3-phenylpropane-1,2-diamine

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:

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: To a stirred solution of p-toluenesulfonyl chloride (92.0 g, 0.482 mole) and triethylamine (48.8 g, 0.482 mole) in CH2Cl2 (350 ml) at 0° C. under a dry argon atmosphere was added a solution of 1,2-diamino-3-phenylpropane prepared as in Example 6A (34.5 g, 0.230 mole) in CH2Cl2 (100 ml), maintaining the temperature <10° C. The addition required 1 h. The mixture was allowed to warm to room temperature and was stirred an additional 15 h. The mixture was then poured onto ice (500 g) and the CH2Cl2 layer was separated. The CH2Cl2 layer was washed with 1N HCl, H2O and saturated NaCl solution and was dried (MgSO4). The solvent was removed in vacuo and the resulting yellow oil washed with hexane. The crude product was purified by recrystallization from CH2Cl2 -hexane to give 71.4 g (68% yield) of the product as a crystalline solid: mp 128°-31° C.; 1H NMR (CDCl3) δ 2.42 (s, 3 H), 2.43 (s, 3 H), 2.69 (ABq of dd, γν=44.0 Hz, J=14.0, 6.6 Hz, 2 H), 3.02 (m, 2 H), 3.36 (hex, J=6.6 Hz, 2 H), 4.85 (d, J=6.6 Hz, 1 H), 5.16 (t, J=6.5 Hz, 1 H), 6.87 (m, 2 H), 7.15 (m, 5 H), 7.29 (m, 2 H), 7.50 (m, 2 H), 7.70 (m, 2 H). maintaining the temperature <10° C The addition required 1 h The mixture was then poured onto ice (500 g) the CH2Cl2 layer was separated The CH2Cl2 layer was washed with 1N HCl, H2O and saturated NaCl solution was dried (MgSO4) The solvent was removed in vacuo the resulting yellow oil washed with hexane The crude product was purified by recrystallization from CH2Cl2 -hexane

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

実験手順: To a stirred slurry of D,L-phenylalanine amide hydrochloride (50.0 g, 0.249 mole) in anhydrous THF (200 ml) at room temperature under a dry argon atmosphere was added a solution of lithium aluminum hydride (1000 ml-1.0M in THF, 1.00 mole) over a 30 minute period. The mixture was refluxed for 7.5 h and then quenched by the dropwise addition of H2O (200 ml) while cooling in an ice bath. The solid was filtered, washed with hot THF (2×500 ml) and then hot methanol (2×500 ml). The filtrate and washings were combined and the solvent was removed in vacuo. The resulting yellow oil was dissolved in CHCl3 and the solution was filtered and dried (MgSO4). The solvent was removed in vacuo to give 34.6 g (92% yield) of the crude product as a yellow oil which crystallized on standing: 1H NMR (CDCl3) δ 1.68 (br s, 4 H), 2.51 (m, 2 H), 2.79 (m, 2 H), 2.95 (m, 1 H), 7.24 (m, 5 H). The mixture was refluxed for 7.5 h quenched by the dropwise addition of H2O (200 ml) while cooling in an ice bath The solid was filtered washed with hot THF (2×500 ml) the solvent was removed in vacuo The resulting yellow oil was dissolved in CHCl3 the solution was filtered dried (MgSO4) The solvent was removed in vacuo

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: The benzathine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N′-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford atorvastatin benzathine Form B. Note that this procedure is the same as above except that the sample was not oven dried. After 2 days of stirring at ambient temperature the solids were isolated by vacuum filtration fitted with a paper filter (#2 Whatman) The solids were rinsed with acetonitrile (75 mL)

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

実験手順: The benzathine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N′-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford atorvastatin benzathine Form B. Note that this procedure is the same as above except that the sample was not oven dried. After 2 days of stirring at ambient temperature the solids were isolated by vacuum filtration fitted with a paper filter (#2 Whatman) The solids were rinsed with acetonitrile (75 mL)

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

実験手順: The benzathine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N′-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford atorvastatin benzathine Form B. Note that this procedure is the same as above except that the sample was not oven dried. After 2 days of stirring at ambient temperature the solids were isolated by vacuum filtration fitted with a paper filter (#2 Whatman) The solids were rinsed with acetonitrile (75 mL)