Ethyl (4-forMylphenyl)acetate

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetramine are dissolved in 200 ml of 20% acetic acid, heated to 100° C. with stirring and stirred for four hours. The reaction solution is allowed to cool and sufficient sodium carbonate is added until a saturated solution is obtained. This solution is extracted with ether, dried and the ether is then removed. The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1). stirred for four hours to cool is obtained This solution is extracted with ether dried the ether is then removed The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1)

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

Procedure: (4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg). the resulting mixture stirred for 18 hours concentrated The residue was dissolved in methanol (5 mL) The resin was washed with methanol (3×20 mL) eluted with 3M methanolic ammonia solution (2×15 mL) The combined elution fractions were evaporated The residue was dissolved in dichloromethane (10 mL) di-tert-butyl dicarbonate (0.42 g) was added The mixture was stirred at room temperature, under nitrogen, for 18 hours Purification on silica eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil stirred for 18 hours, under nitrogen the mixture concentrated to ˜2 mL The aqueous residue was extracted with ethyl acetate (3×10 mL) washed with brine (10 mL) dried (magnesium sulfate) evaporated

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

Procedure: (4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg). the resulting mixture stirred for 18 hours concentrated The residue was dissolved in methanol (5 mL) The resin was washed with methanol (3×20 mL) eluted with 3M methanolic ammonia solution (2×15 mL) The combined elution fractions were evaporated The residue was dissolved in dichloromethane (10 mL) di-tert-butyl dicarbonate (0.42 g) was added The mixture was stirred at room temperature, under nitrogen, for 18 hours Purification on silica eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil stirred for 18 hours, under nitrogen the mixture concentrated to ˜2 mL The aqueous residue was extracted with ethyl acetate (3×10 mL) washed with brine (10 mL) dried (magnesium sulfate) evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetramine are dissolved in 200 ml of 20% acetic acid, heated to 100° C. with stirring and stirred for four hours. The reaction solution is allowed to cool and sufficient sodium carbonate is added until a saturated solution is obtained. This solution is extracted with ether, dried and the ether is then removed. The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1). stirred for four hours to cool is obtained This solution is extracted with ether dried the ether is then removed The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1)

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

Procedure: A mixture of 3.7 g of ethyl p-formylphenylacetate, 5.2 g of pyrrolidinocyclopentene and 20 ml of benzene was heated under reflux for 13 hours. After cooling, 5 ml of conc. hydrochloric acid and 5 ml of water were added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. To the mixture added 100 ml of benzene, a benzene layer was separated, washed with water and dried over anhydrous sodium sulfate. Thereafter, the benzene was distilled off and the residue was subjected to a silica gel column chromatography. Elution was effected with benzene-ethyl acetate 50:1 to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance having a boiling point of 175°-180° C./0.3 mmHg (bath temp.). was heated under reflux for 13 hours After cooling a benzene layer was separated washed with water dried over anhydrous sodium sulfate Thereafter, the benzene was distilled off Elution to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance

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

Procedure: A mixture of 3.7 g of ethyl p-formylphenylacetate, 5.2 g of pyrrolidinocyclopentene and 20 ml of benzene was heated under reflux for 13 hours. After cooling, 5 ml of conc. hydrochloric acid and 5 ml of water were added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. To the mixture added 100 ml of benzene, a benzene layer was separated, washed with water and dried over anhydrous sodium sulfate. Thereafter, the benzene was distilled off and the residue was subjected to a silica gel column chromatography. Elution was effected with benzene-ethyl acetate 50:1 to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance having a boiling point of 175°-180° C./0.3 mmHg (bath temp.). was heated under reflux for 13 hours After cooling a benzene layer was separated washed with water dried over anhydrous sodium sulfate Thereafter, the benzene was distilled off Elution to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance

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

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

Procedure: A mixture of 3.7 g of ethyl p-formylphenylacetate, 5.2 g of pyrrolidinocyclopentene and 20 ml of benzene was heated under reflux for 13 hours. After cooling, 5 ml of conc. hydrochloric acid and 5 ml of water were added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. To the mixture added 100 ml of benzene, a benzene layer was separated, washed with water and dried over anhydrous sodium sulfate. Thereafter, the benzene was distilled off and the residue was subjected to a silica gel column chromatography. Elution was effected with benzene-ethyl acetate 50:1 to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance having a boiling point of 175°-180° C./0.3 mmHg (bath temp.). was heated under reflux for 13 hours After cooling a benzene layer was separated washed with water dried over anhydrous sodium sulfate Thereafter, the benzene was distilled off Elution to give an oily substance, which was then distilled under reduced pressure to afford 0.5 g of an oily substance

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A screw cap tube was loaded with (4-formylphenyl)boronic acid (450 mg, 3 mmol), ethylbromoacetate (0.22 mL, 2 mmol), potassium carbonate (830 mg, 6 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), tri-1-naphtylphosphine (62 mg, 0.15 mmol), H2O (0.5 mL), and THF (4.5 mL). The mixture was degased with nitrogen for 5 minutes and then heated to 65° C. for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with water (2×50 mL). The organic phase was filtered through a phase separator and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to yield ethyl 2-(4-formylphenyl)acetate as colourless oil (327 mg, 57%). A screw cap tube The mixture was degased with nitrogen for 5 minutes The reaction was cooled to room temperature diluted with ethyl acetate (50 mL) washed with water (2×50 mL) The organic phase was filtered through a phase separator the solvent was removed in vacuo The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in isohexane

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

Procedure: (4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg). the resulting mixture stirred for 18 hours concentrated The residue was dissolved in methanol (5 mL) The resin was washed with methanol (3×20 mL) eluted with 3M methanolic ammonia solution (2×15 mL) The combined elution fractions were evaporated The residue was dissolved in dichloromethane (10 mL) di-tert-butyl dicarbonate (0.42 g) was added The mixture was stirred at room temperature, under nitrogen, for 18 hours Purification on silica eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil stirred for 18 hours, under nitrogen the mixture concentrated to ˜2 mL The aqueous residue was extracted with ethyl acetate (3×10 mL) washed with brine (10 mL) dried (magnesium sulfate) evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetramine are dissolved in 200 ml of 20% acetic acid, heated to 100° C. with stirring and stirred for four hours. The reaction solution is allowed to cool and sufficient sodium carbonate is added until a saturated solution is obtained. This solution is extracted with ether, dried and the ether is then removed. The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1). stirred for four hours to cool is obtained This solution is extracted with ether dried the ether is then removed The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1)