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7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol; at 20 - 80℃; for 15.1667h;
Step B.; A solution of 1-<strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (3.35 g, 17.0 mmol) and 4-piperidone hydrochloride monohydrate (2.6 g, 17.0 mmol) in IPA(50.0 mL) was stirred at 20 C. for 10 min, following by stirring at 80 C. for 15 h. The reaction mixture was filtered to obtain the title compound (3.2g, 12.5 mmol) as a beige solid: MS (ES) 269.0 (M-H).
Example 15 7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride Step A.; A solution of sodium nitrite (12.5 g, 85.9 mmol) and H2O (21.4 mL) was added dropwise at 0 C. to a solution of 3-chloro-2-fluorobenzenamine hydrochloride (2.0 g, 8.45 mmol) in 12N HCl (203.3 mL) and TFA (23.4 mL). The reaction mixture was stirred at 0 C. for 1 h followed by the dropwise addition of a solution of tin(II)chloride (35.8 g, 188.9 mmol) in 12N HCl (51.6 mL) and H2O (6.8 mL) at 0 C. The reaction mixture stirred for 15 h at 20 C. and was filtered and placed under vacuum to give 1-(3-chloro-2-fluorophenyl)hydrazine hydrochloride as a gold solid (23.5 g, 119.0 mmol).
With acetic acid; zinc(II) chloride; at 105℃; for 48h;
(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105 C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).
With triethylamine; In ethanol; at 20℃; for 0.166667h;
[00375] Intermediate 25 A. Ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole- 4-carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at rt. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole -4-carboxylate (200 mg, 28%), was obtained as an off white solid. MS(ESI) m/z: 283.1 (M+H)+.
28%
With triethylamine; In ethanol; at 20℃; for 0.166667h;
Intermediate 15A. Ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4- carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at room temperature t. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxylate (200 mg, 28%), was obtained as an off-white solid. MS (ESI) m/z: 283.1 (M+H)+.
28%
With triethylamine; In ethanol; at 20℃; for 0.166667h;
A solution of ethyl 2-((dimethylamino) methylene)-3-oxobutanoate (0.5 17 g, 2.79mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) inEtOH (2.54 ml) and TEA (0.707 ml, 5.08 mmol) was stirred at rt. After 10 mm, thereaction mixture was concentrated and purified by normal phase chromatography. Thedesired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5-methyl- 1 H-pyrazole-4-carboxyl ate(200 mg, 28%), was obtained as an off white solid. MS (ESI) m/z: 283.1 (M+H)t
[00390] Intermediate 33A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSC^ and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.
Intermediate 45 A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgS04 and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.
With sodium acetate; In water; acetic acid; at 20 - 100℃;
[00319] Intermediate 2 A. Ethyl 5-amino-l-(3-chloro-2-fluorophenyl)-lH-pyrazole-4- carboxylate: To a mixture of <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.67 g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) at rt was added AcOH and H20 to form a slurry. The reaction mixture was continued to stir at rt for 0.25 h and then heated at 100 C for overnight. After overnight stirring, the reaction mixture was quenched with H20 (200 mL) and a yellowish brown solid separated. The solids were filtered and washed thoroughly with H20. Re-dissolved the residue in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS(ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCls) delta 7.76 (s, 1H), 7.51 - 7.29 (m, 2H), 7.27 - 7.03 (m, 1H), 5.30 - 5.06 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.38 - 1.04 (m, 3H) ppm.
With sodium hydroxide; In methanol; at 20℃; for 2.5h;
[00405] Intermediate 40 A. (E)-l-Benzylidene-2-(3-chloro-2-fluorophenyl)hydrazine: Using a modified procedure described by Deprez-Poulain. (Deprez-Poulain, R. et al, European Journal of Medicinal Chemistry, 46:3867 (2011).) To a clear, orange brown solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (3 g, 15.23 mmol) in methanol (60.9 ml) was added benzaldehyde (1.543 mL, 15.23 mmol) followed by the slow addition of 1.0 M NaOH (15.23 mL, 15.23 mmol). The resulting dark brown solution was stirred at rt. Over time, a precipitate formed. After 2.5 h, the reaction was stopped and the solid was collected by filtration. The solid was washed with water, air-dried, and dried under vacuum overnight to give Intermediate 40A (1.01 g, 27%) as an off- white solid. MS(ESI) m/z: 249.0 (M+H)+.
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