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Stage #1: for 1 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water
A2.2: 6-Nitro-7-chlorothieno[3,2-b]pyridine; A2.1 (9.5 g, 48.5 mmol) was suspended in phosphorus oxychloride (100 ml) and refluxed for 1 h (dissolution was apparent after 45 min). The solvent was removed under reduced pressure. Toluene (50 mL) was added to the residue and the volitiles were removed under reduced pressure. This procedure was repeated a second time to provide a dark colored semi-solid. Dichloromethane (400 mL) and saturated aqueous socium bicarbonate (400 mL) was added (Caution: gas evolution), and the layeres separated. The aqueous layer was washed with additional dichloromethane (100 mL). The combined organic layer was washed with water (200 mL) and dried over anhydrous sodium sulfate, decolorized by the addition of activated charcoal, and filtered through celite. The organic layer was concentrated to afford 9.7 g (93percent) of A2.2. M.S. 214 (M+H)+ 100percent, 216, (M+H)+ 35percent.
82%
at 110℃; for 3 h;
POCl3 (20.0 mL) was added to 6-nitrothieno[3,2-b]pyridin-7-ol (1.56 g, 7.95 mmol). The mixture was stirred at 110° C. for 3 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (150 mL), and a saturated aq. NaHCO3 (150 mL) was added slowly. The organic layer was washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 30percent EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (1.39 g, 82percent). LCMS calc. for C2H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
75%
for 1 h; Reflux
6-Nitrothieno[3,2-b]pyridin-7-ol (3.3 g, 17 mmol) was suspended in phosphoryl chloride (30 mL, 400 mmol) and heated at reflux for 1 h (dissolution was apparent after 45 min) The solvent was removed. Toluene was added to the residue and the volatiles were removed in vacuo. Dichloromethane and sat. NaHCO3 solution were added (Caution: gas evolution), and the layers separated. The organic layer was washed with water, dried over MgSO4 and concentrated to give the desired product (2.7 g, 75percent). LCMS calculated for C7H4ClN2O2S (M+H)+: m/z=215.0. Found: 214.9.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 18.0h;
A2.2B: N-Methyl-6-nitrothieno[3,2-b]pyridin-7-amine; A mixture of A2.2 (9.65 g; 44.3 mmol), methylamine hydrochloride (4.6 g; 68 mmol) and diisopropylethylamine (24.5 ml; 133 mmol) in 150 ml of N-methylpyrrolidinone was stirred for 18 hr at rt. After adding 600 ml of water, the resulting thick yellow suspension was stirred for 1.5 hr. Filtration, rinsing the filter cake with water and drying afforded 9.23 g (99%) of A2.3 as a canary yellow solid. 1H-NMR (CDCl3) delta: 9.27 (2H, s), 7.89 (1H, d, J=5.5 Hz), 7.51 (1H, d, J=5.5 Hz), 3.61 (3H, J=5.5 Hz). HPLC (A): 99%, ret. time 0.61 min., LC/MS (M+H)+=210.07.
A2.2: 6-Nitro-7-chlorothieno[3,2-b]pyridine; A2.1 (9.5 g, 48.5 mmol) was suspended in phosphorus oxychloride (100 ml) and refluxed for 1 h (dissolution was apparent after 45 min). The solvent was removed under reduced pressure. Toluene (50 mL) was added to the residue and the volitiles were removed under reduced pressure. This procedure was repeated a second time to provide a dark colored semi-solid. Dichloromethane (400 mL) and saturated aqueous socium bicarbonate (400 mL) was added (Caution: gas evolution), and the layeres separated. The aqueous layer was washed with additional dichloromethane (100 mL). The combined organic layer was washed with water (200 mL) and dried over anhydrous sodium sulfate, decolorized by the addition of activated charcoal, and filtered through celite. The organic layer was concentrated to afford 9.7 g (93%) of A2.2. M.S. 214 (M+H)+ 100%, 216, (M+H)+ 35%.
82%
With trichlorophosphate; at 110℃; for 3.0h;
POCl3 (20.0 mL) was added to 6-nitrothieno[3,2-b]pyridin-7-ol (1.56 g, 7.95 mmol). The mixture was stirred at 110 C. for 3 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (150 mL), and a saturated aq. NaHCO3 (150 mL) was added slowly. The organic layer was washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 30% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (1.39 g, 82%). LCMS calc. for C2H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
75%
With trichlorophosphate; for 1.0h;Reflux;
6-Nitrothieno[3,2-b]pyridin-7-ol (3.3 g, 17 mmol) was suspended in phosphoryl chloride (30 mL, 400 mmol) and heated at reflux for 1 h (dissolution was apparent after 45 min) The solvent was removed. Toluene was added to the residue and the volatiles were removed in vacuo. Dichloromethane and sat. NaHCO3 solution were added (Caution: gas evolution), and the layers separated. The organic layer was washed with water, dried over MgSO4 and concentrated to give the desired product (2.7 g, 75%). LCMS calculated for C7H4ClN2O2S (M+H)+: m/z=215.0. Found: 214.9.
(3) 7-Amino-6-nitrothieno[3,2-b]pyridine 16 To a suspension of 2.55 g of <strong>[110651-92-8]7-chloro-6-nitrothieno[3,2-b]pyridine</strong> 15 in 130 ml of 2-propanol is introduced excess anhydrous ammonia at 45 C. (bath temperature) during 4 hours and the mixture is evaporated in vacuo. The residue is suspended in water, collected by filtration, and then washed with water and ether to give 2.30 g (99%) of Compound 16. An analytical sample is recrystallized from chloroform methanol, affording yellow crystals melting at 266-268.5 C. Anal. Calcd. (%) (for C7 H5 N3 O2 S): C, 43.07; H, 2.58; N, 21.52. Found (%): C, 43.02; H, 2.76; N, 21.46.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 60℃;
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.060 g, 0.28 mmol), <strong>[1245724-46-2](3S)-tetrahydro-2H-pyran-3-amine hydrochloride</strong> (from J&W Pharmatech, 0.059 g, 0.43 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) in isopropyl alcohol (0.95 mL) was heated at 60 C. overnight. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (30 mg, 38%). LCMS calculated for C12H14N3O3S (M+H)+: m/z=280.1. Found: 280.0.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃; for 2h;
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, Step 2), <strong>[1467-84-1](trans-4-aminocyclohexyl)methanol</strong> (from J&W Pharmatech, 0.25 g, 2.0 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.9 mmol) in isopropyl alcohol (3.3 mL) was heated at 90 C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (0.26 g, 86%). LCMS calculated for C14H18N3O3S (M+H)+: m/z=308.1. Found: 308.0.
With triethylamine; In isopropyl alcohol; at 100℃; for 1h;
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (97 mg, 0.45 mmol), <strong>[76308-26-4]ethyl (trans-4-aminocyclohexyl)acetate hydrochloride</strong> (from Activate Scientific, 120 mg, 0.54 mmol) and triethylamine (0.19 mL, 1.4 mmol) in isopropyl alcohol (4 mL) was heated at 100 C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C17H22N3O4S (M+H)+: m/z=364.1. Found: 364.1