2,3-dihydro-1,4-benzodioxin-3-yl(piperazin-1-yl)methanone

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

Procedure: The title compound was prepared by the procedure of Part A, above, by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and N-(1,4-benzodioxan-2-carbonyl)-piperazine in methylisobutylketone, M.P. 194°-196° C.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-amino-2-chloro-6,7-dimethoxyquinazoline (3.2 g, 13.35 mmol) and compound 1 (3.4 g, 13.75 mmol) prepared from Example 3 were dissolved in 72 mL of n-butanol. The mixture was refluxed under nitrogen for 3.5 hours. After cooling to 75° C., the solid product was obtained by filtration and dried to afford 5.25 g of hydrochloride salt of Doxazosin (10.76 mmol, 81% yield). 1 N NaOH solution was added to the salt. The mixture was heated to help the salt dissolved. After cooling, the mixture was extracted with 150 mL of dichloromethane twice. The organic layer was dried with anhydrous sodium sulfate and concentrated to afford 4.61 g of Doxazosin. The mixture was refluxed under nitrogen for 3.5 hours the solid product was obtained by filtration dried

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-amino-2-chloro-6,7-dimethoxyquinazoline (3.2 g, 13.35 mmol) and compound 1 (3.4 g, 13.75 mmol) prepared from Example 3 were dissolved in 72 mL of n-butanol. The mixture was refluxed under nitrogen for 3.5 hours. After cooling to 75° C., the solid product was obtained by filtration and dried to afford 5.25 g of hydrochloride salt of Doxazosin (10.76 mmol, 81% yield). 1 N NaOH solution was added to the salt. The mixture was heated to help the salt dissolved. After cooling, the mixture was extracted with 150 mL of dichloromethane twice. The organic layer was dried with anhydrous sodium sulfate and concentrated to afford 4.61 g of Doxazosin. The mixture was refluxed under nitrogen for 3.5 hours the solid product was obtained by filtration dried

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-benzodioxan-2-ethylcarboxylate, (31.2 g, 150 -mmol) and piperazine (15.5 g, 180 mmol) were stirred under nitrogen and heated to 110° C. After 5 hours, the reaction was completed, which was confirmed by thin film chromatography. The crude product was cooled to room temperature, extracted with chloroform, washed with NaHCO3 solution and water. The organic layer was dried with anhydrous sodium sulfate, filtered to afford 34.96 g of compound 1 (94% yield). extracted with chloroform washed with NaHCO3 solution and water The organic layer was dried with anhydrous sodium sulfate filtered

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

Procedure: As an illustration of the improved synthesis, 1,4-benzodioxan-2-ethylcarboxylate and piperazine were reacted to form N-(1,4-benzodioxan-2-ylcarbonyl)piperazine. Since piperazine includes secondary amines, it is known that the amidization reaction can proceed only in the presence of a solvent and catalyst, e.g., a Lewis acid, strong base, or enzyme. Therefore, the solvent, e.g, THF, acetonitrile, benzene, toluene, or chlorine-containing solvent, was used to dissolve 1,4-benzodioxan-2-ethylcarboxylate and piperazine. The reactants were dissolved in anhydrous THF and potassium carbonate was added to catalyze the reaction. The mixture was stirred under nitrogen and heated to 110° C. After extraction and purification, it was found that the yield of 1-(1,4-benzodioxan-2-yl-carbonyl)piperazine (compound 1) was very low. The yield was less than 5%. Most of the product was 1,4-benzodioxan-2-carboxylic acid, which was obtained from hydrolysis of the reactant 1,4-benzodioxan-2-ethyl carboxylate. were reacted

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

Procedure: The title compound was prepared by the procedure of Part A, above, by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and N-(1,4-benzodioxan-2-carbonyl)-piperazine in methylisobutylketone, M.P. 194°-196° C.

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

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

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

Procedure: Organic Preparations and Procedures International (2003); 35; 603-608 describes the procedure for synthesizing doxazosin by treating (2,3-dihydrobenzo[b][1,4]dioxin-2-yl) (piperazin-1-yl)methanone with 2-chloro-6,7-dimethoxy quinazolin-4-amine in presence of n-butanol to obtain doxazosin hydrochloride; which on further treatment with aqueous ammonia solution yields doxazosin base.