2,3-dihydro-1,4-benzodioxine-3-carbonyl chloride

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: A suspension of piperazine (11.88 g.) and sodium acetate (20.30 g.) in a mixture of water (70 ml.) and acetone (95 ml.) was stirred at 10°-15° C., then concentrated hydrochloric acid was added (about 35 ml.) until the pH of the solution reached 1.5. 1,4-Benzodioxan-2-carbonyl chloride (31.0 g.) and sodium hydroxide (5 N, about 45 ml.) were then added portionwise while maintaining the temperature at 10°-15° C., the sodium hydroxide maintaining the pH at 1.7-2.2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide, the suspension was stirred for a further 30 minutes. Water was then added until a homogeneous solution resulted, the acetone removed in vacuo, and the aqueous phase was basified to pH 8-9 with sodium hydroxide (5 N), re-extracted with chloroform (3×200 ml.) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N-(1,4-benzodioxan-2-carbonyl)-piperazine hydrochloride (4.85 g.), M.P. 265°-267° C. while maintaining the temperature at 10°-15° C. After the addition the suspension was stirred for a further 30 minutes resulted the acetone removed in vacuo re-extracted with chloroform (3×200 ml.) the extracts washed with water dried (MgSO4) evaporated in vacuo The oily residue was dissolved in ethyl acetate treated with ethereal hydrogen chloride evaporated in vacuo the solid residue triturated with ether followed by recrystallization from methanol

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (6-Methyl-2-p-tolyl-imidazo[1,2,a]pyridin-3-yl)-acetic acid methyl ester 35a (447 mg, 1.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to −78° C. Potassium hexamethyldisilazide (0.5M in toluene, 3.0 mL, 1.5 mmol) was added slowly and the resulting bright orange solution was stirred at −78° C. for 10 minutes. 2,3-Dihydro-benzo[1,4]dioxine-2-carbonyl chloride (150 mg, 0.76 mmol) dissolved in anhydrous THF (10 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 1 h at −78° C. and quenched with H2O (30 mL). After the solution warmed to room temperature, it was washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. The crude keto-ester (0.76 mmol) was dissolved in concentrated acetic acid (4.5 mL) and concentrated HCl (4.5 mL). A reflux condenser was attached and the yellow solution was heated at 120° C. for 16 h. The solution was cooled to room temperature and saturated aqueous K2CO3 was added slowly until pH=6. The suspension was poured into saturated aqueous K2CO3 and washed with EtOAc (3×50 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Purification was affected via silica gel column chromatography with 0–5% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40–80% CH3CN/H2O over 20 minutes, monitoring at 254 nm. The product eluted at 14.3 minutes. Product fractions were collected and concentrated to remove CH3CN, then washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Final purification by silica gel column chromatography with 0–5% MeOH/CH2Cl2 yielded 1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (6.0 mg, 2%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.56–7.50 (m, 3H), 7.42 (s, 1H), 7.23 (d, J=8.07, 2H), 7.04 (dd, J=1.1, 9.2 Hz, 1H), 6.95–6.89 (m, 4H), 4.82–4.80 (m, 1H), 4.51–4.42 (m, 2H), 4.33–4.26 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H). Mass spectrum (m/e) 399 (M+1)+. The resulting yellow solution was stirred for 1 h at −78° C. quenched with H2O (30 mL) After the solution warmed to room temperature it was washed with EtOAc (3×30 mL) The combined organic washes were dried (Na2SO4) filtered concentrated A reflux condenser was attached the yellow solution was heated at 120° C. for 16 h The solution was cooled to room temperature washed with EtOAc (3×50 mL) The combined organic washes were dried (Na2SO4) filtered concentrated Purification Conditions: 20 mL/min flow rate, gradient of 40–80% CH3CN/H2O over 20 minutes The product eluted at 14.3 minutes Product fractions were collected concentrated to remove CH3CN washed with EtOAc (3×30 mL) The combined organic washes were dried (Na2SO4) filtered concentrated Final purification by silica gel column chromatography with 0–5% MeOH/CH2Cl2

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

Procedure: A solution of 1,4-benzodioxan-2-carbonyl chloride (0.75 g) in chloroform (10 ml) was added dropwise to a stirred solution of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (1.0 g) in chloroform (50 ml) with triethylamine (1.06 g) at 5°-10°. The reaction was stirred at 5°-10° for one hour, then allowed to attain room temperature and stirred overnight. The mixture was then evaporated in vacuo and the residue partitioned between chloroform (50 ml) and sodium carbonate solution (10%, 50 ml). The chloroform layer was separated, the aqueous phase extracted with chloroform (2×50 ml), the extracts combined, washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was then taken up in chloroform and chromatographed on silica (Merck 9385, 60 g) eluting with chloroform/methanol (100:0→97:3). A solution of the purified product in chloroform was treated with ethereal hydrogen chloride, evaporated in vacuo and the residue recrystallised from isopropanol to give 4-amino-2-[ 4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline hydrochloride hydrate (0.28 g), m.p. 201°. to attain room temperature stirred overnight The mixture was then evaporated in vacuo the residue partitioned between chloroform (50 ml) and sodium carbonate solution (10%, 50 ml) The chloroform layer was separated the aqueous phase extracted with chloroform (2×50 ml) washed with brine dried (Na2SO4) evaporated in vacuo chromatographed on silica (Merck 9385, 60 g) eluting with chloroform/methanol (100:0→97:3) A solution of the purified product in chloroform was treated with ethereal hydrogen chloride evaporated in vacuo the residue recrystallised from isopropanol

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

Procedure: A solution of 1,4-benzodioxan-2-carbonyl chloride (0.75 g) in chloroform (10 ml) was added dropwise to a stirred solution of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (1.0 g) in chloroform (50 ml) with triethylamine (1.06 g) at 5°-10°. The reaction was stirred at 5°-10° for one hour, then allowed to attain room temperature and stirred overnight. The mixture was then evaporated in vacuo and the residue partitioned between chloroform (50 ml) and sodium carbonate solution (10%, 50 ml). The chloroform layer was separated, the aqueous phase extracted with chloroform (2×50 ml), the extracts combined, washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was then taken up in chloroform and chromatographed on silica (Merck 9385, 60 g) eluting with chloroform/methanol (100:0→97:3). A solution of the purified product in chloroform was treated with ethereal hydrogen chloride, evaporated in vacuo and the residue recrystallised from isopropanol to give 4-amino-2-[ 4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline hydrochloride hydrate (0.28 g), m.p. 201°. to attain room temperature stirred overnight The mixture was then evaporated in vacuo the residue partitioned between chloroform (50 ml) and sodium carbonate solution (10%, 50 ml) The chloroform layer was separated the aqueous phase extracted with chloroform (2×50 ml) washed with brine dried (Na2SO4) evaporated in vacuo chromatographed on silica (Merck 9385, 60 g) eluting with chloroform/methanol (100:0→97:3) A solution of the purified product in chloroform was treated with ethereal hydrogen chloride evaporated in vacuo the residue recrystallised from isopropanol

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

Procedure: To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (120 mg, 0.362 mmol, 1 eq.) and pyridine (0.044 ml, 0.543 mmol, 1.5 eq) in dry dichloromethane (2.0 ml) at room temperature was added 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride (108 mg, 0.543 mmol, 1.5 eq) and stirring was allowed overnight. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in EtOAc and 0.5 ml of 1N NaOH was added. The solution was filtered through a chemelut pad and washed with EtOAc. After concentration, the residue was purified by chromatography on silica gel to give N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide (190 mg, 99% yield). The reaction was quenched by addition of water concentrated to dryness 0.5 ml of 1N NaOH was added The solution was filtered through a chemelut pad washed with EtOAc After concentration the residue was purified by chromatography on silica gel

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

Procedure: To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (120 mg, 0.362 mmol, 1 eq.) and pyridine (0.044 ml, 0.543 mmol, 1.5 eq) in dry dichloromethane (2.0 ml) at room temperature was added 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride (108 mg, 0.543 mmol, 1.5 eq) and stirring was allowed overnight. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in EtOAc and 0.5 ml of 1N NaOH was added. The solution was filtered through a chemelut pad and washed with EtOAc. After concentration, the residue was purified by chromatography on silica gel to give N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide (190 mg, 99% yield). The reaction was quenched by addition of water concentrated to dryness 0.5 ml of 1N NaOH was added The solution was filtered through a chemelut pad washed with EtOAc After concentration the residue was purified by chromatography on silica gel

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

Procedure: To a mixture of 2,3-dihydrobenzo[1,4]dioxine-2-carbonyl chloride (2.0 g, 10.0 mmol) and 4-oxopiperidine-3-carboxylic acid methyl ester (2.14 g, 11.0 mmol) in DMF (5 ml) was added triethylamine (1.54 ml). The reaction mixture was stirred at RT for 5 h. The reaction mixture was taken up in water, made alkaline with aq NaOH and extracted with DCM to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-4-oxopiperidine-3-carboxylic acid methyl ester. A mixture of this product (0.2 g, 0.62 mmol), K2CO3 (0.17 g, 1.23 mmol) and methyl iodide (0.08 ml, 1.25 mmol) in acetone (20 ml) was irradiated in the microwave reactor at 56° C. for 90 min. Water was added and the reaction mixture extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methyl-4-oxopiperidine-3-carboxylic acid methyl ester, which was finally reduced with LiAlH4 in THF to afford the title compound. extracted with DCM

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

Procedure: To a mixture of 2,3-dihydrobenzo[1,4]dioxine-2-carbonyl chloride (2.0 g, 10.0 mmol) and 4-oxopiperidine-3-carboxylic acid methyl ester (2.14 g, 11.0 mmol) in DMF (5 ml) was added triethylamine (1.54 ml). The reaction mixture was stirred at RT for 5 h. The reaction mixture was taken up in water, made alkaline with aq NaOH and extracted with DCM to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-4-oxopiperidine-3-carboxylic acid methyl ester. A mixture of this product (0.2 g, 0.62 mmol), K2CO3 (0.17 g, 1.23 mmol) and methyl iodide (0.08 ml, 1.25 mmol) in acetone (20 ml) was irradiated in the microwave reactor at 56° C. for 90 min. Water was added and the reaction mixture extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methyl-4-oxopiperidine-3-carboxylic acid methyl ester, which was finally reduced with LiAlH4 in THF to afford the title compound. extracted with DCM

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

Procedure: A suspension of piperazine (11.88 g.) and sodium acetate (20.30 g.) in a mixture of water (70 ml.) and acetone (95 ml.) was stirred at 10°-15° C., then concentrated hydrochloric acid was added (about 35 ml.) until the pH of the solution reached 1.5. 1,4-Benzodioxan-2-carbonyl chloride (31.0 g.) and sodium hydroxide (5 N, about 45 ml.) were then added portionwise while maintaining the temperature at 10°-15° C., the sodium hydroxide maintaining the pH at 1.7-2.2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide, the suspension was stirred for a further 30 minutes. Water was then added until a homogeneous solution resulted, the acetone removed in vacuo, and the aqueous phase was basified to pH 8-9 with sodium hydroxide (5 N), re-extracted with chloroform (3×200 ml.) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N-(1,4-benzodioxan-2-carbonyl)-piperazine hydrochloride (4.85 g.), M.P. 265°-267° C. while maintaining the temperature at 10°-15° C. After the addition the suspension was stirred for a further 30 minutes resulted the acetone removed in vacuo re-extracted with chloroform (3×200 ml.) the extracts washed with water dried (MgSO4) evaporated in vacuo The oily residue was dissolved in ethyl acetate treated with ethereal hydrogen chloride evaporated in vacuo the solid residue triturated with ether followed by recrystallization from methanol

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

Procedure: A suspension of piperazine (11.88 g.) and sodium acetate (20.30 g.) in a mixture of water (70 ml.) and acetone (95 ml.) was stirred at 10°-15° C., then concentrated hydrochloric acid was added (about 35 ml.) until the pH of the solution reached 1.5. 1,4-Benzodioxan-2-carbonyl chloride (31.0 g.) and sodium hydroxide (5 N, about 45 ml.) were then added portionwise while maintaining the temperature at 10°-15° C., the sodium hydroxide maintaining the pH at 1.7-2.2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide, the suspension was stirred for a further 30 minutes. Water was then added until a homogeneous solution resulted, the acetone removed in vacuo, and the aqueous phase was basified to pH 8-9 with sodium hydroxide (5 N), re-extracted with chloroform (3×200 ml.) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N-(1,4-benzodioxan-2-carbonyl)-piperazine hydrochloride (4.85 g.), M.P. 265°-267° C. while maintaining the temperature at 10°-15° C. After the addition the suspension was stirred for a further 30 minutes resulted the acetone removed in vacuo re-extracted with chloroform (3×200 ml.) the extracts washed with water dried (MgSO4) evaporated in vacuo The oily residue was dissolved in ethyl acetate treated with ethereal hydrogen chloride evaporated in vacuo the solid residue triturated with ether followed by recrystallization from methanol