| 51.7% |
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: With potassium iodide In water at 0 - 20℃; |
To a solution of 2-amino-4-chloro-phenol 4a (50 g, 0.35 mol) in HC1 (2.5 mol, 500 mL) was added drop-wise a solution of sodium nitrite (25.25 g, 0.35 mol) in water (50 mL) at 0 °C. The mixture was stirred at this temperature for 30 min. Then a cooled solution of KI (70 g, 0.42 mol) in H2O (100 mL) was slowly added at 0 °C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and the separated aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic fraction was washed with Na2S2C>3 (10percent, 100 mL), water (100 mL x 2) and brine (200 mL), dried over Na2S04 and concentrated to dryness. The residue was purified by column on silica gel to afford 4-chloro-2-iodo-phenol 4b as a yellow solid (46 g, yield 51.7percent). .H NMR (400 MHz, CDCI3): 8 7.67 (d, J= 2.4 Hz, 1 H), 7.21 (dd, J= 2.4, 8.4, Hz, 1 H), 6.91 (d, J= 8.4 Hz, 1 H), 5.33 (s, 1 H).[0223] To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol), (1-benzyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0 °C under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na2CC>3 solution (10percent 100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (200 mL), dried over Na2S04, concentrated to dryness. The residue was purified by column on silica gel to afford l-benzyl-4-(4- chloro-2-iodo-phenoxymethyl)-l, 2, 3, 6-tetrahydro-pyridine 4c (30 g, 86percent). XH NMR (400 MHz, CDC13): 8 7.73 (d, J= 2.4 Hz, 1 H), 7.22-7.38 (m, 6 H), 6.70 (d, J= 8.8 Hz, 1 H), 5.82 (s, 1 H), 4.43 (s, 2 H), 3.63 (s, 2 H), 3.05 (s, 2 H), 2.67 (t, J= 5.6 Hz, 2 H), 2.28 (s, 2 H). To a refluxing solution of l-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-l, 2, 3, 6-tetrahydro- pyridine 4c (26.7 g, 0.06 mol) and AIBN (0.05g, 0.003 mol) in dry benzene was added a solution of Bu3SnH (40 g, 0.137 mol) in benzene (100 mL) over lh under nitrogen atmosphere. After addition, the mixture was refluxed for 3 hr and additional AIBN (0.5g, 0.003 mol) and BU3S11H (20 g, 0.68 mol) were added. After refluxing for 4 hr, the mixture was concentrated to dryness, and EtOAc (100 mL) and HC1 (10percent, 40 mL) were added. The precipitate was filtered and washed with petroleum ether to give 2, 3-dihydro-l'-benzyl-5-chlorospiro (benzofuran-3, 4'-piperidine) as its HC1 salt, which was basified by NaHCCh solution to give 2, 3-dihydro-l'-benzyl-5-chlorospiro (benzofuran-3,4'-piperidine) 4d (13 g, 68percent).[0225] To a solution of 2, 3-dihydro-l'-benzyl-5-chlorospiro (benzofuran-3, 4'-piperidine) 4d (13g, 0.04 mol) in CH2CI2 (130 mL) was added drop-wise 1-chloroethyl chloroformate (7.2 g, 0.05 mol). The mixture was stirred for 3 hr at room temperature and then concentrated to dryness. The residue was dissolved in CH3OH (30 mL) and the solution was heated to reflux for 30 min. After removing of the solvent, ether was added. The resulted solid was filtered and washed with ether to the debenzylated product 4e as the HC1 salt (5.5g, yield 48percent). .H NMR (400 MHz, DMSO-4): 5 9.08 (hr s, 1 H), 7.16-7.19 (m, 2 H), 6.82 (d, /= 8.4 Hz, 1 H), 4.50 (s, 2 H), 3.25-9.29 (m, 2 H), 2.98-2.92 (m, 2 H), 2.12-2.05 (m, 2 H), 1.83-1.8 (m, 2 H). [0226] The chloro-dihydrobenzofuran spiro amine 4e (3.18 mmol) was dissolved in anhydrous DCE (15 mL) and treated with triethylamine (322 mg, 3.18 mmol), followed by (+)-2-norcamphor (421 mg, 3.82 mmol), acetic acid (382 mg, 6.36 mmol) and NaBH(OAc)3 (1.35 g, 6.37 mmol). The reaction was stirred vigorously under nitrogen at room temperature for ~36 hours. The reaction was quenched with methanol (15 mL) and stirred vigorously for 10 min at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue obtained dissolved in a mixture of DMSO:CH30H (20 mL, 1:3 v/v). The solution was filtered and purified by reverse-phase HPLC (2-99percent CH3CN/0.05percent TFA, 35 mL/min). The combined pure fractions were concentrated under reduced pressure until ~25 mL of solvent remained. The suspension was treated with 1 N NaOH (25 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic extracts were washed with H2O, saturated brine, dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford 522 mg pure free base (1.64 mmol) as a crystalline white solid. The free base was readily dissolved in anhydrous diethyl ether (10 mL) and treated with 1.0 eq 1 N ethereal HC1 (1.7 mL). The thick, gelatinous suspension obtained was cooled in an ice/H20 bath for 1 hour, filtered, rinsed with ET2O (3 x 10 mL), and dried overnight under reduced pressure to yield compound no. 1 as a fine white powder. 1H-NMR (400 MHz, DMSO-d6) 8 10.1 (br s, 1 H), 7.77 (d, J= 2.2 Hz, 0.2 H), 7.21 (dd, J= 2.3 Hz, 8.5 Hz, 1H), 7.08 (d, J= 2.3 Hz, 0.8 H), 6.85 (d, J= 8.5 Hz, 0.8 H), 6.84 (d, J= 8.5 Hz, 0.2H), 4.52 (s, 1.6 H), 4.45 (s, 0.4 H), 3.41 (m, 1.8 H), 3.24 (m, 0.8 H), 3.01 (br m, 1.6 H), 2.63 (brm, 2H), 2.44 (m, 0.9 H), 2.27 (br s, 1.1H), 1.86 (brm, 4H), 1.51 (br m, 3.3H), 1.39 (brm, 2.7H), 1.24 (brm, 0.7H); LC/MS m/z 318.0 [M+H]+, retention time 2.14 min (RP-Cis, 10-99percent CH3CN/0.05percent TFA). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
