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5-Chloro- 2,3-dihydro-1-benzofuran-3-amine hydrochoride salt (10.8 g, 53 mmol) was dissolved in saturated aqueous NaHCO3 solution (300 ml_). The pH was adjusted to 9 by the addition of aqueous NaOH solution (3 N), and the mixture was extracted with CH2CI2/Me0H (90/10) and CHCI3/MeOH (90/10). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound. Yield: 5.00 g, 29.6 mmol, 56%. 1H NMR of the aqueous layer indicated the presence of additional product. The aqueous layer was concentrated to dryness and the residue was stirred in CHCI3/MeOH (80/20) overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to furnish additional title compound (0.50 g, 2.96 mmol, 5%). 1H NMR of the MgSO4 pad indicated the presence of a significant amount of the desired product. The solids were suspended in a mixture of isopropanol (420 ml_) and a 7 N solution of ammonia in MeOH (7 ml_) and stirred for 15 minutes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford an additional 3.24 g (19.2 mmol, 36%) of the title compound. The title compound was obtained as a white solid. Combined yield = 8.74 g, 52 mmol, 98%.
98%
With sodium hydrogencarbonate; sodium hydroxide; In water;pH 9.0;
Step 7. Synthesis of 5-chloro-2,3-dihydro-1 -benzofuran-3-amine. 5-Chloro-2,3-dihydro-1 -benzofuran-3-amine hydrochloride salt (10.8 g, 53 mmol) was dissolved in saturated aqueous NaHC03 solution (300 mL). The pH was adjusted to 9 by the addition of aqueous NaOH solution (3 N), and the mixture was extracted with CH2Cl2/MeOH (90/10) and CHCI3/MeOH (90/10). The combined organic layers were dried over MgS04 and concentrated under reduced pressure to give the title compound. Yield: 5.00 g, 29.6 mmol, 56%. 1 H N MR of the aqueous layer indicated the presence of additional product. The aqueous layer was concentrated to dryness and the residue was stirred in CHCI3/MeOH (80/20) overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to furnish additional title compound (0.50 g, 2.96 mmol, 5%). H N MR of the MgS04 pad indicated the presence of a significant amount of the desired product. The solids were suspended in a mixture of isopropanol (420 mL) and a 7 N solution of ammonia in MeOH (7 mL) and stirred for 15 minutes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford an additional 3.24 g (19.2 mmol, 36%) of the title compound. The title compound was obtained as a white solid. Combined yield: 8.74 g, 51.7 mmol, 98%.
(+)-2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinan-2-one[ No CAS ]
5-chloro-2,3-dihydro-1-benzofuran-3-amine[ No CAS ]
(+)-phencyphos salt of 5-chloro-2,3-dihydro-1-benzofuran-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
Step 8. Synthesis of 5-chloro-2,3-dihydro-1 -benzofuran-3-amine enantiomer 1 (P6 entantiomer 1 ). Racemic 5-chloro-2,3-dihydro-1 -benzofuran-3-amine (8.74 g, 51 .7 mmol) and (+)-phencyphos (2-hydroxy-5,5-dimethyl-4-phenyl-1 ,3,2- dioxaphosphorinan-2-one) (12.52 g, 51 .7 mmol) were suspended in EtOH (300 mL) and water (2 mL). The mixture was heated to reflux using a heat gun and then allowed to cool slowly to room temperature overnight. The resulting solid was isolated by filtration and recrystallized from EtOH/water (120 mL / 0.7 mL). The solids were dissolved in aqueous NaOH (3 N , 70 mL) and CH2CI2 (100 mL) and stirred at room temperature for 2 h, whereupon the mixture was filtered to remove the (+)- phencyphos sodium salt. The solids were washed with CH2CI2 and the two layers from the combined filtrate and washings were separated. The aqueous layer was extracted with CH2CI2 and the combined organic layers were dried by adding Na2S04 and stirring for 10 min followed by filtration through a pad of Na2S04 to afford the title compound as a yellow oil. Yield: 2.92 g, 17.3 mmol, 33%, 96% ee. The spectral data was identical to that of enantiomer 2 in Step 9.
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