5-Bromo-3-methyl-1H-indazole

5-Bromo-3-methyl-lH-indazole: l-(5-Bromo-2-fluro-phenyl)-ethanone(66.0 g, 304 mmol) and 350 mL anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 1 17Compound (4c) (66.0 g, 304 mmol) and 350ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The A solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (10 g, 46 mmol) in hydrazine hydrate (80 mL) was heated at reflux (130 Hydrazine (20 ml) and the product from Step B (5.1 g, 24.0 mmol) were heated to reflux and held for 24 h. N2H4Example 102C To a 50 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, were added 1-(5-bromo-2-fluorophenyl)ethan-1-one (6.00 g, 27.7 mmol) and hydrazine hydrate (30 mL). The solution was stirred for 14 h at 17°C. The reaction mixture was concentrated under vacuum. The residue was dissolved in water and extracted with 3 times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column eluting with petroleum ethenethyl acetate (5:1). The collected fractions were combined and concentrated under vacuum. This resulted in 3.00 g (51 percent) of 5-bromo-3- methyl-1 H-indazole as a yellow solid.A mixture of the ketone (0.64 g, 2.95 mmol) from step A in ethylene glycol (5 mL) was placed in a sealed vial and heated at 165° C. overnight (about 15 h). The mixture was mixed with water (50 mL) and extracted with ethyl acetate (50 mL.x.2). The combined extracts were dried, filtered, and evaporated to give an oil. The oil was purified by chromatography (silica gel, hexane/ethyl acetate 3:1) to give the title compound (0.25 g, 43percent) as a yellow solid. LC/MS (+APCI) 211, 213 m/z.A mixture of the ketone (0.64 g, 2.95 mmol) from step A in ethylene glycol (5 mL) was placed in a sealed vial and heated at 165° C. overnight (about 15 h). The mixture was mixed with water (50 mL) and extracted with ethyl acetate (50 mL.x.2). The combined extracts were dried, filtered, and evaporated to give an oil. The oil was purified by chromatography (silica gel, hexane/ethyl acetate 3:1) to give the title compound (0.25 g, 43percent) as a yellow solid. LC/MS (+APCI) 211, 213 m/z.2-amino-5-bromoacetophenone 80 g was added to 600 ml of hydrochloric acid (37percent). To the aqueous solution of NaNO2 (80 g of sodium nitrite was added to 400 ml of water) at 0 to 10 ° C, the mixture was stirred at room temperature for 1 hour and slowly at that temperature A solution of SnCl2 · H2O hydrochloric acid (200 g dissolved in 300 ml (37percent) hydrochloric acid) was added dropwise overnight. The reaction solution was poured into ice water and filtered. The filtrate was adjusted to pH = 8. At this time, a large amount of solid precipitated and filtered to obtain 64 g of white solid. The yield was 81percent, Example 81Preparation of 4-(Benzyloxy)- 1 -(3 -methyl- 1 -(2-(pyrrolidin- 1 -yPethyl)- l/J-indazol-5- yl)pyridin-2( liJ)-one hydrochloridea) 5-Bromo-3-methyl-l//-indazole; Beilstein Registry Number 10424854 Chemical Formula: CStep 1. 5-Bromo-3-methyl-7H-indazoleTo a solution of 4-bromo-2-ethylbenzenamine (1.5 g, 7.50 mmol) in AcOH (20 mL) was added NaN0To a suspension of sodium hydride (0.98 g, 24.5 mmol, 60 % in mineral oil) in A^/V-dimethylformamide (70 mL), 5-bromo-3-methyl-li7-indazol (4.30 g, 20.4 mmol) was added in portions under an inert atmosphere at room temperature, and the obtained suspension was stirred further for 15 minutes lodomethane (1.7 ml, 27.5 mmol) was added, and the mixture was stirred further for 3 hours at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 2 M Na2S203 solution and water, dried over Na2S04, and evaporated to dryness. The regioisomeric products w'ere separated by column chromathography on silica gel, using a mixture of ethyl acetate and cyclohexane (2: 1) as eluent. Yield: 3 16 g (69 %) for the desired product 5-bromo-l, 3- dimethyl- l//-indazoi and 1.26 g (27 %) for 5-bromo-2, 3-dimethyl-l//-indazolGeneral procedure: The above mixture of the N1- and N2-alkylation isomers (0.42 g, 0.87 mmol) in THF/MeOH/H2O (4:1:1 v/v/v, 18 mL) was treated with LiOH aqueous solution (1 M in H2O, 3 mL, 3 mmol). The reaction mixture was stirred in an oil bath at 60C for 2 h. Hydrocholoric acid (1 M in H2O) was added to neutralize the mixture. Brine was added, and it was extracted with EtOAc thrice. The combined extracts were washed with brine and dried over Na2SO4. Filtration and concentration of the filtrate gave the crude acid product as yellowish solid, which contained 4-(1-(6-chloro-3-iodo-1H-indazol-1-yl)-3-methylbutyl)benzoic acid as the major component.General procedure: A mixture of 6-chloro-3-iodo-1H-indazole (0.47 g, 1.69 mmol), methyl 4-(1-bromo-3-methylbutyl)benzoate (0.48 g, 1.69 mmol) and Cs2CO3 (0.66 g, 2.03 mmol) in DMF (12 mL) under N2 was heated in an oil bath at 68 C for 18 h. The reaction mixture was diluted with CH2Cl2. Filtration and concentration of the filtrate gave the crude product. Chromatography on silica gel (heptane to 10% EtOAc in heptane) gave a 7:2 mixture of the N1-alkylation product and the N2-alkylation product (yellow solid, 0.54g, 66% combined).

Molecular Weight:211.06
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:209.97926
Monoisotopic Mass:209.97926
Topological Polar Surface Area:28.7
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes