2-chloro-6-fluorobenzenecarbothioamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-7.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzonitrile (1230 g, 7.91 mol) was weighed into a 22 L jacketed glass reactor (without bottom drain), along with Et3N (1.5 L, 10.76 mol) and pyridine (2.4 L, 29.67 mol) and the stirring solution was cooled to −18° C. under a blanket of N2. The reactor N2 purge mineral oil bubbler was vented to a carboy containing 16 L of 12% bleach solution. Hydrogen sulfide gas (407 g, 11.94 mol) was introduced below the surface of the cold reactor solution over a period of 5.5 hrs. During this time the reactor temperature rose from −18 to −4° C. The solution was stirred overnight at −7° C. (16 hrs), sampled by GC to ensure complete conversion of 2,6-CFBN, then quenched by vacuum transfer of the reactor solution into a second 22 L flask containing 14 L of cold water stirring at 300 RPM (Note: Quenching into a well-stirred tank of cold water produces small white particles of easily filtered product). After the vacuum transfer was completed, another 2 L of cold water was added to the stirring slurry. The light yellow slurry of white solid was drained from the quench tank into bottles, and the solid product was collected by filtration through a course glass buchner funnel, followed by washing of the solid product with an excess of de ionized water. The white solid was air suction dried for 3 h, air dried in a glass pan overnight, then dried in a vacuum oven at 50° C. at 0.3 mm Hg for 8 hrs to give 1004 g (67%) of dry 2-chloro-6-fluorobenzenecarbothioamide, m.p. 153-157° C. The reactor N2 purge mineral oil bubbler containing 16 L of 12% bleach solution rose from −18 to −4° C sampled by GC then quenched by vacuum transfer of the reactor solution into a second 22 L flask containing 14 L of cold water stirring at 300 RPM ( Quenching into a well-stirred tank of cold water produces small white particles of easily filtered product) the solid product was collected by filtration through a course glass buchner funnel by washing of the solid product with an excess of de dried for 3 h air dried in a glass pan overnight dried in a vacuum oven at 50° C. at 0.3 mm Hg for 8 hrs

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

Procedure: A mixture of 94.82 g (0.5 mole) of 2-chloro-6-fluorobenzthioamide, 50 mL (0.525 mole) of dimethyl sulfate, and 800 mL of 1,2-dichloroethane was heated at reflux temperature for 1 h. LC analysis indicated complete conversion to the thioimidate. The reaction solution was cooled to RT with ice-bath cooling, and the thioimidate salt precipitated from the solution. To the thick slurry was added 100 mL (1.25 mole) of pyridine. The salts instantly dissolved into solution, followed by immediate precipitation of pyridine salts. After further cooling to 10° C., 125 g (0.5 mole) of 3,4,5-trichloro-2-thiophenecarbonyl chloride dissolved in 200 mL of 1,2-dichloroethane was added in three portions. Temperature of the reaction mixture rose to 20° C. during each addition and was allowed to cool back to 10° C. before the next addition. The reaction mixture was allowed to stir at RT for 0.5 h. LC analysis indicated major acylated thioimidate and <2% area of starting thioimidate. To the slurry was added 1.0 L of water and the layers separated. LC internal standard analysis of the organics indicated a 94% in-pot yield of the acylated intermediate. The 1,2-dichloroethane solution was heated to 70° C., and a solution of 40 mL (0.75 mole) of methylhydrazine in 60 mL of water was added via a pump over 20 min. The temperature of the reaction mixture was maintained between 70° and 73° C. The solution was heated an additional 2 h, when GC analysis indicate no remaining acylated intermediate and a 38:1 ratio of desired product/off-isomer. The reaction mixture was cooled to RT, and 500 mL of octane followed by 1 L of 0.5 N LiOH was added. After stirring for 10 min, the layers were separated. The organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h to remove remaining mercaptan compounds. The temperature of the mixture rose to 31° C. during this reaction. The layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator, a tan sandy precipitate formed. This solid was filtered and exposed to vacuum oven drying at 40° C. to give 144.8 g (73% wt) of the desired product as a tan crystalline powder. GC analysis indicated <0.2% area of the off-isomer, and LC internal standard analysis indicated a 98% purity, giving an overall isolated 72% yield of 1-methyl-3-(2-chloro-6-fluoro)phenyl-5-(3,4,5-trichloro-2-thienyl)-1H-1,2,4-triazole. was heated at reflux temperature for 1 h cooling the thioimidate salt precipitated from the solution The salts instantly dissolved into solution followed by immediate precipitation of pyridine salts After further cooling to 10° C. was added in three portions Temperature of the reaction mixture rose to 20° C. during each addition to cool back to 10° C. before the next addition the layers separated The 1,2-dichloroethane solution was heated to 70° C. The temperature of the reaction mixture was maintained between 70° and 73° C The solution was heated an additional 2 h The reaction mixture was cooled to RT was added After stirring for 10 min the layers were separated The organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h to remove The temperature of the mixture rose to 31° C. during this reaction The layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator a tan sandy precipitate formed This solid was filtered drying at 40° C.

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

Procedure: A mixture of 94.82 g (0.5 mole) of 2-chloro-6-fluorobenzthioamide, 50 mL (0.525 mole) of dimethyl sulfate, and 800 mL of 1,2-dichloroethane was heated at reflux temperature for 1 h. LC analysis indicated complete conversion to the thioimidate. The reaction solution was cooled to RT with ice-bath cooling, and the thioimidate salt precipitated from the solution. To the thick slurry was added 100 mL (1.25 mole) of pyridine. The salts instantly dissolved into solution, followed by immediate precipitation of pyridine salts. After further cooling to 10° C., 125 g (0.5 mole) of 3,4,5-trichloro-2-thiophenecarbonyl chloride dissolved in 200 mL of 1,2-dichloroethane was added in three portions. Temperature of the reaction mixture rose to 20° C. during each addition and was allowed to cool back to 10° C. before the next addition. The reaction mixture was allowed to stir at RT for 0.5 h. LC analysis indicated major acylated thioimidate and <2% area of starting thioimidate. To the slurry was added 1.0 L of water and the layers separated. LC internal standard analysis of the organics indicated a 94% in-pot yield of the acylated intermediate. The 1,2-dichloroethane solution was heated to 70° C., and a solution of 40 mL (0.75 mole) of methylhydrazine in 60 mL of water was added via a pump over 20 min. The temperature of the reaction mixture was maintained between 70° and 73° C. The solution was heated an additional 2 h, when GC analysis indicate no remaining acylated intermediate and a 38:1 ratio of desired product/off-isomer. The reaction mixture was cooled to RT, and 500 mL of octane followed by 1 L of 0.5 N LiOH was added. After stirring for 10 min, the layers were separated. The organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h to remove remaining mercaptan compounds. The temperature of the mixture rose to 31° C. during this reaction. The layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator, a tan sandy precipitate formed. This solid was filtered and exposed to vacuum oven drying at 40° C. to give 144.8 g (73% wt) of the desired product as a tan crystalline powder. GC analysis indicated <0.2% area of the off-isomer, and LC internal standard analysis indicated a 98% purity, giving an overall isolated 72% yield of 1-methyl-3-(2-chloro-6-fluoro)phenyl-5-(3,4,5-trichloro-2-thienyl)-1H-1,2,4-triazole. was heated at reflux temperature for 1 h cooling the thioimidate salt precipitated from the solution The salts instantly dissolved into solution followed by immediate precipitation of pyridine salts After further cooling to 10° C. was added in three portions Temperature of the reaction mixture rose to 20° C. during each addition to cool back to 10° C. before the next addition the layers separated The 1,2-dichloroethane solution was heated to 70° C. The temperature of the reaction mixture was maintained between 70° and 73° C The solution was heated an additional 2 h The reaction mixture was cooled to RT was added After stirring for 10 min the layers were separated The organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h to remove The temperature of the mixture rose to 31° C. during this reaction The layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator a tan sandy precipitate formed This solid was filtered drying at 40° C.

Conditions: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile. The reactor was purged with a slow stream of N2 During the gas addition rose to −11° C to gradually warm to 25° C. purge of the reactor head space into bleach solution The solution was poured into 1.6 L of ice water the resulting white crystals were collected on a buchner funnel rinsed with additional water After 2 h of air drying dried for 5 h at 65° C.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzthioamide (21.9 g, 0.12 mol) and dimethyl sulfate (12 mL, 16.0 g, 0.13 mol) were stirred together in 100 mL of toluene and refluxed for 2 h. The slurry was cooled to 25° C. and the white crystals collected on a glass buchner funnel and rinsed with a small quantity of acetone. After air suction drying for 1 h, 35.5 g of methyl 2-chloro-6-fluorobenzthioimidate methylsulfate salt was obtained, mp 147-151° C., representing a nominal wt. % yield of 96%. refluxed for 2 h the white crystals collected on a glass buchner funnel rinsed with a small quantity of acetone After air suction drying for 1 h

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzthioamide (21.9 g, 0.12 mol) and dimethyl sulfate (12 mL, 16.0 g, 0.13 mol) were stirred together in 100 mL of toluene and refluxed for 2 h. The slurry was cooled to 25° C. and the white crystals collected on a glass buchner funnel and rinsed with a small quantity of acetone. After air suction drying for 1 h, 35.5 g of methyl 2-chloro-6-fluorobenzthioimidate methylsulfate salt was obtained, mp 147-151° C., representing a nominal wt. % yield of 96%. refluxed for 2 h the white crystals collected on a glass buchner funnel rinsed with a small quantity of acetone After air suction drying for 1 h

Conditions: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile. The reactor was purged with a slow stream of N2 During the gas addition rose to −11° C to gradually warm to 25° C. purge of the reactor head space into bleach solution The solution was poured into 1.6 L of ice water the resulting white crystals were collected on a buchner funnel rinsed with additional water After 2 h of air drying dried for 5 h at 65° C.

Conditions: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile. The reactor was purged with a slow stream of N2 During the gas addition rose to −11° C to gradually warm to 25° C. purge of the reactor head space into bleach solution The solution was poured into 1.6 L of ice water the resulting white crystals were collected on a buchner funnel rinsed with additional water After 2 h of air drying dried for 5 h at 65° C.

Conditions: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile. The reactor was purged with a slow stream of N2 During the gas addition rose to −11° C to gradually warm to 25° C. purge of the reactor head space into bleach solution The solution was poured into 1.6 L of ice water the resulting white crystals were collected on a buchner funnel rinsed with additional water After 2 h of air drying dried for 5 h at 65° C.