| 80.1% |
Stage #1: at 60℃; for 1.5 h; Heating / reflux
Stage #2: With sodium hydroxide In water; 4-methyl-2-pentanone |
Example 1; To 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.; Example 2; 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.; Example 3; 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.; Example 4; 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.; Example 5; 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.; Example 6; 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.; Example 7; 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.; Example 10; 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.; Example 11 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. |
| 65.9% |
at 50℃; for 0.5 h; |
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) 1H-NMR (CDC13, 270 MHz, 5/ppm) 3.50 (brs, 2H), 3.82 (s, 7.33 (s, 1H)13C-NMR (CDC13, 68 MHz, 5/ppm) 48.85,72.34, 138.73,139.29, 151.71 The 1,3,5-tris{(2-chlorothiazol-5-yl)methyl}-1,3,5- hexahydrotriazine thus obtained was hydrolyzed with hydrochloric acid in methanol to obtain 2-chloro-5- (aminomethyl) thiazole. Yield: 65.9percent. The yield of bis{(2- chlorothiazol-5-yl)methyl}amine was 0.5percent.; Example 9; To a stainless-steel autoclave, 15.5 parts of 2- chloro-5- (chloromethyl)thiazole (content: 96.5percent), 8.7 parts of paraformaldehyde (content: 92percent) and 24.4 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 0.02 MPa. The reaction mixture containing 1,3,5-tris{(2-chlorothiazol-5-yl)methyl}-1,3,5- hexahydrotriazine obtained was transferred into another flask by washing the autoclave with about 15 parts of methanol, and then concentrated under reduced pressure to obtain 45.2 parts by weight of a concentrated residue. To the concentrated residue was added methanol so as to make up the solution volume to 228 parts, and then added 32.5 parts of 35percent hydrochloric acid, and the mixture was maintained with stirring at an inner temperature of 50°C for 30 minutes. Then, the mixture was cooled to room temperature, and water was added thereto to obtain 260.2 parts of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole. The yield of 2-chloro-5- (aminomethyl) thiazole was 93.3percent, and the yield of bis{(2- chlorothiazol-5-yl)methyl}amine was 2.0percent. |
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