JP2008214473A - Triazine chloride derivative, its production method and its use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid condensing agent inducing dehydration condensation reaction in an aqueous solution in a high yield. <P>SOLUTION: A solid triazine chloride derivative is obtained by reacting a bis-triazine chloride derivative with a hydrophilic compound, provided that the hydrophilic compound is at least one compound chosen from the group consisting of methanol, taurine, 2-(aminoethyl)trimethyl ammonium chloride and a mixture of taurine and 2-(aminoethyl)trimethyl ammonium. In a production method of the solid triazine chloride derivative, bis-triazine chloride derivative and at least one compound chosen from the group of hydrophilic compounds are used. The solid triazine chloride derivative is used as a hydrophilic condensing agent in an aqueous solution in the presence of N-methylmorpholine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a triazine chloride derivative, a process for its production and its use. More specifically, the present invention relates to a novel triazine chloride derivative that acts as a condensing agent useful in an amide bond formation reaction in an aqueous solution in combination with N-methylmorpholine and a method for producing the same.

  Conventionally, a condensing agent well known to those skilled in the art, such as a carbodiimide derivative, is used as a dehydrating condensing agent for forming an amide bond by condensation of a carboxy group and an amino group in peptide synthesis. In such a condensation reaction, an excessive condensing agent is usually used.

  However, in the solution reaction using the condensing agent as described above, even if the condensation reaction proceeds quantitatively, in order to isolate the target compound, an excess condensing agent or the condensing agent after the reaction and the target compound are used. It is necessary to separate and purify.

  For such separation and purification of the target compound, a purification method in which operations such as column chromatography, liquid high-performance chromatography, distillation or recrystallization are complicated is usually used.

  Usually, the separation / purification after the above condensation reaction requires more time, labor and solvent than the reaction requires.

  In recent years, a morpholinium salt which is a reaction product of 2,4,6-trichloro-1,3,5-triazine (hereinafter also referred to as triazine chloride) and N-methylmorpholine (hereinafter also referred to as NMM) has been converted to a carboxy group. It has been found that it reacts with to form activated esters and promotes the formation of peptide bonds with amino groups (eg, Non-Patent Document 1).

  Further, 4- (4,6-dimethoxy-1) obtained by reacting 2-chloro-4,6-dimethoxy-1,3,5-triazine with N-methylmorpholine as a new type of dehydrating condensing agent. , 3,5-triazin-2-yl) -4-methylmorpholinio chloride (hereinafter also referred to as DMT-MM) can be used not only in non-aqueous organic solvents such as methylene chloride or ethyl acetate, but also in methanol or ethanol. It has also been found that the amide bond formation reaction is accelerated in a high yield in such alcohols or aqueous alcohols, and even in aqueous solutions (eg, Non-Patent Documents 2 and 3).

  On the other hand, in recent years, various insoluble polymer (solid) -supported reagents for reaction have been developed for use in solid-liquid reactions in order to eliminate the complicated purification method after the reaction as described above (for example, non-patents). Document 4), a solid-supported condensation reaction reagent in which triazine chloride is bound to polystyrene-polyethylene glycol resin has also been reported (for example, Non-Patent Document 5).

  Recently, 2,4,6-trichloro-1,3,5-triazine was reacted with tetraethylene glycol to produce tetraethylenebis (4,6-dichloro-1,3,5-triazin-2-yl. ) Ether, and tris (2-aminoethyl) amine is further reacted therewith, and a triazine chloride polymer or an N-methylmorpholine adduct thereof is also reported as a solid composite reactant (for example, Non-Patent Document 6). And Patent Document 1).

  These insoluble polymer-supported reagents for reaction have the feature that the target substance can be easily separated from the solid-supported reagent by extraction or washing with a solvent after the reaction, so that a robotic automatic synthesis system or combinatorial In chemistry, its use is expanding dramatically.

Z.J.Kaminski et al., J. Org. Chem., 1998, 63, 4248 M. Kunishima et al., Tetrahedron, 55 (1999), 13159-13170 M. Kunishima et al., Tetrahedron, 57 (2001), 1551-1558 Andreas Kirschning et al., Angew. Chem. Int. Ed., 2001, 40, 650-679 S. Masala et al., Organic Letters, 1999, 1 (9), 1355-1357 M. Kunishima et al., Chem. Commun., 2698 (2005) JP-A-2005-255672

However, conventionally developed solid-supported reagents are produced by a reaction between a solid that is insoluble in a solvent and a reagent, so that the efficiency of introducing a reagent into the solid is poor and a decrease in reaction yield is prevented. However, an excessive amount of reagent is used in the reaction, and there is a problem that after the reaction, purification such as removal of the remaining excessive reagent is necessary.
Furthermore, the conventional triazine type polymer has a problem in the yield of the dehydration condensation reaction in an aqueous solution.

  An object of the present invention is to provide a solid condensing agent that can perform a dehydration condensation reaction in an aqueous solution with a high yield and can easily separate a reaction product from the condensing agent after the reaction. More specifically, as described above, an object is to provide a solid condensing agent without binding the condensing agent to an already polymerized resin or solid.

  The present invention solves the above problems by a solid triazine chloride derivative obtained by reacting a bischloride triazine derivative, tris (2-aminoethyl) amine, and a hydrophilic compound.

［式中、Ｒ₁はテトラエチレングリコジオキシ基を表す］
で表されるビス塩化トリアジン誘導体と、トリス（２-アミノエチル）アミンと、メタノール、ブチルアミン、タウリンおよび塩化２-（アミノエチル）トリメチルアンモニウムからなる群から選択される１以上の親水性化合物とを反応させて得られる、一般式（１）： That is, according to the present invention, the following formula (1 ′):

[Wherein R ₁ represents a tetraethyleneglycodioxy group]
A tris (2-aminoethyl) amine represented by the formula: one or more hydrophilic compounds selected from the group consisting of methanol, butylamine, taurine and 2- (aminoethyl) trimethylammonium chloride General formula (1) obtained by reaction:

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂はエチレン基を表し、Ｒはメトキシ基、ｎ-ブチルアミノ基、２-スルホエチルアミノ基、塩化２-トリメチルアンモニオエチルアミノ基を表すかまたはＲは同一分子内で独立して２-スルホエチルアミノ基もしくは塩化２-トリメチルアンモニオエチルアミノ基を表し、ａは１〜１００００を表し、ｂは０〜１００００の整数を表す］
で表される、固体の塩化トリアジン誘導体が提供される。

[Wherein R ₁ is as defined in formula (1 ′), R ₂ represents an ethylene group, R is a methoxy group, an n-butylamino group, a 2-sulfoethylamino group, a 2-trimethylammonium chloride. O represents an ethyl group or R independently represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride group in the same molecule, a represents 1 to 10,000, and b represents 0 to 10,000. Represents an integer]
A solid triazine chloride derivative represented by:

  According to the present invention, there is provided a solid triazine chloride derivative capable of condensing a carboxylic acid compound and an amine compound in a high yield in an aqueous solution in the presence of N-methylmorpholine and easily separated after the reaction. .

  More specifically, since the solid triazine chloride derivative of the present invention can be produced by a solution reaction, the yield is high, the production is easy, and the raw material is a general compound, so that the production cost is kept low. Can do. Furthermore, if the solid triazine chloride derivative according to the present invention is used for the amide bond forming reaction, it can be condensed in a high yield, and after the reaction, it can be simply filtered and treated according to a known method. There is an advantage that the amide compound can be easily separated from the product and can be obtained in a high yield.

  Therefore, the solid triazine chloride derivative according to the present invention is particularly useful as a condensing agent in the amide formation reaction.

  A bis (triaminochloride) derivative according to the present invention, tris (2-aminoethyl) amine, and one or more hydrophilic compounds selected from the group consisting of methanol, butylamine, taurine and 2- (aminoethyl) trimethylammonium chloride. As a result of considering the reaction, the solid triazine derivative obtained by the reaction is considered to be represented by the structural formula of the above general formula (1), for example.

In the above general formula (1), a and b are mainly determined by the amounts of the bischloride triazine derivative, tris (2-aminoethyl) amine, and the hydrophilic compound used for the preparation of the solid triazine chloride. However, it is considered that a can be in the range of 1 to 10,000, and b can be in the range of 0 to 10,000. In addition, when b is 0, it means that the main chain is a linear polymer. When b is a number of 1 or more, the main chain is considered to be a mixture of a linear polymer and a branched polymer, and a polymer called a so-called star polymer. It is done.
In the present invention, the solid chloride triazine derivatives represented by the formulas (2) to (6) are similarly represented by partial estimated structural formulas.

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂、ａおよびｂは式（１）で定義したとおりである］
で表される固体の塩化トリアジン誘導体が提供される。 More specifically, according to the present invention, the hydrophilic compound is methanol, formula (2):

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
A solid triazine chloride derivative represented by the formula:

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂、ａおよびｂは式（１）で定義したとおりである］
で表される固体の塩化トリアジン誘導体が提供される。 Moreover, according to the present invention, the hydrophilic compound is n-butylamine.

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
A solid triazine chloride derivative represented by the formula:

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂、ａおよびｂは式（１）で定義したとおりである］
で表される固体の塩化トリアジン誘導体が提供される。 Moreover, according to the present invention, the hydrophilic compound is taurine (4):

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
A solid triazine chloride derivative represented by the formula:

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂、ａおよびｂはおよび式（１）で定義したとおりである］
で表される記載の固体の塩化トリアジン誘導体が提供される。 Also according to the present invention, the hydrophilic compound is 2- (aminoethyl) trimethylammonium chloride, formula (5):

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in and formula (1)]
A solid triazine chloride derivative as described above is provided.

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂、ａおよびｂは式（１）で定義したとおりであり、Ｒ'は同一分子内の互いに異なる位置では互いに独立して２-スルホエチルアミノ基または塩化２-トリメチルアンモニオエチルアミノ基を表す］
で表される固体の塩化トリアジン誘導体が提供される。 Also according to the present invention, the hydrophilic compound is a mixture of taurine and 2- (aminoethyl) trimethylammonium chloride.

[Wherein R ₁ is as defined in formula (1 ′), R ₂ , a and b are as defined in formula (1), and R ′ is independent from each other at different positions in the same molecule. Represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride chloride]
A solid triazine chloride derivative represented by the formula:

［式中、Ｒ₁はテトラエチレングリコジオキシ基を表す］
で表されるビス塩化トリアジン誘導体と、トリス（２-アミノエチル）アミンと、メタノール、ブチルアミン、タウリンおよび塩化２-（アミノエチル）トリメチルアンモニウムからなる群から選択される１以上の親水性化合物とを用いることを特徴とする、一般式（１）： Furthermore, according to the present invention, the following formula (1 ′):

[Wherein R ₁ represents a tetraethyleneglycodioxy group]
A tris (2-aminoethyl) amine represented by the formula: one or more hydrophilic compounds selected from the group consisting of methanol, butylamine, taurine and 2- (aminoethyl) trimethylammonium chloride General formula (1) characterized in that it is used:

［式中、Ｒ₁は式（１'）で定義したとおりであり、Ｒ₂はエチレン基を表し、Ｒはメトキシ基、ｎ-ブチルアミノ基、２-スルホエチルアミノ基、塩化２-トリメチルアンモニオエチルアミノ基を表すかまたはＲは同一分子内で独立して２-スルホエチルアミノ基もしくは塩化２-トリメチルアンモニオエチルアミノ基を表し、ａは１〜１００００を表し、ｂは０〜１００００の整数を表す］
で表される、固体の塩化トリアジン誘導体の製造方法が提供される。

[Wherein R ₁ is as defined in formula (1 ′), R ₂ represents an ethylene group, R is a methoxy group, an n-butylamino group, a 2-sulfoethylamino group, a 2-trimethylammonium chloride. O represents an ethyl group or R independently represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride group in the same molecule, a represents 1 to 10,000, and b represents 0 to 10,000. Represents an integer]
A method for producing a solid triazine chloride derivative represented by the formula:

［式中、Ｒ₁はテトラエチレングリコジオキシ基を表す］
で表されるビス塩化トリアジン誘導体(テトラエチレングリコールビス(４,６-ジクロロ-１,３,５-トリアジン-２-イル))は、２,４,６-トリクロロ-１,３,５-トリアジンとテトラエチレングリコールから、例えば前記特許文献１に記載の公知の方法に従って調製できる。 Formula (1 ′) used for the production of solid chloride triazine derivatives according to the invention:

[Wherein R ₁ represents a tetraethyleneglycodioxy group]
The bischloride triazine derivative represented by the formula (tetraethylene glycol bis (4,6-dichloro-1,3,5-triazin-2-yl)) is 2,4,6-trichloro-1,3,5-triazine And tetraethylene glycol, for example, according to a known method described in Patent Document 1.

Therefore, the term “tetraethyleneglycodioxy group” used in the present invention means a group — (OCH ₂ CH ₂ ) ₄ O—.

  Examples of the hydrophilic compound used in the production of the solid triazine chloride derivative according to the present invention include methanol, ethanol, n-propanol, methylamine, ethylamine, n-propylamine, n-butylamine, taurine and 2- (aminoethyl) chloride. Examples include trimethylammonium. Of these, methanol, n-butylamine, taurine, 2- (aminoethyl) trimethylammonium chloride, and the like are more preferable from the viewpoint of ease of operation and yield.

  Each of the above hydrophilic compounds can be used alone, but can also be used as a mixture thereof.

  The hydrophilic compound is in an amount of 1 mol% to 75 mol%, preferably 5 mol% to 50 mol%, based on the bischlorinated triazine derivative represented by the formula (1 ′). Preferably used.

  When the amount of the hydrophilic compound used relative to the bischloride triazine derivative is 1 mol% or less, amide bond formation by a condensation reaction in an aqueous solution using the solid chloride triazine derivative according to the present invention and N-methylmorpholine is used. This is because, in the reaction, the solid chloride triazine derivative has low hydrophilicity, so that the yield of the condensation reaction is lowered.

  Conversely, when the amount of the hydrophilic compound used relative to the bischloride triazine derivative is 75 mol% or more, it is considered that the solid chloride triazine derivative molecular weight according to the present invention is reduced, that is, the degree of polymerization is reduced. This is because the yield of the solid triazine chloride derivative decreases.

  The compound represented by the general formula (1) or the formulas (2) to (6) includes a bischlorinated triazine derivative represented by the formula (1 ′), tris (2-aminoethyl) amine, and the hydrophilic It can be obtained by reacting any one of the sex compounds or a mixture thereof.

This reaction is usually carried out in a solvent in the presence of a base at room temperature.
Examples of the solvent used in the above reaction include water, tetrahydrofuran (THF), dioxane, or a mixture thereof.

As the base used in the above reaction, NaHCO ₃ , KaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , N-ethyldiisopropylamine, triethylamine, or the like can be used.

That is, the compound represented by the general formula (1) or the formulas (2) to (6) is, for example, an aqueous solution obtained by dissolving NaHCO ₃ , tris (2-aminoethyl) amine and the hydrophilic compound in water, To this aqueous solution, a tetrahydrofuran solution of the bischloride triazine derivative is added at room temperature with stirring, and when the stirring is continued, a polymer (solid triazine derivative) as a reaction product is precipitated.

In the case where the above polymer is difficult to precipitate, it is possible to promote the precipitation of the polymer by adding water, THF, methanol or the like to the reaction mixture as necessary after the completion of the reaction.
The precipitated polymer is collected by filtration according to a conventional method, washed, vacuum dried or suspended in water and freeze-dried.

  The solid triazine chloride derivative according to the present invention can be used as a condensing agent in a condensation reaction of a carboxy group and an amino group in an aqueous solution in combination with N-methylmorpholine (for a detailed reaction mechanism, for example, non-patent literature). 2-6).

  Examples of the solvent used in these condensation reactions include methylene chloride, tetrahydrofuran, methanol, ethanol, ethyl acetate, acetonitrile, and water. The solid triazine derivative according to the present invention can produce an amide compound in a high yield even in an aqueous solution. Producing is a feature of the present invention.

  The amidation reaction in which the solid triazine derivative according to the present invention is used to condense a carboxy group and an amino group in the presence of N-methylmorpholine usually proceeds with stirring at room temperature.

  Therefore, the solid triazine chloride according to the present invention can be suitably used as a hydrophilic condensing agent for amidation reaction in an aqueous solution in the presence of N-methylmorpholine.

The following examples illustrate the invention and do not limit the invention.
In the examples, the following measuring devices and reagents were used unless otherwise specified.

Infrared absorption measuring device: manufactured by Nicolet, FT-IR AVATER360
NMR spectrometer: Bruker, DPX400 spectrometer Potentiometric titrator: Metrohm, Metrohm 794 Basic Titrino
Tris (2-aminoethyl) amine (manufactured by Kanto Chemical Co., Inc.)
Tetraethylene glycol (manufactured by Kanto Chemical Co., Inc.)
2,4,6-trichloro-1,3,5-triazine (manufactured by Kanto Chemical Co., Inc.)
In addition, about the reagent which can be obtained easily as a commercial item, the description to the above was omitted.

Production Example 1
Preparation of bis chloride triazine derivative Sodium hydride (60% oil dispersion; 9.11 g, substantial amount 5.74 g, 228 mmol) washed with anhydrous tetrahydrofuran (THF) in anhydrous THF (40 ml) under nitrogen atmosphere Tetraethylene glycol (23.2 g, 119 mmol) was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 1 hour. The resulting reaction mixture was cooled to −78 ° C., and a solution of 2,4,6-trichloro-1,3,5-triazine (20.0 g, 109 mmol) in anhydrous THF (70 ml) was added dropwise.

  Next, the mixture was stirred at −78 ° C., −40 ° C., 0 ° C. and room temperature for 1 hour, respectively, and then dry diethylene glycol dimethyl ether (4 ml) was added. The mixture was stirred at 50 ° C. for 1 hour, then heated to 125 ° C. to distill off THF, and stirring was continued at the same temperature for 16 hours. After completion of the reaction, the reaction mixture was cooled to 0 ° C. and allowed to stand for 30 minutes, and then the solid compound was collected by suction filtration and washed successively with THF, water, and THF. The filtered product was dried under reduced pressure to obtain 14.8 g of a cream-colored target bischloride triazine derivative (tetraethylene glycol bis (4,6-dichloro-1,3,5-triazin-2-yl)) in a yield of 45%. Got in. The IR spectrum of the obtained compound was completely consistent with that of the standard product.

Example 1
Preparation of solid chloride triazine derivative (OMe50) using 50 mol% methanol to bis chloride triazine derivative diisopropylethylamine (2.64 g, 2.0 eq), tris (2-aminoethyl) amine (746 mg, 0.5 eq), Methanol (163 mg, 0.5 eq) was dissolved in THF (5 mL) and added dropwise at −78 ° C. to a solution of the bischlorinated triazine derivative (5.0 g, 1.0 eq) obtained in Production Example 1 in THF (10 mL). After completion of dropping, the dry ice bath was removed and the mixture was stirred for 2 hours. During this time, the reaction solution reached room temperature in about 1 hour.

About 20 mL of methanol was added to this reaction solution, and the mixture was stirred at 35 to 40 ° C. After 15 hours, the polymer was filtered, washed in order of THF, water and THF, dried under reduced pressure, and solid triazine chloride as a polymer compound having 50 mol% of methoxy groups in the molecule with respect to the bischloride triazine. The derivative (OMe50) 3.16 g was obtained with a yield of 61%.
IR (KBr): ν = 3265, 2873, 1559, 1429, 1333, 1288, 1115, 1055, 806 cm ⁻¹ .

Measurement of Chlorine Value of Individual Triazine Chloride Derivatives A dried polymer (20 mg) was precisely weighed, 1 M NaNO ₃ (2 mL) was added, and the polymer was washed by shaking for 20 minutes and filtered. 0.2 M N-methylmorpholine aqueous solution (2 mL) was added to the polymer, and the mixture was shaken and stirred. After 20 minutes, 1 M NaNO ₃ (3 mL) was further added and the stirring was continued. After 24 hours, it was filtered, and the polymer was washed and filtered with 1 M NaNO ₃ (2 mL) and water (5 mL × 3), respectively. All the filtrates were combined, and potentiometric titration with 0.01 M AgNO ₃ aqueous solution. Titration using the instrument.
From the amount of AgNO ₃ aqueous solution required for titration, the following formula:
Chlorine number (mmol / g) = AgNO ₃ (mL) × 0.01 × 1.005 (f) / Polymer (g)
The chlorine value was determined to be 3.031 mmol / g (average of 2 times).

Measurement of swelling rate
Set the filter on the 2.5 mL syringe outer tube, put the dried polymer obtained in Example 1 (about 0.5 mL), and tap lightly to pack. The internal volume is read from the scale of the syringe and is defined as a dry volume V ₀ . Pass water through the syringe to remove air bubbles, and leave it for 12 hours with water stored up to the top of the syringe. The volume after standing is V ₁ and the following formula:
Swell ratio (%) = (V ₁ -V ₀ ) / V ₀ × 100
When the volume increase fraction with respect to the volume at the time of drying calculated | required as a swelling rate was measured, the swelling rate of OME50 was 38%.

  For the solid triazine chloride derivatives obtained in the following examples, the chlorine value and the swelling rate were determined in the same manner.

Example 2
Preparation of solid chloride triazine derivative (OMe30) using 30 mol% methanol relative to bis chloride triazine derivative Diisopropylethylamine (1.58 g, 2.0 eq), Tris (2-aminoethyl) amine (506 mg, 0.57 eq), Methanol (59 mg, 0.3 eq) was dissolved in THF (4 mL) and added dropwise at −78 ° C. to a solution of the bischloride triazine derivative (3.0 g, 1.0 eq) obtained in Preparation Example 1 in THF (8 mL). After completion of dropping, the dry ice bath was removed and the mixture was stirred for 2 hours. During this time, the reaction solution reached room temperature in about 1 hour. About 10 mL of methanol was added and stirred at 35-40 ° C. After 15 hours, the polymer was filtered, washed with THF, water and THF in that order, dried under reduced pressure, and a solid triazine chloride derivative which was a polymer compound having 30 mol% of methoxy groups in the molecule with respect to the bischloride triazine. (OMe30) 1.60 g was obtained with a yield of 51%.

Chlorine value = 1.917 mmol / g (average of 2 times).
IR (KBr): ν = 3270, 2873, 1570, 1430, 1333, 1289, 1125, 1062, 807 cm ^-1

Example 3
Preparation of solid chloride triazine derivative (OMe10) using 10 mol% methanol relative to bis chloride triazine derivative Diisopropylethylamine (1.58 g, 2.0 eq), Tris (2-aminoethyl) amine (564 mg, 0.63 eq), Methanol (20 mg, 0.1 equivalent) was dissolved in THF (4 mL), and added dropwise at −78 ° C. to a solution of the bischloride triazine derivative (3.0 g, 1.0 equivalent) obtained in Preparation Example 1 in THF (8 mL). After completion of dropping, the dry ice bath was removed and the mixture was stirred for 2 hours. During this time, the reaction solution reached room temperature in about 1 hour. About 10 mL of methanol was added and stirred at 35-40 ° C. After 15 hours, the polymer was filtered, washed with THF, water, and THF in that order, dried under reduced pressure, and a solid triazine chloride derivative that was a polymer compound having 10 mol% of methoxy groups in the molecule with respect to the bischloride triazine. (OMe10) 1.50 g was obtained with a yield of 48%.

Chlorine value = 2.381 mmol / g (average of 2 times).
IR (KBr): ν = 3274, 2872, 1578, 1429, 1334, 1289, 1125, 1057, 806 cm ^-1

Example 4
Preparation of solid chloride triazine derivative (Bu50) using 50 mol% n-butylamine based on bis chloride triazine derivative Diisopropylethylamine (1.05 g, 2.0 eq), Tris (2-aminoethyl) amine (298 mg, 0.5 eq) ), Butylamine (149 mg, 0.5 eq) dissolved in THF (4 mL) and tetraethylene glycol bis (4,6-dichloro-1,3,5-triazin-2-yl) ether (5.0 g, 1.0 eq) ) In THF (4 mL) at -78 ° C. After stirring at -78 ° C for 30 minutes, dry ice was removed from the refrigerant, and the temperature was gradually raised to room temperature. After 24 hours, the precipitated polymer is filtered, washed in order of THF, water, and THF, dried under reduced pressure, and a polymer compound having 50 mol% of n-butylamino group in the molecule with respect to the bischloride triazine. 686 mg of a solid triazine chloride derivative (Bu50) was obtained with a yield of 32%.

Chlorine value = 3.101 mmol / g (average of 2 times).
IR (KBr): ν = 2868, 1596, 1457, 1420, 1333, 1288, 1120, 1059, 978, 939, 873, 807 cm ^-1

Example 5
Preparation of solid triazine chloride derivative (T5) using 5 mol% taurine with respect to bis chloride triazine derivative
NaHCO ₃ (3.47 g, 4.1 eq), tris (2-aminoethyl) amine (970 mg, 0.65 eq), taurine (64 mg, 0.05 eq) were dissolved in water (15 mL) and obtained in Preparation Example 1. A solution of bis-triazine chloride derivative (5.0 g, 1.0 eq) in THF (10 mL) was added at room temperature and stirred vigorously. About 40 minutes later, water (5 mL) was added when the reaction solution became muddy due to the precipitated polymer. After 1.5 hours from the start, since the polymer became a jelly-like mass, THF (10 mL) was added, and the mixture was crushed into granules of about 2 mm with strong stirring and a spatula, and further stirred. After 5 hours from the start, THF (10 mL) is added, and after stirring for 30 minutes, the solution is poured into a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), lyophilized, and 5 mol% of the bistriazine chloride in the molecule. 3.44 g of a solid triazine chloride derivative (T5) which is a polymer compound having a 2-sulfoethylamino group was obtained in a yield of 65%.

Chlorine value = 3.364 mmol / g (average of 2 times).
Swelling rate (T5): Water, 50%
IR (KBr): ν = 2919, 2846, 1629, 1560, 1541, 1456, 1335, 1221, 1128, 1097, 1053, 807 cm ^-1 .

Example 6
Preparation of solid triazine chloride derivative (T30) using 30 mol% taurine with respect to bis chloride triazine derivative
NaHCO ₃ (1.47 g, 4.3 eq), tris (2-aminoethyl) amine (337 mg, 0.57 eq), taurine (153 mg, 0.3 eq) were dissolved in water (8 mL) and obtained in Preparation Example 1. A solution of a bischloride triazine derivative (2.0 g, 1.0 equivalent) in THF (4 mL) was added at room temperature, and the mixture was vigorously stirred. After about 4 hours, the reaction solution was poured into THF (100 mL), stirred for several minutes, and then methanol (200 mL) was added. The precipitated polymer was filtered, washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), lyophilized, and 30 mol of bistriazine chloride in the molecule. % 1.98 g of a solid triazine derivative (T30), which is a polymer compound having 2-sulfoethylamino group, was obtained in a yield of 89%.

Chlorine value: 2.851 mmol / g (average of 2 times).
Swell rate: water, 100%.

Example 7
Preparation of solid chloride triazine derivative (T50) using 50 mol% taurine with respect to bis chloride triazine derivative
NaHCO ₃ (1.54 g, 4.5 eq), tris (2-aminoethyl) amine (298 mg, 0.5 eq), taurine (255 mg, 0.5 eq) were dissolved in water (8 mL) and obtained in Preparation Example 1. A solution of a bischloride triazine derivative (2.0 g, 1.0 equivalent) in THF (4 mL) was added at room temperature, and the mixture was vigorously stirred. After about 1 hour, water (8 mL) and THF (12 mL) were added, and the mixture was crushed into particles of about 2 mm with a spatula and stirred for another 1 hour. Pour the reaction mixture into THF (100 mL), add methanol (200 mL) to precipitate the polymer and filter. The polymer was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), lyophilized, and 50 mol% of methoxy groups in the molecule were added to the bischloride triazine. As a result, 1.82 g of a solid triazine derivative (OMe50) as a polymer compound having a yield of 79% was obtained.

Chlorine number: 3.432 mmol / g (average of 2 times).
Swell rate: water, 100%.

Example 8
Preparation of solid triazine chloride derivative (N10) using 10 mol% 2- (aminoethyl) trimethylammonium chloride based on bis chloride triazine derivative
NaHCO ₃ (2.31 g, 4.5 eq), tris (2-aminoethyl) amine (564 mg, 0.63 eq), 2- (aminoethyl) trimethylammonium chloride hydrochloride (107 mg, 0.1 eq), water (9 mL) ), A solution of the bischloride triazine derivative (3.0 g, 1.0 equivalent) obtained in Production Example 1 in THF (6 mL) was added at room temperature, and the mixture was vigorously stirred. Water (3 mL) was added after about 15 minutes and 1 hour, respectively. After 2.5 hours from the start, the reaction mixture is poured through a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), freeze-dried, and 50 mol% of the bistriazine chloride in the molecule. As a polymer compound having a methoxy group, 2.93 g of a solid triazine chloride derivative (N10) was obtained with a yield of 91%.

Chlorine value = 4.226 mmol / g (average of 2 times).
Swelling ratio: water, 67%.

Example 9
Preparation of solid triazine derivative (N50) using 50 mol% 2- (aminoethyl) trimethylammonium chloride to bistriazine chloride derivative
NaHCO ₃ (2.31 g, 4.5 eq), tris (2-aminoethyl) amine (448 mg, 0.5 eq), 2- (aminoethyl) trimethylammonium chloride hydrochloride (536 mg, 0.5 eq), water (9 mL ), A solution of the bischloride triazine derivative (3.0 g, 1.0 equivalent) obtained in Production Example 1 in THF (6 mL) was added at room temperature, and the mixture was vigorously stirred. Water (3 mL) was added after about 15 minutes and 1 hour, respectively. After 3 hours from the start, the reaction mixture is poured through a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), freeze-dried, and 50 mol% of the bistriazine chloride in the molecule. 2.32 g of a solid triazine chloride derivative (OMe50) which is a polymer compound having a methoxy group was obtained in a yield of 66%.

Chlorine value = 4.280 mmol / g (average of 2 times).
Swelling ratio: water, 50%

Example 10
Preparation of solid triazine chloride derivative (TN10) using 5 mol% taurine and 5 mol% 2- (aminoethyl) trimethylammonium chloride for the bischloride triazine derivative
NaHCO ₃ (3.86 g, 4.5 eq), tris (2-aminoethyl) amine (940 mg, 0.63 eq), 2- (aminoethyl) trimethylammonium chloride hydrochloride (89 mg, 0.05 eq), taurine (64 mg, 0.05 equivalent) was dissolved in water (15 mL), a solution of the bischloride triazine derivative (5.0 g, 1.0 equivalent) obtained in Production Example 1 in THF (10 mL) was added at room temperature, and the mixture was vigorously stirred. After 1 hour, water (10 mL) and THF (10 mL) were added, and further 10 minutes later, water (10 mL) was added. After 1.5 hours from the start, the reaction mixture is poured through a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), freeze-dried, and 5 mol% 2 in the molecule with respect to the bischloride triazine. 4.46 g of a solid triazine chloride derivative (TN10) which is a polymer compound having -sulfoethylamino group and 5 mol% 2-trimethylammonioethylamino group was obtained in a yield of 84%.

Chlorine value = 2.661 mmol / g (average of 2 times).
Swelling ratio: water, 78%.

Example 11
Preparation of solid triazine chloride derivative (TN30) using 15 mol% taurine and 15 mol% 2- (aminoethyl) trimethylammonium chloride for the bischloride triazine derivative
NaHCO ₃ (3.86 g, 4.5 eq), tris (2-aminoethyl) amine (843 mg, 0.57 eq), 2- (aminoethyl) trimethylammonium chloride hydrochloride (268 mg, 0.15 eq), taurine (192 mg, 0.15 equivalent) was dissolved in water (15 mL), and a solution of the bischloride triazine derivative (5.0 g, 1.0 equivalent) obtained in Production Example 1 in THF (15 mL) was added at room temperature, followed by vigorous stirring. After 1.5 hours, when the reaction solution became muddy with the precipitated polymer, water (10 mL) and THF (5 mL) were added. Two hours after the start, it became a granule of about 2 to 3 mm by vigorous stirring. 3 hours after the start, THF (10 mL) is added, and after stirring for 30 minutes, the solution is poured into a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), freeze-dried, and 5 mol% 2 in the molecule with respect to the bischloride triazine. 4.89 g of a solid triazine derivative (TN30), which is a polymer compound having a -sulfoethylamino group and a 5-mol% 2-trimethylammonioethylamino group, was obtained in a yield of 88%.

Chlorine value = 2.033 mmol / g (average of 2 times).
Swelling rate: water, 50%.

Example 12
Preparation of solid triazine chloride derivative (TN50) using 25 mol% taurine and 25 mol% 2- (aminoethyl) trimethylammonium chloride for bischloride triazine derivative
NaHCO ₃ (3.86 g, 4.5 eq), tris (2-aminoethyl) amine (746 mg, 0.5 eq), 2- (aminoethyl) trimethylammonium chloride hydrochloride (447 mg, 0.25 eq), taurine (319 mg, (0.25 equivalent) was dissolved in water (15 mL), a solution of the bischloride triazine derivative (5.0 g, 1.0 equivalent) obtained in Preparation Example 1 in THF (15 mL) was added at room temperature, and the mixture was vigorously stirred. After 1.5 hours, when the reaction solution became muddy with the precipitated polymer, water (10 mL) and THF (5 mL) were added. Two hours after the start, it became a granule of about 2 to 3 mm by vigorous stirring. 3 hours after the start, THF (10 mL) is added, and after stirring for 30 minutes, the solution is poured into a sieve (200 mesh: 75 μm) and filtered. The polymer on the sieve was washed with THF, water, 1 M NaNO ₃ aqueous solution and water in this order, suspended in water (50 mL), lyophilized, and 25 mol% 2 in the molecule with respect to the bischloride triazine. A solid triazine derivative (TN50) (3.22 g), which is a polymer compound having a -sulfoethylamino group and a 25 mol% 2-trimethylammonioethylamino group, was obtained in a yield of 58%.

Chlorine value = 3.315 mmol / g (2 times average value).
Swelling rate: water, 50%.

Test example 1
Amidation reaction in aqueous solution using solid triazine chloride derivative (OMe50)

4-Polysulfobenzoic acid monopotassium (10 mg, 1.0 eq), ethylamine hydrochloride (6.8 mg, 2.0 eq) and N-methylmorpholine (NMM) (29.5 mg, 7.0 eq) in water (2.0 mL) In addition to the reagent (solid triazine chloride derivative) (10.0 equivalents; calculated from the chlorine value of the polymer), the mixture was shaken and stirred at room temperature for 12 hours. The reaction solution was filtered, combined with the filtrate obtained by washing the polymer with 1 M NaNO ₃ (2 mL), 1 MK ₂ CO ₃ (2 mL), and water (5 mL × 2), and freeze-dried. Precisely weighed maleic acid was added as an internal standard substance to the residue, and the yield was calculated by NMR. The yield of the amidation reaction was 100%.

Test Examples 2-12
The yield of each amidation reaction was measured in the same manner as in Test Example 1 for each solid triazine derivative obtained in Examples 2-12. The results are shown in the following table.

2 is a schematic diagram showing the measurement of the swelling ratio of the solid triazine derivative (OMe50) obtained in Example 1. FIG. 2 is an IR spectrum of a triazine chloride derivative (OMe50) obtained in Example 1. 4 is an IR spectrum of a triazine chloride derivative (OMe30) obtained in Example 2. 4 is an IR spectrum of a triazine chloride derivative (OMe10) obtained in Example 3. 3 is an IR spectrum of a triazine chloride derivative (Bu50) obtained in Example 4. 3 is an IR spectrum of the triazine chloride derivative (T5) obtained in Example 5. 4 is an IR spectrum of the triazine chloride derivative (T30) obtained in Example 6.

4 is an IR spectrum of the triazine chloride derivative (T50) obtained in Example 7. 4 is an IR spectrum of a triazine chloride derivative (N10) obtained in Example 8. 4 is an IR spectrum of the triazine chloride derivative (N50) obtained in Example 9. 4 is an IR spectrum of the triazine chloride derivative (TN10) obtained in Example 10. 4 is an IR spectrum of the triazine chloride derivative (TN30) obtained in Example 11. 4 is an IR spectrum of a triazine chloride derivative (TN50) obtained in Example 12.

Claims (8)

The following formula (1 ′):

[Wherein R ₁ represents a tetraethyleneglycodioxy group]
A tris (2-aminoethyl) amine represented by the formula: one or more hydrophilic compounds selected from the group consisting of methanol, butylamine, taurine and 2- (aminoethyl) trimethylammonium chloride General formula (1) obtained by reaction:

[Wherein R ₁ is as defined in formula (1 ′), R ₂ represents an ethylene group, R is a methoxy group, an n-butylamino group, a 2-sulfoethylamino group, a 2-trimethylammonium chloride. O represents an ethyl group or R independently represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride group in the same molecule, a represents 1 to 10,000, and b represents 0 to 10,000. Represents an integer]
Solid triazine derivative represented by the formula: Formula (2), wherein the hydrophilic compound is methanol:

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
The solid triazine chloride derivative according to claim 1, represented by: Formula (3), wherein the hydrophilic compound is n-butylamine:

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
The solid triazine chloride derivative according to claim 1, represented by: Formula (4), wherein the hydrophilic compound is taurine:

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in formula (1)]
The solid triazine chloride derivative according to claim 1, represented by: Formula (5), wherein the hydrophilic compound is 2- (aminoethyl) trimethylammonium chloride:

[Wherein R ₁ is as defined in formula (1 ′) and R ₂ , a and b are as defined in and formula (1)]
The solid triazine chloride derivative according to claim 1, represented by: Formula (6), wherein the hydrophilic compound is a mixture of taurine and 2- (aminoethyl) trimethylammonium chloride.

[Wherein R ₁ is as defined in formula (1 ′), R ₂ , a and b are as defined in formula (1), and R ′ is independent from each other at different positions in the same molecule. Represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride chloride]
The solid triazine chloride derivative according to claim 1, represented by: The following formula (1 ′):

[Wherein R ₁ represents a tetraethyleneglycodioxy group]
A tris (2-aminoethyl) amine represented by the formula: one or more hydrophilic compounds selected from the group consisting of methanol, butylamine, taurine and 2- (aminoethyl) trimethylammonium chloride General formula (1) characterized in that it is used:

[Wherein R ₁ is as defined in formula (1 ′), R ₂ represents an ethylene group, R is a methoxy group, an n-butylamino group, a 2-sulfoethylamino group, a 2-trimethylammonium chloride. O represents an ethyl group or R independently represents a 2-sulfoethylamino group or a 2-trimethylammonioethylamino chloride group in the same molecule, a represents 1 to 10,000, and b represents 0 to 10,000. Represents an integer]
The manufacturing method of the solid chloride triazine derivative represented by these.   Use of the compound according to any one of claims 1 to 6 as a hydrophilic condensing agent in an aqueous solution in the presence of N-methylmorpholine.

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