KR100345464B1 - Method for preparing 2-(2'-chloroethylsulfonyl)ethylamine HCl salt - Google Patents

Abstract

The present invention relates to a method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride (2- (2'-chloroethylsulfonyl) ethylamine HCl salt) represented by the following Chemical Formula 1, specifically 2-aminoethyl sulfur As a method of preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Chemical Formula 1 by reacting an oxyhydrogen salt with 2-mercaptoethanol in the presence of an inorganic base and then simultaneously performing a chlorination and an oxidation reaction, the present invention According to the method, the reaction process can be shortened and high-purity 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride can be prepared with high yield, and the starting material is inexpensive and easy to supply so that it can be applied industrially usefully. Can be.

Description

Method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride {Method for preparing 2- (2'-chloroethylsulfonyl) ethylamine HCl salt}

The present invention relates to a method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride (2- (2'-chloroethylsulfonyl) ethylamine HCl salt) represented by the following Chemical Formula 1, specifically 2-aminoethyl sulfur The present invention relates to a method of preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Chemical Formula 1 by reacting an oxyhydrogen salt with 2-mercaptoethanol in the presence of an inorganic base and then simultaneously performing a chlorination and an oxidation reaction.

Formula 1

2- (2'-chloroethylsulfonyl) ethylamine hydrochloride represented by Chemical Formula 1 is a useful intermediate compound that is used as an additive reactor matrix in the preparation of reactive dyes. , Used in combination with a substituted reactor such as chlorotriazine, fluorotriazine or fluoropyrimidine to prepare heterodifunctional bifunctional reactive dyes (European Patent Nos. 70,806 and 70,807) as well as in combination with nicotinic acid (Japan Patent No. 03 247,664) or in combination with aromatic vinyl sulfone-based reactors (Japanese Patent No. 04 202,368 and European Patent No. 492,114), which are widely used to prepare reactive dyes.

Currently known methods for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride represented by the general formula (1) are known in US Pat. Nos. 2,785,190 and 2,824,887. This preparation method uses 2-chloroethylamine hydrochloride (2-chloroethyl-amine HCl salt) as a starting material and reacts with 2-mercaptoethanol in 95% aqueous ethanol solution to 2- (2'-hydride. 2- (2'-hydroxyethylmercapto) ethylamine was synthesized and reacted with thionyl chloride in a chloroform solvent to react with 2- (2'-chloroethyl mercapto) ethyl Synthesis of amine (2- (2'-chloroethylmercapto) ethylamine) to obtain 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula 1 using 40% peracetic acid (AcO ₂ H) in water It consists of

The method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Chemical Formula 1 uses relatively expensive 2-chloroethylamine hydrochloride as a starting material and it is difficult to use industrially to introduce chlorine groups. Since Oyl chloride is used and peracetic acid, which is a risk of explosion, is used as a raw material, there is a problem in industrializing the compound of Chemical Formula 1 in various aspects such as production cost and production facilities.

Accordingly, the present inventors have studied to solve the above problems, and as a starting material, 2- (2-aminoethyl hydrogensulfate), which is a much cheaper compound than 2-chloroethylamine hydrochloride, is used as a starting material. Synthesized oxyethyl mercapto) ethylamine, dissolved it in concentrated hydrochloric acid, and then chlorination and oxidation with chlorine gas to prepare high purity 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride in high yield. The present invention was found to be possible.

It is an object of the present invention to provide a process for the preparation of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride with a simple production process and high yield and purity.

In order to achieve the above object, the present invention provides a method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride represented by the following formula (1).

Formula 1

Method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula 1 according to the present invention is the reaction of 2-aminoethyl hydrogensulfate with 2-mercaptoethanol To synthesize 2- (2'-hydroxyethylmercapto) ethylamine, followed by chlorination and oxidation.

Hereinafter, the present invention will be described in detail.

The present invention provides a process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula (1) represented by Scheme 2.

Specifically, the preparation method of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Chemical Formula 1 according to the present invention is

1) 2-aminoethyl hydrogensulfate of Formula 2 and 2-mercaptoethanol of Formula 3 are reacted under an inorganic base in a solvent to form 2- (2'-hydroxy). Obtaining ethyl mercapto) ethylamine (2- (2'-hydroxyethyl-mercapto) ethylamine) (step 1); And

2) chlorination and oxidation of the compound of formula 4 obtained in step 1 to obtain 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride (2- (2'-chloroethylsufonyl) -ethylamine HCl salt) of formula 1 It consists of a step (step 2).

Step 1 is a step of reacting the 2-aminoethyl hydrogen sulfate of Formula 2 with 2-mercaptoethanol of Formula 3 in the presence of an inorganic base in a suitable solvent, to 1.0 mole of 2-mercaptoethanol of Formula 3 Preference is given to using 1.0-1.5 moles of 2-aminoethyl hydrogen sulfate. At this time, 2-aminoethyl hydrogen sulfate of the formula (2) can be easily purchased from a reagent company such as Aldrich or Acros (Acros), etc. as well as cheap and industrially easy to supply.

It is preferable to use NaOH, KOH, LiOH, Na ₂ CO ₃ , K ₂ CO _3, and the like for the inorganic base, and it is preferable to use 2.0-3.0 moles with respect to 1.0 mole of 2-mercaptoethanol of the formula (3).

Preferably, the reaction solvent is water or lower alcohol, and the lower alcohol is preferably 80-95% water-soluble methanol, ethanol or 2-propanol. It is preferable to use 300-350 mL of said solvent with respect to 1.0 mol of 2-mercaptoethanol.

In addition, the reaction temperature is preferably carried out in the range of 65-95 ^° C., preferably 10-24 hours.

The reaction mixture obtained by the reaction of step 1 may be cooled, and then the resulting inorganic salt may be filtered off and then distilled off only the reaction solvent of the filtrate without separation or purification such as recrystallization, distillation separation or silica gel chromatography. have.

Step 2 is a step of dissolving 2- (2'-hydroxyethylmercapto) ethylamine of Chemical Formula 4 produced in step 1 in concentrated hydrochloric acid and then performing chlorination and oxidation by passing chlorine gas.

In this case, it is preferable to use 30-35% concentrated hydrochloric acid as the reaction solvent, and the concentrated hydrochloric acid may be used in an amount of 300-400 mL based on 1.0 mole of 2- (2'-hydroxyethyl mercapto) ethylamine of the formula (4). desirable. The chlorine gas is preferably used 3.0-4.0 moles for the compound of formula (4). In addition, the chlorine gas is preferably passed over 1-4 hours and the reaction temperature is preferably maintained at 25-45 ^° C.

2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula 1 is preferably obtained as colorless crystals by cooling the reaction mixture of step 2 to 0-5 ° C and stirring for 5-12 hours by adding a lower alcohol. Do. At this time, it is preferable to use methanol, ethanol, 2-propanol, and the like as the lower alcohol.

The 2- (2'-hydroxyethylmercapto) ethylamine of Formula 4 obtained in step 1 was used as a reactant in step 2 without separating and purifying, but the compound was separated and purified in high yield as in High purity 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Formula 1 may be prepared.

In the present invention, the chlorination reaction of the hydroxyl group of 2- (2'-hydroxyethylmercapto) ethylamine of the general formula (4) uses thionyl chloride, which has limited industrial use, in an organic solvent such as chloroform or carbon dichloride. Instead of using a separate oxidizing agent to make the sulfido group into the sulfonic group in oxidized form, it is carried out together with the oxidation reaction using chlorine gas in concentrated hydrochloric acid, which greatly shortens the reaction time and reaction process than the conventional method, thereby reducing energy and manufacturing cost. Can reduce the cost.

In addition, the reaction process is simple because it is obtained by crystallizing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula 1 in the reaction solution using an appropriate amount of lower alcohol after the chlorination and oxidation of step 2. 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride having a purity of 99% or more can be obtained 88-92% with respect to 2-mercaptoethanol of the formula (3).

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention.

Example 1 Preparation of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride 1

(Step 1) Preparation of 2- (2'-hydroxyethyl mercapto) ethylamine

85% KOH (39.5 g, 0.6 mole) was added to 90% 2-propanol (200 mL) to completely dissolve, then slowly add 2-mercaptoethanol (21.04 mL, 0.3 mole) while maintaining 30-35 ^o C and then 50 ^o C Stir for about 30 minutes. 2-aminoethyl hydrogensulfate (42.3 g, 0.3 mol) was slowly added to the solution and heated to reflux at 80 ^° C. for about 12 hours. After the reaction was completed, the reaction mixture was cooled with ice, the resulting inorganic salt was filtered off, and the filtrate was distilled under reduced pressure. The oily residue was distilled under reduced pressure (12 mmHg, 120 ^° C.) to obtain 32.7 g (90%) of 2- (2'-hydroxyethyl mercapto) ethylamine.

HPLC Experiments and Results: Column; Capsule pack (CAPCELL PAK C ₁₈ UG120 S-5 μm, Shiseido) flow rate; 1.0 mL / min, Chart speed; 5 mm / min, RI Detector (Varian 9040), Eluent; MeOH / H ₂ O = 70/30, retention time (RT); 3.18 minutes

¹ H-NMR (CDCl ₃ ): δ 4.3 (bs, 2H), 3.5 (t, 2H), 2.6 (t, 2H), 2.5 (m, 4H), 1.5 (bs, 1H)

(Step 2) Preparation of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride

2- (2'-hydroxyethylmercapto) ethylamine (12.1 g, 0.1 mol) obtained in step 1 was slowly added dropwise to concentrated hydrochloric acid (35 mL) in an ice bath. After completion of the dropwise addition, the reaction temperature was maintained at 30-40 ^° C. and the reaction mixture was stirred while passing 21.3 g of chlorine gas for about 2 hours. When the reaction is complete, the excess hypochlorite (HOCl) is removed by adding a small amount of sodium hydrosulfite until the color of the potassium iodide-starch test paper is colorless. 2-propanol (70 mL) was added to the ice bath, and the colorless crystals formed were filtered to obtain 20.4 g (98%) of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride as a final compound having a purity of 99%.

HPLC Experiments and Results: Colum; Capsule pack (CAPCELL PAK C18 UG120 S-5 μm, Shiseido) flow rate; 1.0 mL / min, carart rate; 5 mm / min, RI detector (Varian 9040), eluent; MeOH / H ₂ O = 70/30, retention time; 2.87 minutes

Boiling Point: 131-133 ^o C

Elemental Analysis: Theory C 23.09 H 5.33 N 6.73 S 15.41

Found C 23.10 H 5.31 N 6.83 S 15.60

¹ H-NMR (DMSO-d ₆ ): δ 8.4 (bs, 3H), 3.9 (t, 3H), 3.8 (t, 3H), 3.6 (t, 3H), 3.2 (bs, 2H) ¹³ C-NMR (DMSO-d ₆ ): δ 53.9, 50.2, 36.2, 32.2 IR (KBr): 3652, 2974, 1296, 1120 cm ^-1

Example 2 Preparation of 2- (2'-Chloroethylsulfonyl) ethylamine Hydrochloride 2

85% KOH (1.32kg, 20 mole) was added as a 90% 2-propanol (10L) maintaining the 30-35 ^o C and then completely dissolved in 2-mercaptoethanol (0.701L, 10 mol) was slowly added to 50 ^o C Stir for about 30 minutes. 2-Aminoethyl hydrogen sulfate (1.41 kg, 10 mol) was slowly added to the solution and heated to reflux at 80 ^° C. for about 12 hours. At the end of the reaction, the reaction mixture was cooled with ice, the resulting inorganic salt was filtered off, and the filtrate was distilled under reduced pressure to yield 1.24 kg of 2- (2'-hydroxyethylmercapto) ethylamine. 2- (2'-hydroxyethylmercapto) ethylamine (1.24 kg) obtained in the above reaction was slowly added dropwise to concentrated hydrochloric acid (3.7 L) in an ice bath without purification. After completion of the dropwise addition, the reaction temperature was maintained at 30-40 ^° C. and the reaction mixture was stirred while passing 2.13 kg of chlorine gas for about 3 hours. When the reaction is completed, the excess hypochlorite (HOCl) is removed by adding a small amount of sodium hydrosulfite until the color of the potassium iodide-starch test paper is colorless. 2-propanol (7 L) was added to the ice bath, and the colorless crystals formed were filtered to obtain 1.91 kg (92%) of 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride as a final compound having a purity of 99%.

HPLC Experiments and Results: Colum; Capsule pack (CAPCELL PAK C18 UG120 S-5 μm, Shiseido) flow rate; 1.0 mL / min, carart rate; 5 mm / min, RI detector (Varian 9040), eluent; MeOH / H ₂ O = 70/30, retention time; 2.87 min

Boiling Point: 131-133 ^o C

Elemental Analysis: Theory C 23.09 H 5.33 N 6.73 S 15.41

Found C 23.15 H 5.30 N 6.85 S 15.56

¹ H-NMR (DMSO-d ₆ ): δ 8.4 (bs, 3H), 3.9 (t, 3H), 3.8 (t, 3H), 3.6 (t, 3H), 3.2 (bs, 2H) ¹³ C-NMR (DMSO-d ₆ ): δ 53.9, 50.2, 36.2, 32.2 IR (KBr): 3652, 2974, 1296, 1120 cm ^-1

As described above, according to the method of the present invention, the production cost can be drastically reduced by using 2-aminoethyl hydrogen sulfate of Formula 2 as a starting material which is inexpensive and easy to supply and using water or a lower alcohol as a reaction solvent. In addition, 2- (2'-chloroethyl mercapto) ethylamine of the general formula (4) synthesized in step 1 can be used directly in the next step without separation and purification, and the reaction time and The reaction process can be shortened. In addition, high purity 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of Chemical Formula 1 may be prepared in high yield.

Claims (15)

1) 2-aminoethyl hydrogensulfate of Formula 2 and 2-mercaptoethanol of Formula 3 are reacted under an inorganic base in a solvent to form 2- (2'-hydroxy). Obtaining ethyl mercapto) ethylamine (2- (2'-hydroxyethyl-mercapto) ethylamine) (step 1); And 2) chlorination and oxidation of the compound of formula 4 obtained in step 1 to obtain 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride (2- (2'-chloroethylsufonyl) -ethylamine HCl salt) of formula 1 A process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride of formula (I) comprising the step (step 2). The process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, wherein the reaction temperature of step 1 is 65-95 ^° C. The process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, wherein step 1 is carried out for 10-24 hours. 2. The 2- (2'-chloroethylsulfonyl) ethyl according to claim 1, wherein the 2-aminoethyl hydrogen sulfate of formula (2) is used in an amount of 1.0-1.5 moles based on 1.0 mole of 2-mercaptoethanol of formula (3). Method for preparing amine hydrochloride. 2. The 2- (2'-chloroethylsulfonyl) ethyl of claim 1, wherein the inorganic base of step 1 is selected from the group consisting of NaOH, KOH, LiOH, Na ₂ CO ₃ and K ₂ CO ₃ . Method for preparing amine hydrochloride. The method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 5, wherein the inorganic base is used in an amount of 2.0-3.0 moles based on 1.0 mole of 2-mercaptoethanol represented by Chemical Formula 3. The method of claim 1, wherein the solvent of step 1 is water or 80-95% of a water-soluble lower alcohol. A method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride. 8. The process for producing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 7, wherein the water-soluble lower alcohol is methanol, ethanol or 2-propanol. The process for producing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, wherein the chlorination and oxidation reaction of step 2 uses concentrated hydrochloric acid and chlorine gas. 10. The 2- (2'-chloroethylsulfonyl according to claim 9, wherein chlorine gas is used in an amount of 3.0 to 4.0 moles based on 1.0 mole of 2- (2'-hydroxyethylmercapto) ethylamine of the formula (4). ) Method for preparing ethylamine hydrochloride The process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, wherein the reaction temperature of step 2 is at 25-45 ^° C. The process for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, wherein step 2 is carried out for 1-4 hours. The method for preparing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 1, further comprising the step of crystallizing the 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride obtained in step 2. . The method according to claim 13, wherein the crystallization step is obtained by adding a lower alcohol to 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride and stirring at 0-5 ^o C for 5-12 hours. Method for preparing 2'-chloroethylsulfonyl) ethylamine hydrochloride. The process for producing 2- (2'-chloroethylsulfonyl) ethylamine hydrochloride according to claim 14, wherein the lower alcohol is methanol, ethanol or 2-propanol.