitation purification in which the product is dissolved in an active solvent and poured into a non-solvent to produce a precipitate.

The order of addition of reagents used in the reaction is not particularly limited. The concentration of polyalkylene glycol and its derivatives in the reaction solvent is usually 1×
It is 10 ^-3 mol/or more, preferably 5×10 ^-3 mol/or more. The concentration of cyanuric halide is at least the equivalent molar amount of polyalkylene glycol in the case of a polyalkylene glycol that is blocked at one end, but is less than the equivalent molar amount when reacting a polyalkylene glycol that is not blocked at both ends. This is necessary in order to avoid reaction of the cyanuric halide with both ends of the polyalkylene glycol.

The amount of acid acceptor is equal to or more than the equivalent mole of polyalkylene glycol and its derivatives, preferably 5
More than twice the molar amount is used.

The reaction temperature is usually 0~50℃, preferably 5~40℃
is used. Temperatures exceeding 50°C are not preferred because hydrolysis tends to occur and a compound in which two or more polyalkylene glycol derivatives are bonded to a cyanuric halide is produced as a by-product. 0℃
Temperatures lower than this are not preferred because the reaction rate is greatly reduced. The temperature used in the dissolution process of the further precipitation operation is preferably 50°C or lower in order to avoid hydrolysis.

As mentioned above, the present invention relates to a novel method for producing HCPA, and by employing the method of the present invention, HCPA can be obtained stably and in good yield.

The effects of the method of the present invention will be specifically explained below in Comparative Examples and Examples, but it goes without saying that the present invention is not limited thereto.

Comparative Example 1 Monomethoxypolyethylene glycol (molecular weight 5000) 10g (2 x 10 ^-3 mol) and sodium carbonate were placed in a 200ml Erlenmeyer flask containing a Teflon rotor.
2 gr (1.89 x 10 ^-2 mol) and 100 ml of anhydrous benzene dehydrated and distilled using metallic sodium in a conventional manner were charged, and a distillation device was attached to the upper part of the flask. The distillation equipment was equipped with calcium chloride pipes to prevent moisture from entering. Using a magnetic stirrer, the system was heated while stirring, and 20ml of the initially charged 100ml of benzene was distilled out.
Water in the system was removed azeotropically.

After cooling the Erlenmeyer flask equipped with distillation equipment, transfer the contents to a 300ml polyethylene container, add cyanuric chloride (1.11gr46 x 10 ^-3 mol) in powder form, and after sealing the cap, transfer to a 300ml polyethylene container. (168
The mixture was shaken at After 14 hours of continuous shaking, the contents were filtered and the liquid was poured into 100 ml of anhydrous petroleum ether to form a precipitate. The powder collected in a glass filter was dissolved in 100 ml of anhydrous benzene at room temperature, reprecipitated again in 100 ml of petroleum ether, and the precipitate was collected in a glass filter. This reprecipitation operation is repeated once more, and the powder obtained by drying under reduced pressure at room temperature for 24 hours does not contain cyanuric chloride as a raw material, other low molecular weight impurities, and compounds substituted with two or more monomethoxypolyethylene glycols. This was confirmed by gel permeation chromatography (solvent: chloroform).

When the obtained powder was analyzed for chlorine using a conventional method,
It was only 0.29×10 ⁻⁴ mol/gr (theoretical value as 2-0-methoxypolyethylene glycol-4,6-dichloro-S-triazine 4×10 ⁻⁴ mol/g).

The initial moisture content in this reaction system was confirmed to be 5 ppm using a Karl-Fisscher moisture meter.

Comparative Example 2 After carrying out the same reaction as in Comparative Example 1 for 38.5 hours,
When the powder obtained through the same reprecipitation purification was subjected to chlorine analysis, it was found to be 0.44×10 ⁻⁴ mol/g.

Comparative Example 3 After carrying out the reaction of Comparative Example 1 for 64 hours, the chlorine analysis value of the powder obtained through the same reprecipitation purification was 1.18×
It was 10 ^-4 mol/g.

Comparative Example 4 Monomethoxypolyethylene glycol (molecular weight 5000) as a polyalkylene glycol derivative
The chlorine analysis value of the powder obtained by the same reaction and purification operations as in Comparative Example 1 except that monoethoxy polypropylene glycol (molecular weight 2000) was used instead of 0.98 x 10 ^-4 mol/g (2-0-ethoxy The theoretical value as polypropylene glycol-4,6-dichloro-S-triazine is 1×10 ⁻³ mol/g).

Example 1 The same reactions as in Comparative Examples 1, 2, and 3 were carried out by adding various amounts of water, and then the powder obtained through the same reprecipitation purification was analyzed for chlorine. The results are shown in FIG. 1 together with comparative examples, and it is clear that when 50 to 10,000 ppm of water is added, very good results can be obtained in terms of reaction rate and yield.

Example 2 The same reaction as in Comparative Example 4 was carried out in benzene containing 5000 ppm of water, and when the powder obtained through similar purification was analyzed for chlorine, a value of 1.01 × 10 ^-3 mol/g was obtained. . It can be seen that under these conditions, the desired 2-0-ethoxypolypropylene glycol-4,6-dichloro-S-triazine can be obtained with a yield of approximately 100%.

[Brief explanation of the drawing]

Figure 1 shows the moisture content and chlorine analysis values of the reprecipitated product.

Claims (1)

[Scope of Claims] 1. A halogen represented by the general formula () is produced by reacting a cyanuric halide with a polyalkylene glycol represented by the general formula () or a derivative thereof in an inert organic solvent in the presence of an acid acceptor. A method for producing a halogenated cyanuric derivative, characterized in that water is contained in the reaction solvent at a ratio of 50 to 10,000 ppm. General formula (): RO [(CH ₂ ) nO] mH General formula (): [In the above general formulas () and (), R represents hydrogen, an alkyl group, an aromatic group, an alkylcarbonyl group, an aromatic carbonyl group, an alkylaminocarbonyl group, or an aromatic aminocarbonyl group, and X represents fluorine and Indicates a member selected from the group consisting of chlorine, m indicates a number of 30 or more on average,
n represents an integer of 2 to 4. ]