2-chloro-5-aminomethylthiazole

Comparative To a stainless-steel autoclave, 15.7 parts of 2- chloro-5- (chloromethyl)thiazole (content: 95.7percent) and 25.4 parts of a 24percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.28 MPa. The reaction mixture obtained was transferred into another flask by washing the autoclave with about 15 parts of methanol, and then concentrated under reduced pressure to obtain 26.1 parts of a concentrated residue. To the concentrated residue was added methanol to obtain 228 parts of a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5- (aminomethyl)thiazole 41.4percent, and the yield of bis{(2-chlorothiazol-5-yl)methyl}amine was 24.5percent.Comparative A stainless autoclave was charged with 15.7 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.7percent) and 25.4 parts of a 24percent ammonia/methanol solution, and the mixture was reacted by stirring at an inner temperature of 70To a glass autoclave, 95.3 parts of 2-chloro-5- (chloromethyl) thiazole (content: 96.5percent), 51.9 parts of paraformaldehyde (content: 95percent) and 311 parts of a 12percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.09 MPa. The reaction mixture containing 1, 3, 5-tris{(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine thus obtained was transferred into a four-neck flask by washing the autoclave with 150 parts of methanol, bubbled with nitrogen for 15 minutes to expel ammonium remaining in the reaction mixture, and then concentrated under reduced pressure to distill off 60 parts of methanol. To the resultant concentrated residue were added 60 parts of methanol and 188 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 246 parts of a concentrated residue. To the concentrated residue were added 57.5 parts of water, 282 parts of methyl isobutyl ketone and 367 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl)thiazole. yield of 2-chloro-5-(aminomethyl)thiazole was 91.2percent, and the yield of bis{(2-chlorothiazol-5-yl)methyl}amine was 2.8percent. The solution containing 2-chloro-5- (aminomethyl) thiazole thus obtained was washed with 33.6 parts of an aqueous 14percent sodium hydroxide solution, followed by addition of 100 parts of water and 55.7 parts of 35percent hydrochloric acid to adjust to pH 3.3. Then, the layers were separated, and 230 parts of the resultant aqueous layer was concentrated under reduced pressure to obtain 194 parts of a concentrated residue. To the concentrated residue was added 1 part of activated charcoal and the mixture was maintained with stirring at room temperature for 1 hour. The activated charcoal was filtered and washed with about 10 parts of water to obtain 204 parts of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride. The content of 2- chloro-5- (aminomethyl)thiazole hydrochloride was 42.4percent and the yield was 85.2percent.; To a glass autoclave, 16.7 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.7percent), 9.04 parts of paraformaldehyde (content: 95percent) and 16.7 parts of methanol were charged, and adjusted to an inner temperature of 70°C. To this was added dropwise 57.9 parts by weight of a 14percent ammonia solution in methanol over 1 hour. After completion of addition, the mixture was reacted at the same temperature for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.15 MPa. The reaction mixture containing 1, 3, 5-tris((2-chlorothiazol-5- yl) methyl}-1, 3, 5-hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 50 parts of methanol, and concentrated under reduced pressure to obtain 42.7 parts of a concentrated residue. To the concentrated residue was added 73.2 parts of methanol and 32.8 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 42.2 parts of a concentrated residue. To the concentrated residue were added 49 parts of methyl isobutyl ketone and 69 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 87.1percent, and the yield of bis{(2- chlorothiazol-5-yl)methyl}amine was 1.2percent.; To a glass autoclave, 16.8 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.6percent), 9.05 parts of paraformaldehyde (content: 95percent) and 135 parts of a 24percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.37 MPa. The reaction mixture containing 1, 3, 5-tris{(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 20 parts of methanol, and concentrated under reduced pressure to obtain 40 parts by a concentrated residue. To the concentrated residue were added 73.2 parts of methanol and 32.8 parts of 35percent hydrochloric acid, and refluxed at an inner temperature of about 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 41.7 parts of a concentrated residue. To the concentrated residue were added 49 parts of toluene and 51.8 parts of an aqueous 30percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with toluene, and the toluene layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl)thiazole. yield of 2-chloro-5- (aminomethyl)thiazole was 93.3percent, and the yield of bis{.(2-chlorothiazol-5-yl)methyl}amine was 2.6percent. The solution containing 2-chloro-5- (aminomethyl) thiazole obtained was washed with 5.8 parts of an aqueous 14percent sodium hydroxide solution, followed by addition of 17.5 parts of water and 9 parts of 35percent hydrochloric acid to adjust to pH 4.9 to obtain 38.9 parts of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride. The content of 2- chloro-5- (aminomethyl)thiazole hydrochloride was 38.6percent and the yield was 85.1percent.; To a glass autoclave, 16.6 parts of 2-chloro-5- (chloromethyl) thiazole (content: 96.5percent), 9.04 parts of paraformaldehyde (content: 95percent) and 54.1 parts of a 10.5percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.08 MPa. The reaction mixture containing 1, 3, 5-tris{(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 60 parts of methanol, and then concentrated under reduced pressure to obtain 40 parts of a concentrated residue. To the concentrated residue were added 73.2 parts of methanol and 32.8 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 42.8 parts of a concentrated residue. To the concentrated residue were added 11.4 parts of water, 49 parts of methyl isobutyl ketone and 60.9 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 91.2percent, and the yield of bis{(2- chlorothiazol-5-yl)methyl)amine was 2.0percent.; To a glass autoclave, 29 parts of 2-chloro-5- (chloromethyl) thiazole (content: 96.5percent), 10.5 parts of paraformaldehyde (content: 95percent) and 94.6 parts of a 9percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.09 MPa. The reaction mixture containing 1, 3, 5-tris{(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine obtained was transferred into four-neck flask by washing the autoclave with 60 parts of methanol, and then concentrated under reduced pressure to obtain 57.8 parts of a concentrated residue. To the concentrated residue were added 128 parts of methanol and 57.4 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 75.1 parts of a concentrated residue. To the concentrated residue were added 20 parts of water, 85.7 parts of methyl isobutyl ketone and 113.5 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted with. methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5- (aminomethyl)thiazole was 86.2percent, and the yield of bis{(2-chlorothiazol-5-yl)methyl}amine was 4.3percent.; To a glass autoclave, 10.6 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95percent), 2.3 parts of paraformaldehyde (content: 95percent) and 30.5 parts of a 10percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.10 MPa. The reaction mixture containing 1, 3, 5-tris{(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 30 parts of methanol, and then concentrated under reduced pressure to obtain 27.1 parts by weight of a concentrated residue. To the concentrated residue were added 45.8 parts of methanol and 11.8 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 35.8 parts of a concentrated residue. To the concentrated residue were added 30.6 parts of methyl isobutyl ketone and 24.5 parts of an aqueous 30percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 80.1percent, and the yield of bis{(2- chlorothiazol-5-yl)methyl}amine was 8.9percent.; To a glass autoclave, 16.7 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.7percent), 23.2 parts of formalin (content: 37percent) and 30.9 parts of a 21percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.05 MPa. The reaction mixture containing 1, 3, 5-tris {(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 60 parts of methanol, and then concentrated under reduced pressure to obtain 50.9 parts of a concentrated residue. To the concentrated residue were added 73.2 parts of methanol and 32.8 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 52.5 parts of a concentrated residue. To the concentrated residue were added 49 parts of methyl isobutyl ketone and 67.3 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with methyl isobutyl ketone, and the methyl isobutyl ketone layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl)thiazole. yield of 2-chloro-5-(aminomethyl)thiazole was 87.5percent, and the yield of bis{(2-chlorothiazol-5-yl)methyl}amine was 2.2percent.; To a glass autoclave, 29.3 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.7percent), 15.8 parts of paraformaldehyde (content: 95percent), 56.9 parts of a 20percent ammonia solution in methanol and 43.9 parts of toluene were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 5 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.09 MPa. The reaction mixture containing 1, 3, 5-tris{(2- chlorothiazol-5-yl) methyl}-1, 3, 5-hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 46 parts of methanol, and then concentrated under reduced pressure to obtain 162.4 parts of a concentrated residue. To the concentrated residue was added 23.6 parts of methanol and 57.4 parts of 35percent hydrochloric acid, and the mixture was refluxed at an inner temperature of 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 74.3 parts of a concentrated residue. To the concentrated residue were added 20 parts of water, 85.7 parts of methyl isobutyl ketone and 108.2 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining organic layer and an aqueous layer. The aqueous layer was further extracted three times with toluene, and the toluene layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 92.3percent, and the yield of bis{(2- chlorothiazol-5-yl) methyl}amine was 2.2percent. Since the aqueous layer after extracted with toluene contained 2.5percent of 2-chloro-5- (aminomethyl)thiazole calculated from the yield, the reaction yield of 2-chloro- 5- (aminomethyl)thiazole was 94.8percent.; To a glass autoclave, 15.8 parts of paraformaldehyde (content: 95percent) and 94.6 parts of a 12percent ammonia solution in methanol were charged. To the mixture was added 29 parts of 2-chloro-5- (chloromethyl)thiazole 96.6percent) at room temperature, and the resultant mixture was reacted with stirring at an inner temperature of 40°C for 3 hours, then at an inner temperature of 50°C for 3 hours, and further at an inner temperature of 70°C for 1 hour. The maximum inner pressure (gauge pressure) during the reaction was 0.09 MPa. The reaction mixture containing 1, 3, 5- tris {(2-chlorothiazol-5-yl)methyl}-1, 3, 5-hexahydrotriazine obtained was transferred into a four-neck flask by washing the autoclave with 60 parts of methanol, and then concentrated under reduced pressure to obtain 87.9 parts of a concentrated residue. To the concentrated residue was added 101 parts of water, and then the mixture was concentrated under reduced pressure to obtain 146.9 parts of a concentrated residue. To the concentrated residue was added 117 parts of toluene to subject the mixture to extraction treatment at an inner temperature of 75°C to obtain 149 parts of a toluene layer and an aqueous layer. When the toluene layer was analyzed by HPLC, 1, 3, 5-tris{(2- chlorothiazol-5-yl) methyl}-1, 3, 5-hexahydrotriazine, 2- chloro-5- (aminomethyl)thiazole and bis{(2-chlorothiazol-5- yl) methyl}amine were contained in yields of 91.8percent, 2.7percent and 2.1percent, respectively. To 148.6 parts of the obtained toluene layer was added 21.5 parts of 35percent hydrochloric acid with stirring, and then allowed to stand to separate into an oil layer and an aqueous layer. To the oil layer was added 1.2 parts of water to subject the mixture to extraction treatment, and the aqueous layer obtained was combined with the previously obtained aqueous layer. To the combined aqueous layer was added 39.5 parts of methanol, and the mixture was refluxed at an inner temperature of about 60°C for 1.5 hours. The mixture was cooled to an inner temperature of not higher than 40°C, and then concentrated under reduced pressure to obtain 38.9 parts of a concentrated residue. To the concentrated residue were added 20 parts of water, 82.6 parts of toluene and 35 parts of an aqueous 27percent sodium hydroxide solution to adjust to pH 13, thereby subjecting the mixture to extraction treatment, and obtaining an organic layer and an aqueous layer. The aqueous layer was further extracted three times with toluene, and the toluene layers obtained were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 87.2percent, and the yield of bis{(2- chlorothiazol-5-yl)methyl}amine was 1.9percent.Example 8; To a glass autoclave, 29.3 parts of 2-chloro-5- (chloromethyl) thiazole (content: 95.7percent), 15.8 parts of paraformaldehyde (content: 95percent by weight) and 87.3 parts of a 13percent ammonia solution in methanol were charged, and the mixture was reacted with stirring at an inner temperature of 70°C for 3 hours. The maximum inner pressure (gauge pressure) during the reaction was 0.08 MPa. After completion of the reaction, the reaction mixture containing 1, 3, 5-tris {(2-chlorothiazol-5-yl)methyl}-1, 3, 5- hexahydrotriazine was cooled to an inner temperature of 5°C to precipitate a solid, and the solid was collected by filtration. The collected solid was dried under reduced pressure to obtain 21.9 parts of 1, 3, 5-tris{(2- chlorothiazol-5-yl) methyl}-1, 3, 5-hexahydrotriazine. MS (FD): m/z 480 at monoisotopic peak (isotopic pattern of Cl x 3) To a flask were added 5 parts of 1, 3, 5-tris{ (2- chlorothiazol-5-yl)methyl}-l, 3, 5-hexahydrotriazine, 15 parts of toluene and 3.2 parts of 35percent hydrochloric acid, and the mixture was retained at an inner temperature of 60To a flask were added 5 parts of 1, 3, 5-tris{ (2- chlorothiazol-5-yl)methyl}-l, 3, 5-hexahydrotriazine, 15 parts of toluene, 15 parts of water and 3.3 parts of 35percent hydrochloric acid, and the mixture was retained at an inner temperature of 6025.3 g of the above mentioned off-white solid and 150 mL of ethanol were added into a 250 mL of three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, and 9.1 g of hydrazine hydrate was added dropwise. After that, the reaction mixture was refluxed for 4 to 6 hours, and then the solvent was removed under a reduced pressure condition to obtain 9.1 g (2-chlorothiazol-5-yl)methanamine as an orange oil.EXAMPLE 6 A mixture of 1.0 g of 2-chloro-5-(chloromethyl)thiazole obtained by the procedures in Example 2, 4 ml of 25% aqueous ammonia and 6 ml of acetonitrile was placed in a stainless steel autoclave and reacted at 80 C. for 2 hours. After cooling, 0.6 ml of a 10N aqueous solution of sodium hydroxide and 12 ml of ethanol were added, and the mixture stirred at room temperature for 30 min. The reaction mixture was concentrated followed by addition of 20 ml of dichloromethane and dried over anhydrous magnesium sulfate. Insoluble materials were separated by filtration and the filtrate was then concentrated. The concentrate was purified by column chromatography (eluted with dichloromethane-methanol 10:1) to afford 0.49 g of EXAMPLE 8 To a mixture of 27.5 g of hexamethylenetetramine and 150 ml of chloroform was dropwise added 30.0 g of 2-chloro-5-(chloromethyl)thiazole over 30 min. while heating under reflux. The mixture was heated under reflux with stirring for 3 hours and then allowed to stand overnight. Crystals thus formed were separated by filtration and washed with 100 ml of chloroform. Combined filtrate and washing were concentrated to 100 ml. Crystals formed after being allowed to stand for half a day were separated by filtration and washed with 20 ml of chloroform. Combined filtrate and washing were treated two more times in the same way as above. There was obtained a total of 55.0 g (yield, 99.7%) of a quaternary ammonium salt. A mixture of 32.5 g of the quaternary ammonium salt, 104 g of 36% hydrochloric acid, 97.5 ml of water and 325 ml of ethanol was stirred at 70 C. for one hour and then allowed to stand overnight. Solids then formed were separated by filtration, and the filtrate was concentrated to about a half of the original volume. Solids formed were again separated by filtration, and the filtrate was concentrated to dryness. To the residue was added 100 ml of acetone, and insoluble materials collected by filtration. To the filtrate was added 250 ml of water, and pH adjusted with 6N aqueous sodium hydroxide to 13. The mixture was extracted three times with dichloromethane, and the dichloromethane layers washed with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate and concentrated. There was obtained 14.3 g of crude EXAMPLE 7 A mixture of 0.50 g of 2-chloro-5-(chloromethyl)thiazole, 4 ml of 25% aqueous ammonia and 6 ml of acetonitrile was heated under reflux for 30 min. followed by supplement of 8 ml of 25% aqueous ammonia. The mixture was heated under reflux for 30 additional min. After-treatment in the same way as in Example 6 yielded 0.22 g of Into an autoclave under cooling in an acetone-dry ice bath was placed 20 ml of liquid ammonia and a mixture of 2-chloro-5-(chloromethyl)thiazole (3.36 g) and toluene (10 ml) was added to the autoclave before sealing. The mixture was allowed to set at a bath temperature of -30 C. followed by elevating to 0 C. under stirring over 2.5 hours. Then stirring was continued for 7 hours in an ice bath and for 16 hours at room temperature followed by ambient pressure. The reaction mixture was transferred into 10 ml of 6N aqueous sodium hydroxide, and extracted two times with dichloromethane (100 ml and 50 ml). The organic layer was concentrated and then purified by column chromatography (eluted with dichloromethane-methanol 10:1) to yield 2.20 g (74.0%) of 2, 3-dichloro-5-trifluoromethylpyridine (0.8 g, 3.8 mmol) was sequentially added to a single-mouth bottle.Potassium carbonate (0.7 g, 5.1 mmol), DMSO (20 mL), After stirring at room temperature for 20 minutes,

Molecular Weight:148.61
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:147.9861970
Monoisotopic Mass:147.9861970
Topological Polar Surface Area:67.2
Heavy Atom Count:8
Complexity:80.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes