2-amino-5-fluorobenzenethiol

Conditions: temp:1.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 0 to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.0 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol. The system had a pH of 0.90. Thereto was added 20.0 g (0.105 mole) of p-toluenesulfonic acid monohydrate. Then, a solution of D-alanine-N-carboxyanhydride (16.7 g, purity: 78.3%, 0.318 mole) dissolved in tetrahydrofuran (30 ml) (the solution was beforehand prepared at 16 to 20° C.) was added dropwise at 16 to 20° C. Aging was conducted at 15 to 20° C. for 4 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 31.5 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 98.95%) (the yield was 75.5% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. was beforehand prepared at 16 to 20° C.) was added dropwise at 16 to 20° C The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.1 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.02. Thereto were added 19.4 g (0.102 mole) of p-toluenesulfonic acid monohydrate and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.2 g (0.110 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 30.9 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 92%) (the yield was 75.6% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 300-ml flask as a reactor, and cooled to 3° C. Thereto was dropwise added, at 2 to 5° C. with stirring, 96 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.23. Thereto were added 20 g (0.105 mole) of p-toluenesulfonic acid monohydrate and 30 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.7 g (0.114 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 36.0 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 95.2%) (the yield was 82.8% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 2 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 2,000-ml flask as a reactor were placed 166.7 g of water, 589.3 g of a 50% aqueous potassium hydroxide solution (5.25 moles as KOH) and 168.2 g (1.00 mole) of 6-fluoro-2-aminobenzothiazole. They were heated, aged for 8 hours with refluxing at 113 to 115° and then cooled to 40° C. The resulting mixture was washed with 311 g of toluene and then subjected to phase separation to obtain 904.0 g of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol (concentration: 20%, yield: 99.7%). This aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol can be used for production of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine or an aqueous solution of [2-(6-fluorobenzothiazolyl)]ethylamine hydrochloride, according to the description in Example 1 to Example 7. In a 2,000-ml flask as a reactor were placed They were heated with refluxing at 113 to 115° The resulting mixture was washed with 311 g of toluene subjected to phase separation

Conditions: temp:1.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 0 to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.0 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol. The resulting mixture had a pH of 0.90. Further, 20.0 g (0.105 mole) of p-toluenesulfonic acid monohydrate was added. Thereto was dropwise added, at 16 to 20° C., a solution of D-alanine-N-carboxyanhydride (16.7 g, purity: 78.3%, 0.318 mole) dissolved in tetrahydrofuran (30 ml) (the solution was beforehand prepared at 16 to 20° C.). Aging was conducted at 15 to 20° C. for 4 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 31.5 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 98.95%) (the yield was 75.5% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. Thereto was dropwise added, at 16 to 20° C. was beforehand prepared at 16 to 20° C.) The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230.4 g of water and 172.8 g (1.706 mole) of 36% hydrochloric acid were placed in a 2-liter flask as a reactor, and cooled to 3° C. Thereto was dropwise added 276.5 g (0.315 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol at 0 to 5° C. with stirring, followed by stirring for 1 hour. Further, 15.8 g of 50% potassium hydroxide was added dropwise to adjust the system pH to 4.95. Aging was conducted for 1 hour. Then, 56.4 g (0.296 mole) of p-toluenesulfonic acid monohydrate was added, followed by aging at 3° C. for 30 minutes. Thereto was dropwise added, at 16 to 19° C., a beforehand prepared solution of D-alanine-N-carboxyanhydride (46.8 g, purity: 78.3%, 0.318 mole) dissolved in tetrahydrofuran (73 ml). Aging was conducted at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 96.6 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 93.76%) (the yield was 78.0% relative to the potassium salt of 2 amino-5-fluorothiophenol). at 0 to 5° C. by stirring for 1 hour by aging at 3° C. for 30 minutes Thereto was dropwise added, at 16 to 19° C. Aging was conducted at 15 to 20° C. for 18 hours The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.1 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.02. Thereto were added 19.4 g (0.102 mole) of p-toluenesulfonic acid monohydrate and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.2 g (0.110 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 33.9 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 92.04%) (the yield was 75.6% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:1.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 48.2 g (0.056 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol was placed in a 300-ml flask as a reactor, and cooled to 1° C. Thereto was dropwise added 72.0 g (0.296 mole) of 15% hydrochloric acid at 0 to 5° C. with stirring, followed by stirring for 1 hour. The system had a PH of 5.40. Thereto were added 9.7 g (0.051 mole) of p-toluenesulfonic acid monohydrate and 15 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 8.1 g (0.055 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 12.2 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 76.5%) (the yield was 45.2% relative to the potassium salt of 2-amino-5-fluorothiophenol). at 0 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:1.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 0 to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.0 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol. The system had a pH of 0.90. Thereto was added 20.0 g (0.105 mole) of p-toluenesulfonic acid monohydrate. Then, a solution of D-alanine-N-carboxyanhydride (16.7 g, purity: 78.3%, 0.318 mole) dissolved in tetrahydrofuran (30 ml) (the solution was beforehand prepared at 16 to 20° C.) was added dropwise at 16 to 20° C. Aging was conducted at 15 to 20° C. for 4 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 31.5 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 98.95%) (the yield was 75.5% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. was beforehand prepared at 16 to 20° C.) was added dropwise at 16 to 20° C The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.1 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.02. Thereto were added 19.4 g (0.102 mole) of p-toluenesulfonic acid monohydrate and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.2 g (0.110 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 30.9 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 92%) (the yield was 75.6% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 300-ml flask as a reactor, and cooled to 3° C. Thereto was dropwise added, at 2 to 5° C. with stirring, 96 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.23. Thereto were added 20 g (0.105 mole) of p-toluenesulfonic acid monohydrate and 30 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.7 g (0.114 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 36.0 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 95.2%) (the yield was 82.8% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 2 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 80 ml of water and 60 g (0.592 mole) of 36% hydrochloric acid were placed in a 500-ml flask as a reactor, and cooled to 2° C. Thereto was dropwise added, at 0 to 5° C. with stirring, 96.1 g (0.112 mole) of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol, followed by stirring for 1 hour. The system had a pH of 5.02. Thereto were added 19.4 g (0.102 mole) of p-toluenesulfonic acid monohydrate and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. Thereto was added 16.2 g (0.110 mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) at 0° C. The resulting mixture was aged at 15 to 20° C. for 18 hours. The resulting crystals were collected by filtration and dried at 60° C. to obtain 30.9 g of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine (purity: 92%) (the yield was 75.6% relative to the potassium salt of 2-amino-5-fluorothiophenol). Thereto was dropwise added, at 0 to 5° C. by stirring for 1 hour by stirring for 30 minutes The resulting crystals were collected by filtration dried at 60° C.