2-(bromomethyl)-2,3-dihydro-1-benzofuran

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

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

Procedure: 1.07 g (5.0 mmol) of compound 001C, which had been prepared in Step C of Reference Example 1, was dissolved in 11 ml of acetonitrile. To the resultant solution were added 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate. The resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 100 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 002A, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 50 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with chloroform, to thereby obtain 873 mg of compound 002A as a yellow oily substance (yield: 73%). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with chloroform

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

Procedure: 430 mg (2.0 mmol) of compound 001C, which had been prepared in Step C, was dissolved in 4 ml of acetonitrile. To the resultant solution were added 0.92 ml (10.0 mmol) of 4-amino-1-buthanol and 550 mg (4.0 mmol) of potassium carbonate and then, the resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001D, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1), to thereby obtain 300 mg of compound 001D as a light yellow oily substance (yield: 67 %). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1)

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

Procedure: 430 mg (2.0 mmol) of compound 001C, which had been prepared in Step C, was dissolved in 4 ml of acetonitrile. To the resultant solution were added 0.92 ml (10.0 mmol) of 4-amino-1-buthanol and 550 mg (4.0 mmol) of potassium carbonate and then, the resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001D, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1), to thereby obtain 300 mg of compound 001D as a light yellow oily substance (yield: 67 %). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 340 mg (1.0 mmol) of compound 001B, which had been prepared in Step B, was dissolved in 3 ml of ethanol, followed by cooling to 0° C. To the resultant solution was dropwise added 1.2 ml (1.2 mmol) of a 1N solution of sodium ethoxide in ethanol and then, the resultant mixture was stirred at 0° C. for 2 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001C, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of hexane-ethyl acetate (30:1), to thereby obtain 140 mg of compound 001C as a transparent oily substance (yield: 66%). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with a mixed solvent of hexane-ethyl acetate (30:1)

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

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

Procedure: A solution of bromine (90 g) in carbon disulphide (100 ml) was added dropwise to a well stirred solution of O-acetyl-2-allylphenol (100 g) in carbon disulphide (300 ml) at -10° C. over 1 hour. The solution was evaporated to dryness in vacuo, to afford O-acetyl-2-allylphenol dibromide which was immediately dissolved in dry ethanol (300 ml) containing 10 ml of a saturated ethanolic-hydrogen chloride solution. The solution was heated under gentle reflux for 2 hours, and then evaporated to dryness in vacuo. The residue was triturated with n-pentane, and the solid 2-allylphenol dibromide (135 g) was collected and washed twice with portions of n-pentane. The product is pure enough for further reaction. 2-Allylphenol dibromide (135 g) in dry ethanol (300 ml) was treated with a solution of sodium ethoxide (38 g) in ethanol (100 ml) with cooling and stirring, keeping the temperature of the reaction between 30° and 35° C. After addition, the reaction was stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue was partioned between n-pentane and water. The n-pentane fraction was washed with 2% sodium hydroxide solution, water, and dried (Na2SO4). Evaporation to dryness in vacuo afforded crude (2,3-dihydro-2-benzofuranyl)-methyl bromide (90 g), which distilled at 110°-118° C./0.5 mm to afford product (78 g) of slightly higher purity. The solution was heated under gentle reflux for 2 hours evaporated to dryness in vacuo The residue was triturated with n-pentane the solid 2-allylphenol dibromide (135 g) was collected washed twice with portions of n-pentane The product is pure enough for further reaction with cooling the temperature of the reaction between 30° and 35° C After addition the reaction was stirred at room temperature for 1 hour evaporated to dryness in vacuo The n-pentane fraction was washed with 2% sodium hydroxide solution, water dried (Na2SO4) Evaporation to dryness in vacuo afforded crude (2,3-dihydro-2-benzofuranyl)-methyl bromide (90 g), which distilled at 110°-118° C./0.5 mm

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

Procedure: 1.07 g (5.0 mmol) of compound 001C, which had been prepared in Step C of Reference Example 1, was dissolved in 11 ml of acetonitrile. To the resultant solution were added 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate. The resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 100 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 002A, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 50 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with chloroform, to thereby obtain 873 mg of compound 002A as a yellow oily substance (yield: 73%). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with chloroform

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

Procedure: 430 mg (2.0 mmol) of compound 001C, which had been prepared in Step C, was dissolved in 4 ml of acetonitrile. To the resultant solution were added 0.92 ml (10.0 mmol) of 4-amino-1-buthanol and 550 mg (4.0 mmol) of potassium carbonate and then, the resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001D, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1), to thereby obtain 300 mg of compound 001D as a light yellow oily substance (yield: 67 %). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 20 ml of a saturated aqueous sodium hydrogencarbonate solution, 20 ml of water and 20 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with a mixed solvent of chloroform-methanol-concentrated aqueous ammonia (10:1:0.1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 340 mg (1.0 mmol) of compound 001B, which had been prepared in Step B, was dissolved in 3 ml of ethanol, followed by cooling to 0° C. To the resultant solution was dropwise added 1.2 ml (1.2 mmol) of a 1N solution of sodium ethoxide in ethanol and then, the resultant mixture was stirred at 0° C. for 2 hours to effect a reaction. To the resultant reaction mixture was added 20 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 001C, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 10 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with a mixed solvent of hexane-ethyl acetate (30:1), to thereby obtain 140 mg of compound 001C as a transparent oily substance (yield: 66%). a reaction To the resultant reaction mixture to obtain a mixture The obtained mixture was successively washed with 20 ml of a 10% aqueous citric acid solution, 20 ml of water and 20 ml of saturated saline to thereby form a chloroform layer followed by separation of the chloroform layer The chloroform layer thus separated filter paper concentrated in vacuo to thereby obtain a residue The obtained residue was purified by silica gel column chromatography eluted with a mixed solvent of hexane-ethyl acetate (30:1)