6-chlorobenzo[b][1,4]benzothiazepine

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

Procedure: To a solution of 11-chlorodibenzo[b,f][1,4]thiazepine, prepared as described in the previous step, (2 g, crude) in dioxane (20 mL) was added Pd2(dba)3 (327 mg, 0.357 mmol), BINAP (225 mg, 0.357 mmol), triethylamine (6 mL, 42.9 mmol) and 2,2,2-trifluoro-N-((1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)acetamide, prepared as described as Step F, (2.4 g, crude). The resulting mixture was heated to reflux overnight under nitrogen atmosphere, filtered through CELITE™, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. ESI-MS (M+1): 509 calc. for C24H27F3N4O3S 508. prepared The resulting mixture was heated to reflux overnight under nitrogen atmosphere filtered through CELITE™ concentrated The residue was purified by silica gel chromatography

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

Procedure: To a solution of 11-chlorodibenzo[b,f][1,4]thiazepine, prepared as described in the previous step, (2 g, crude) in dioxane (20 mL) was added Pd2(dba)3 (327 mg, 0.357 mmol), BINAP (225 mg, 0.357 mmol), triethylamine (6 mL, 42.9 mmol) and 2,2,2-trifluoro-N-((1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)acetamide, prepared as described as Step F, (2.4 g, crude). The resulting mixture was heated to reflux overnight under nitrogen atmosphere, filtered through CELITE™, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. ESI-MS (M+1): 509 calc. for C24H27F3N4O3S 508. prepared The resulting mixture was heated to reflux overnight under nitrogen atmosphere filtered through CELITE™ concentrated The residue was purified by silica gel chromatography

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

Procedure: A solution of dibenzo[b,f][1,4]thiazepin-11(10H)-one, prepared as described in the previous step, (14.6 g, 64 mmol) in phosphorus oxychloride (20 mL) was heated to reflux for 2 hours. The mixture was concentrated to provide the crude product which was used directly without further purification. ESI-MS (M+1): 246 calc. for C13H8ClNS 245. was heated to reflux for 2 hours The mixture was concentrated

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

Procedure: A 1 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 10 gm (0.04 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine (I), 100 cc toluene and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 7.7 gm (0.044 mole) of 1-(2-hydroxyethoxy)ethylpiperazine (II), 8.5 gm (0.08 mole) of sodium carbonate carbonate and 7.7 gm (0.24 mole) of tetra butyl ammonium bromide. The reaction mixture was heated at gentle reflux for 22 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that less than 2% of the starting material remained. The reaction mixture was cooled to room temperature and combined with 300 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers were separated and the aqueous layer was diluted with 100 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate. The layers (aqueous and nonaqueous reaction solvent toluene) were separated and the aqueous layer was extracted with 100 cc toluene. The organic (toluene) layers were combined and washed with 2×100 cc of water. The reaction solvent (toluene) was distilled-off under vacuum at 70 to 80° C. to afford 12 gm oil. HPLC area %: 98.87 A 1 liter round bottom flask equipped thermo pocket, reflux condenser and nitrogen inlet the mixture was stirred for 15 min. at room temperature The reaction mixture was heated at gentle reflux for 22 hrs to get a pH in between 1 to 2 The layers were separated the aqueous layer was diluted with 100 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate The layers (aqueous and nonaqueous reaction solvent toluene) were separated the aqueous layer was extracted with 100 cc toluene washed with 2×100 cc of water was distilled-off under vacuum at 70 to 80° C.

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

Procedure: A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted to about 8 to 9 by addition of sodium carbonate. The layer s were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to obtain an oil. To this oil 50 to 75 cc. toluene was added with 750 to 1000 cc absolute ethanol and activated carbon 5 to 6 gm, and heated to reflux for 90 min. The mixture was cooled to 55 to 60° C. and filtered. The filtrate was further cooled to 25 to 30° C. and fumaric acid 7 to 7.5 gm was added with stirring. The mixture was heated to reflux for 120 min, cooled slowly to 25 to 30° C., maintained for 120 min, filtered, and washed with 125 to 150 cc. of absolute ethanol. The wet material obtained was dried under vacuum at 50 to 60° C. to produce quetiapine fumarate (40 to 45 gm). A 2 liter round bottom flask equipped thermo pocket, reflux condenser and nitrogen inlet the mixture was stirred for 15 min. at room temperature The reaction mixture was heated at gentle reflux for 12 hrs to get a pH in between 1 to 2 The layers (aqueous and nonaqueous reaction solvent) were separated the aqueous layer was extracted with 500 cc toluene and pH was adjusted to about 8 to 9 by addition of sodium carbonate The layer s were separated aqueous layer was again extracted with 500 cc toluene washed with 2×500 cc of water The solvent was distilled under vacuum at 70 to 80° C. to obtain an oil heated to reflux for 90 min The mixture was cooled to 55 to 60° C. filtered The filtrate was further cooled to 25 to 30° C. fumaric acid 7 to 7.5 gm was added with stirring The mixture was heated to reflux for 120 min cooled slowly to 25 to 30° C. maintained for 120 min filtered washed with 125 to 150 cc The wet material obtained was dried under vacuum at 50 to 60° C.

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

Procedure: A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate. The layers were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to afford 47.5 gm oil. HPLC area %: 98.9 A 2 liter round bottom flask equipped thermo pocket, reflux condenser and nitrogen inlet the mixture was stirred for 15 min. at room temperature The reaction mixture was heated at gentle reflux for 12 hrs to get a pH in between 1 to 2 The layers (aqueous and nonaqueous reaction solvent) were separated the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate The layers were separated aqueous layer was again extracted with 500 cc toluene washed with 2×500 cc of water The solvent was distilled under vacuum at 70 to 80° C.

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

Procedure: A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate. The layers were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to afford 47.5 gm oil. HPLC area %: 98.9 A 2 liter round bottom flask equipped thermo pocket, reflux condenser and nitrogen inlet the mixture was stirred for 15 min. at room temperature The reaction mixture was heated at gentle reflux for 12 hrs to get a pH in between 1 to 2 The layers (aqueous and nonaqueous reaction solvent) were separated the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate The layers were separated aqueous layer was again extracted with 500 cc toluene washed with 2×500 cc of water The solvent was distilled under vacuum at 70 to 80° C.

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

Procedure: A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate. The layers were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to afford 47.5 gm oil. HPLC area %: 98.9 A 2 liter round bottom flask equipped thermo pocket, reflux condenser and nitrogen inlet the mixture was stirred for 15 min. at room temperature The reaction mixture was heated at gentle reflux for 12 hrs to get a pH in between 1 to 2 The layers (aqueous and nonaqueous reaction solvent) were separated the aqueous layer was extracted with 500 cc toluene and pH was adjusted between 8 to 9 by addition of sodium carbonate The layers were separated aqueous layer was again extracted with 500 cc toluene washed with 2×500 cc of water The solvent was distilled under vacuum at 70 to 80° C.

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

Procedure: A 2 liter round-bottom flask equipped with a magnetic stirring bar and reflux condenser with a nitrogen inlet was charged with 115.0 g (0.506 mole) of dibenzo[b,f][1,4]thiazepine-11(10-H)one, phosphorous oxychloride 700 ml (7.5 moles) and N,N-dimethylaniline 38.0 g (0.313 mole). The grey suspension was heated to gentle refluxing using a heating mantle. After 6 hours of heating, the resulting amber solution was allowed to cool to room temperature (from about 18°-25°C.) and was analyzed by thin-layer chromatography (TLC) using silica gel plates, developed with ether-hexane (1:1) and detected with ultraviolet light. Analysis revealed the desired imino chloride, Rf =0.70, and an absence of starting lactam. A 2 liter round-bottom flask equipped with a magnetic stirring bar reflux condenser with a nitrogen inlet The grey suspension was heated to gentle refluxing After 6 hours of heating

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

Procedure: To a solution of 11-chlorodibenzo[b,f][1,4]thiazepine, prepared as described in the previous step, (2 g, crude) in dioxane (20 mL) was added Pd2(dba)3 (327 mg, 0.357 mmol), BINAP (225 mg, 0.357 mmol), triethylamine (6 mL, 42.9 mmol) and 2,2,2-trifluoro-N-((1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)acetamide, prepared as described as Step F, (2.4 g, crude). The resulting mixture was heated to reflux overnight under nitrogen atmosphere, filtered through CELITE™, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. ESI-MS (M+1): 509 calc. for C24H27F3N4O3S 508. prepared The resulting mixture was heated to reflux overnight under nitrogen atmosphere filtered through CELITE™ concentrated The residue was purified by silica gel chromatography

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

Procedure: A solution of dibenzo[b,f][1,4]thiazepin-11(10H)-one, prepared as described in the previous step, (14.6 g, 64 mmol) in phosphorus oxychloride (20 mL) was heated to reflux for 2 hours. The mixture was concentrated to provide the crude product which was used directly without further purification. ESI-MS (M+1): 246 calc. for C13H8ClNS 245. was heated to reflux for 2 hours The mixture was concentrated