2,3-DIHYDRO-1,4-BENZODIOXIN-2-YLMETHYLAMINE

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:

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:

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

Procedure: In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH+). were reacted

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

Procedure: In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH+). were reacted

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

Procedure: Commercial grade of 2-chloromethyl-1,4-benzodioxane (10.0 g, 54.7 mmol) and phthalimide potassium salt (12.0 g, 65.0 mmol) were added to N,N-dimethylformamide (350 ml) and subjected to reaction overnight under reflux; thereafter, N,N-dlmethylformamide was distilled off under vacuum. Water (250 ml) was added to the residue and the mixture was stirred well, with the floating solids being subsequently recovered by filtration. The solids were dried, then recrystallized from methanol/methylene chloride, thereby yielding (1,4-benzodioxan-2-ylmethyl)phthalimide as a colorless tabular crystal in an amount of 8.43 g. The thus obtained crystal was dissolved in ethanol (500 ml); to the solution, hydrazine hydrate (4.3 g) was added, followed by refluxing under heating for 3 h. The resulting solids were filtered off and ethanol was distilled off under vacuum, followed by addition of water (300 ml). Thereafter, an aqueous solution of 6N sodium hydroxide was added to adjust pH to 12 and the mixture was subjected to 3 cycles of extraction with methylene chloride. The methylene chloride layers were dried with anhydrous sodium sulfate, and concentrated under vacuum, thereby yielding a crude product of 2-aminomethyl-1,4-benzodioxane as a colorless oil (crude product, 4.3 g). subjected to reaction overnight under reflux thereafter, N,N-dlmethylformamide was distilled off under vacuum Water (250 ml) was added to the residue being subsequently recovered by filtration The solids were dried recrystallized from methanol/methylene chloride The thus obtained crystal was dissolved in ethanol (500 ml) to the solution, hydrazine hydrate (4.3 g) was added by refluxing under heating for 3 h The resulting solids were filtered off ethanol was distilled off under vacuum followed by addition of water (300 ml) Thereafter, an aqueous solution of 6N sodium hydroxide was added the mixture was subjected to 3 cycles of extraction with methylene chloride The methylene chloride layers were dried with anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Dihydro-1,4-benzodioxin-2-methanamine (0.56 g, 4.0 mmole), 5-(3-chloropropoxy)carbostyril (0.70 g, 3.1 mmole), diisopropylethylamine (0.65 g, 5.0 mmole) and sodium iodide (1.0 g, 6.5 mmole) were combined in 50 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 250 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 50 g of silica gel with a gradient elution commencing with chloroform and ending with 2% methanol in chloroform. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 125 mg of title compound as a tan solid, monohydrochloride, quarter hydrate, m.p. 242°-244° C. The solvent was then removed The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride dried over sodium sulfate filtered concentrated in vacuum chromatographed on 50 g of silica gel with a gradient elution commencing with chloroform concentrated in vacuum the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl