* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With sodium tetrafluoroborate In water at 0℃; for 0.666667 h; Stage #3: With potassium acetate In chloroform at 20℃; for 4 h;
General procedure: NaNO2 aqueous solution (13.80g, 0.2mol, 32.20mL) was added dropwise to a mixture of 3a (21.40g, 0.2mol), H2O (190mL), and 12N HCl aqueous solution (50mL, 0.6mol) at 0°C. The mixture was stirred at 0°C for 30min and then was filtered. The precooled NaBF4 (24.20g, 0.22mol) dissolved in H2O (90mL) was added to the filtrate and kept stirring at 0°C for an additional 40min. The precipitate was collected by filtration, washed with cold ethanol (50mL×3), cold ethylether (50mL×3), and concentrated in vacuo to deliver diazonium salt (19.19g) as a yellow solid. To a solution of diazonium salt (19.19g, 0.093mol) in CHCl3 (231mL), KOAc (15.15g, 0.155mol) was added. The mixture was stirred at room temperature for 4h. Afterwards, the reaction was quenched with water (200mL) and extracted with CH2Cl2 (70mL×3). The organic phase was washed with brine (50mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained crude residue was purified by recrystallization to give the title compound 7.51g.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1858 - 1868
[2] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 1, p. 309 - 315
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[4] Liebigs Annalen der Chemie, 1980, # 6, p. 908 - 927
[5] Patent: US2017/174693, 2017, A1, . Location in patent: Paragraph 0864
6-Chloroindazole. A solution of 4-chloro-2-fluorobenzaldehyde (5.0 g, 31.6 mmol) in 12 mL of pyridine was treated with hydrazine hydrate (10 eq., 10 mL) and DMAP (3.85 g, 31.6 mmol) and the mixture heated to 100 °C for several hours. The mixture was allowed to cool to RT and was diluted with EtOAc and washed several times with dilute acid. The EtOAc solution was dried over MgS04 and concentrated in vacuo to give 6-chloroindazole as an off white solid (3.86 g).
Reference：
[1] Liebigs Annalen der Chemie, 1980, # 6, p. 908 - 927
6
[ 698-25-9 ]
[ 717134-47-9 ]
Reference：
[1] Synthesis, 2011, # 19, p. 3089 - 3098
7
[ 698-25-9 ]
[ 885521-34-6 ]
Yield
Reaction Conditions
Operation in experiment
44%
With bromine; sodium hydroxide In water at 20℃; for 1.5 h;
Step la. To a suspension of 6-chloro-lH-indazole (3.0 g, 19.66 mmol) in 2M NaOH (70 mL) was added a solution of Bn (2.32 g, 14.52 mmol) in 2M NaOH (30 mL) drop wise. The mixture was stirred for 1.5 hours at rt. The pH value of the solution was adjusted to 8 with 3M HCl and partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (3.4 g, 44percent). ESI-MS m/z = 231.00, 233.00 [M+H]+
44%
at 20℃; for 1.5 h;
To a suspension of 6-chloro-1H-indazole (3.0 g, 19.66 mmol) in 2M NaOH (70 mL) was added a solution of Bra (2.32 g, 14.52 mmol) in 2M NaOH (30 mL) drop wise. The mixture was stirred for 1.5 hours at rt. The pH value of the solution was adjusted to 8 with 3M HCl, and partitioned (EtOAc-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (3.4 g, 44percent). ESIMS m/z=233.00 [M+H]+.
4.2 g
With bromine; sodium hydroxide In water at 20℃;
(6-Chloro-lH-indazol-3-yl)(2-chloropyridine-3-yl)methanone. 6-Chloro- indazole (3.86 g, 25.4 mmol) was added to 45 mL of 20percent aq. NaOH solution, and reacted with neat Br2 (0.85 mL, 16.3 mmol) for several hours at RT. The reaction was neutralized with the product, 3-bromo-6-chloroindazole, precipitating as a white solid (4.2 g). A solution of 3-bromo-6-chloroindazole (0.46 g, 2 mmol) in diethyl ether (6 mL) was cooled to -78 °C and n-BuLi (1.6 M in hexanes; 1.25 mL, 2 mmol) was added dropwise. After the addition was complete, i-BuLi (1.7 M in hexanes; 2.36 mL, 4 mmol) was added dropwise. The solution was allowed to stir 15 minutes at -78 °C, after which 2-chloronicotinoyl chloride (0.35 g, 2.0 mmol) was added as a solid. The solution was allowed to warm to RT, and was then quenched with IN HC1 and extracted with EtOAc. The EtOAc extract was concentrated in vacuo, and the residue purified by RPHPLC to give 100 mg of (6-chloro-lH-indazol-3-yl)(2-chloropyridine- 3-yl)methanone as an off white solid.
NaH (55%) (2.14 g, 49.15 mmol) was suspended in 70 ml of dry DMF under a N2 atmosphere. <strong>[698-25-9]6-chloro-indazole</strong> (7.5 g, 49.15 mmol) was added at room temperature. The mixture was stirred for 1 hour before cooling with an ice bath and (3-bromo-propoxy)-tert-butyl-dimethyl-silane (11.4 ml, 49.15 mmol) was added dropwise. After stirring for an additional 15 minutes the mixture was allowed to reach room temperature, stirring was continued for another 8 hours. Subsequently, the mixture was concentrated in vacuo and the residue was dissolved in DCM, the organic layer was then washed with water (3*). The organic layer was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (SiO2, eluent: petroleum ether/diethyl ether 5/1? 4/1) to afford the N1 substituted indazole in 61% yield.
With bromine; sodium hydroxide; In water; at 20℃; for 1.5h;
Step la. To a suspension of 6-chloro-lH-indazole (3.0 g, 19.66 mmol) in 2M NaOH (70 mL) was added a solution of Bn (2.32 g, 14.52 mmol) in 2M NaOH (30 mL) drop wise. The mixture was stirred for 1.5 hours at rt. The pH value of the solution was adjusted to 8 with 3M HCl and partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (3.4 g, 44%). ESI-MS m/z = 231.00, 233.00 [M+H]+
44%
With bromine; sodium hydroxide; at 20℃; for 1.5h;
To a suspension of <strong>[698-25-9]6-chloro-1H-indazole</strong> (3.0 g, 19.66 mmol) in 2M NaOH (70 mL) was added a solution of Bra (2.32 g, 14.52 mmol) in 2M NaOH (30 mL) drop wise. The mixture was stirred for 1.5 hours at rt. The pH value of the solution was adjusted to 8 with 3M HCl, and partitioned (EtOAc-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (3.4 g, 44%). ESIMS m/z=233.00 [M+H]+.
4.2 g
With bromine; sodium hydroxide; In water; at 20℃;
(6-Chloro-lH-indazol-3-yl)(2-chloropyridine-3-yl)methanone. 6-Chloro- indazole (3.86 g, 25.4 mmol) was added to 45 mL of 20% aq. NaOH solution, and reacted with neat Br2 (0.85 mL, 16.3 mmol) for several hours at RT. The reaction was neutralized with the product, 3-bromo-6-chloroindazole, precipitating as a white solid (4.2 g). A solution of 3-bromo-6-chloroindazole (0.46 g, 2 mmol) in diethyl ether (6 mL) was cooled to -78 C and n-BuLi (1.6 M in hexanes; 1.25 mL, 2 mmol) was added dropwise. After the addition was complete, i-BuLi (1.7 M in hexanes; 2.36 mL, 4 mmol) was added dropwise. The solution was allowed to stir 15 minutes at -78 C, after which 2-chloronicotinoyl chloride (0.35 g, 2.0 mmol) was added as a solid. The solution was allowed to warm to RT, and was then quenched with IN HC1 and extracted with EtOAc. The EtOAc extract was concentrated in vacuo, and the residue purified by RPHPLC to give 100 mg of (6-chloro-lH-indazol-3-yl)(2-chloropyridine- 3-yl)methanone as an off white solid.
With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 3h;
In a round-bottomed flask, 6-chloro-lH-indazole (90 mg, 0.59 mmol) was dissolved in DMF (1.4 mL). Iodine (300 mg, 1.18 mmol) was added followed by potassium hydroxide (128 mg, 2.28 mmol). The dark reaction mixture was stirred at room temperature for 3 h then was quenched with 10% aq NaHSOs and extracted with diethyl ether (2x). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 169 mg (98%) of 6-chloro-3-iodo-lH-indazole as an orange solid.
71%
With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
To a solution of <strong>[698-25-9]6-chloro-indazole</strong> (3.0 g, 20 mmol) and KOH (4.2 g, 74 mmol) in DMF (80 mL) was added I2(10 g, 40 mmol) at 0 C. The mixture was stirred at rt for 3 h. The reaction was quenched with sat. Na2S203(30 mL) and extracted with EA (50 mL). Organics were dried over Na2S04, filtered, and the filtrate was concentrated and purified by silica gel chromatography (PE/EA = 5/1) to afford 3.9 g (71%) of the title compound as a red solid. [M+H] Calc'd for C7H4C1IN2, 279; Found, 279.
51%
With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 4h;
General procedure: KOH (31.10g, 0.555mol) was added in portions at 0C to a solution of 4a (15.80g, 0.134mol) and I2 (85.40g, 0.336mol) in DMF (263.40mL). The mixture was stirred for 4h at room temperature, quenched with saturated Na2S2O3 solution (50mL), diluted with H2O (150mL), and extracted with EtOAc (70mL×3). The organic phase was washed with brine (50mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15:1, v/v) to give an orange solid (16.78g).
With N-iodo-succinimide; In acetonitrile; at 60℃; for 3h;Inert atmosphere;
An acetonitrile solution (250 mL) containing the intermediate from Step A (6.14 g, 40.2 mmol) and NIS (9.33g, 41.4mmol) was heated at 60 C for 3 hours. The reaction solution was cooled to room temperature and concentrated to approximately 70 mL volume. The reaction was then diluted with water (ca 400 mL). The suspension was stirred for 10 minutes and then filtered. The solid was air dried on the filter to give the indicated product. The material was used in StepC without further purification. NMR (400 MHz, CH3 CN-da ): delta 1.52 (broad s, 1 H); 7.62 (d, J - 1.7 Hz, 1H); 7.44 (d, J - 8.6 Hz, 1H); 7.21 (dd, J - 8.6, 1.7 Hz, 1H). m/z = 279.0 (M+H).
Acetic anhydride (10.0 mL, 106 mmol) was added dropwise to a benzene solution (1 10 mL) containing 5-chloro-2-methylaniline (5.0 g, 35.3 mmol) and potassium acetate (3.8 g, 38.7 mmol) at room temperature. After 10 minutes the reaction mixture, which had formed a thick white suspension, was heated to 80 C. Tert-butyl nitrite (6.99 mL, 90%, 53.0 mmol) was added over 20 minutes. The reaction mixture was kept at 80 C overnight. The reaction was then cooled to room temperature and concentrated. The residue was dissolved in MeOH and stirred for 10 minutes. The solution was concentrated and to the residue was added MeOH (175 mL), THF (30 mL), water (60 mL) and lithium hydroxide monohydrate (8 g, 195 mmol). The solution was then stirred overnight at room temperature. The solution was then concentrated and the residue partitioned between EtOAc and 0.5 M NaOH aq. The aqueous phase was extracted twice withEtOAc. The combined organics were washed with brine, dried over MgS04j filtered and concentrated to give the indicated product. The material was used in Step B without further purification. NMR (400 MHz, CH3CN-d3): delta 1 1.20 (broad s, 1H); 8.01 (s, 1H); 7.75-7.70
With hydrazine hydrate; In ISOPROPYLAMIDE; at 18 - 100℃; for 17.5h;Inert atmosphere;Product distribution / selectivity;
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaIdehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at room temperature. The solution was then stirred at 100 C for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to room temperature. The solid was collected by filtration, washed with water and dried under vacuum to give the indicated product.
3.86 g
With pyridine; dmap; hydrazine hydrate; at 100℃;
6-Chloroindazole. A solution of 4-chloro-2-fluorobenzaldehyde (5.0 g, 31.6 mmol) in 12 mL of pyridine was treated with hydrazine hydrate (10 eq., 10 mL) and DMAP (3.85 g, 31.6 mmol) and the mixture heated to 100 C for several hours. The mixture was allowed to cool to RT and was diluted with EtOAc and washed several times with dilute acid. The EtOAc solution was dried over MgS04 and concentrated in vacuo to give 6-chloroindazole as an off white solid (3.86 g).
With potassium acetate; hydrazine hydrate; In N,N-dimethyl acetamide; at 20 - 100℃; for 17.5h;
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaldehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at RT. The solution was then stirred at 100 C. for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to RT. The solid was collected by filtration, washed with water and dried under vacuum to give the title product.
2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide[ No CAS ]
2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide[ No CAS ]
2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide hydrochloride[ No CAS ]
2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride[ No CAS ]
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