METHYL ALPHA-BROMO-2-CHLOROPHENYLACETATE

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.95 g (23.3 mmol) of the (E)-3-(N,N-dimethylcarbamoyl)methylidene-4-hydroxypiperidine p-toluenesulfonate were dissolved in 50 ml of N,N-dimethylformamide (DMF), followed by the addition of 7.35 g (purity: 80.0%, 22.3 mmol) of 2-chloro-α-methoxycarbonylbenzyl bromide and 7.40 g (53.5 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, 150 ml water were added. The resulting mixture was extracted with toluene and ethyl acetate. The extract was distilled under reduced pressure. The residue was then purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=9/1 to 4/1), whereby 6.38 g (77.9%) of the title compound were obtained as a yellowish brown oil. were added The resulting mixture was extracted with toluene and ethyl acetate The extract was distilled under reduced pressure The residue was then purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=9/1 to 4/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Tetrahydrothienopyridine hydrochloride from Example 1 was reacted with α-bromo-2-chlorophenyl acetic acid methyl ester in acetone in the presence of potassium carbonate to give racemic clopidogrel. After inorganic salt filtration, the product was recovered as bisulfate, by addition of sulfuric acid.

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted with 83 g (0.315 mole) of α-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5 Lt. DMF in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 Hrs. The reaction mixture was filtered at RT and washed the residue with DMF. The DMF was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the base was extracted from the aqueous layer using methylene dichloride. The methylene dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =92% The reaction mixture was filtered at RT washed the residue with DMF The DMF was concentrated under vacuum to obtain a viscous liquid the base was extracted from the aqueous layer The methylene dichloride was concentrated under vacuum

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted with 83 g (0.315 mole) of α-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5 Lt. DMF in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 Hrs. The reaction mixture was filtered at RT and washed the residue with DMF. The DMF was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the base was extracted from the aqueous layer using methylene dichloride. The methylene dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =92% The reaction mixture was filtered at RT washed the residue with DMF The DMF was concentrated under vacuum to obtain a viscous liquid the base was extracted from the aqueous layer The methylene dichloride was concentrated under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred (0° C.) suspension of 0.530 g (4.63 mmol) of a 35% oil dispersion of potassium hydride in 5 mL of anhydrous DMF was added 0.50 g (4.63 mmol) of p-cresol and 0.050 g of 18-crown-6. After stirring at room temperature for 15 minutes, a solution of 1.22 g (4.63 mmol) of the product of Step B in 5 mL of DMF was slowly added. The reaction mixture was stirred and allowed to warm to room temperature during 45 minutes. The reaction mixture was then partitioned between ethyl acetate and water, separated, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.03 g (77%) of the title compound. After stirring at room temperature for 15 minutes The reaction mixture was stirred The reaction mixture was then partitioned between ethyl acetate and water separated dried (MgSO4) filtered evaporated in vacuo The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred (0° C.) suspension of 0.530 g (4.63 mmol) of a 35% oil dispersion of potassium hydride in 5 mL of anhydrous DMF was added 0.50 g (4.63 mmol) of p-cresol and 0.050 g of 18-crown-6. After stirring at room temperature for 15 minutes, a solution of 1.22 g (4.63 mmol) of the product of Step B in 5 mL of DMF was slowly added. The reaction mixture was stirred and allowed to warm to room temperature during 45 minutes. The reaction mixture was then partitioned between ethyl acetate and water, separated, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.03 g (77%) of the title compound. After stirring at room temperature for 15 minutes The reaction mixture was stirred The reaction mixture was then partitioned between ethyl acetate and water separated dried (MgSO4) filtered evaporated in vacuo The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: α-Bromo-2-chlorophenyl acetic acid (350.0 gm) was dissolved in methanol (1.18 Liter) and concentrated sulphuric acid (53.20 gm) was added. The reaction mixture was refluxed for 4 hours. After completion of the reaction, the reaction mixture was distilled out to get a syrupy mass. To the residual mass, water (560 ml) was added and the product was extracted into chloroform (560 ml). The chloroform layer was separated and was treated with 10% aqueous sodium bicarbonate solution (1.12 Litre). The chloroform extract was finally washed with water and chloroform was distilled out to get a syrupy mass to get the titled compound. The reaction mixture was refluxed for 4 hours After completion of the reaction the reaction mixture was distilled out to get a syrupy mass the product was extracted into chloroform (560 ml) The chloroform layer was separated was treated with 10% aqueous sodium bicarbonate solution (1.12 Litre) The chloroform extract was finally washed with water and chloroform was distilled out to get a syrupy mass

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Tetrahydrothienopyridine hydrochloride from Example 1 was reacted with α-bromo-2-chlorophenyl acetic acid methyl ester in acetone in the presence of potassium carbonate to give racemic clopidogrel. After inorganic salt filtration, the product was recovered as bisulfate, by addition of sulfuric acid.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 361 mg (1.37 mmol) of methyl bromo(2-chlorophenyl)acetate were initially charged in 10 ml of acetonitrile, and 89 mg (1.37 mmol) of sodium azide were added. The mixture was stirred at RT for 1 h. 2.7 mg (0.14 mmol) of copper(II) acetate monohydrate and 569 mg (1.64 mmol) of the compound from Example 14A were then added. The resulting mixture was stirred at 50° C. for 48 h. The reaction mixture was then filtered through a little silica gel, the product being eluted with about 10 ml of ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1). This gave 496 mg (53% of theory) of the target compound. The resulting mixture was stirred at 50° C. for 48 h The reaction mixture was then filtered through a little silica gel the product being eluted with about 10 ml of ethyl acetate the filtrate was concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 361 mg (1.37 mmol) of methyl bromo(2-chlorophenyl)acetate were initially charged in 10 ml of acetonitrile, and 89 mg (1.37 mmol) of sodium azide were added. The mixture was stirred at RT for 1 h. 2.7 mg (0.14 mmol) of copper(II) acetate monohydrate and 569 mg (1.64 mmol) of the compound from Example 14A were then added. The resulting mixture was stirred at 50° C. for 48 h. The reaction mixture was then filtered through a little silica gel, the product being eluted with about 10 ml of ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1). This gave 496 mg (53% of theory) of the target compound. The resulting mixture was stirred at 50° C. for 48 h The reaction mixture was then filtered through a little silica gel the product being eluted with about 10 ml of ethyl acetate the filtrate was concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1)