* 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.
[00201] 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 170C for 5 hours. After this period, the reaction mixture was allowed to cool to room temperature, and the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 mL water was poured into the resulting solid and the water was then filtered off. The solid was washed with 400 mL water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 mL EtOAc and washed with 300 mL water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94percent). The product was used directly in the next step without further purification.
94%
at 117℃; for 5 h; Heating / reflux
Compound (4c) (66.0 g, 304 mmol) and 350ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The <.-- EPO <DP n="25"/>--> lηpsujtiugj ijβapsfipn mixture was^efluxed at 117 0C for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94percent). The product was used directly for the next step without further purification.
73%
at 130℃; for 20 h;
A solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (10 g, 46 mmol) in hydrazine hydrate (80 mL) was heated at reflux (130 9C) for 20 hours. The reaction mixture was cooled to room temperature, excess hydrazine hydrate was removed and the crude residue was purified by column chromatography (60-120 mesh silica gel) using 10percent ethyl acetate in pet- ether as eluents to obtain 5-bromo-3-methyl-1 H-indazole (7.09 g, 73percent) as a solid. 1H NMR (CDCI3): δ 10.2-10.6 ( br, 1 H), 7.8-7.9 (s, 1 H), 7.4-7.5 (d, 1 H), 7.2-7.4 (d, 1H),2.5-2.7 (s, 3H).
71%
for 24 h; Heating / reflux
Hydrazine (20 ml) and the product from Step B (5.1 g, 24.0 mmol) were heated to reflux and held for 24 h. The mixture was then cooled to room temperature and quenched with water (250 ml). A precipitate formed; this was isolated by filtration, washing with water, and then the solids were dissolved in ethyl acetate. The organic mixture was dried over sodium sulfate then concentrated, providing the indazole (3.54 g, 71percent) as a beige solid; 1H NMR (300 MHz, CDCl3) δ 9.95 (br s, 1H), 7.83-7.82 (dd, J=1.7, 0.4 Hz, 1H), 7.47-7.44 (dd, J=8.7, 1.8 Hz, 1H), 7.33-7.31 (d, J=8.7 Hz, 1H), 2.56 (s, 3H); ES-MS: (M+H)=211, 213 m/z.
64%
at 50℃; for 20 h;
N2H4'H20 (50 mL) was added to a solution of l-(5-bromo-2-fluorophenyl)ethanone (10 g, 1.00 eq.). The reaction mixture was stirred for 20 h at 50°C. Then it was cooled to room temperature and concentrated in vacuo. The product was purified by silica gel column chromatography with ethyl acetate/hexane (1:90). This afforded 6.2 g (64percent) of 5-bromo-3-methyl-lH-indazole as a white solid. 'H-NMR: (300 MHz, DMSO-d6, ppm): δ 12.82 (s, 1H), 7.96 (s, 1H), 7.43 (m, 2H), 2.48 (s, 3H)
60%
for 9 h; Heating / reflux
Example 102C 5-Bromo-3-methyl-1H-indazole A mixture of 102B (10 g, 46 mmol) and 98percent hydrazine (25 mL) was heated to reflux for 9 hours, and poured over ice. The precipitate was collected and purified by flash chromatography (1:1 Et2O:hexane) to give the desired product as a white solid (5.8 g, 60percent).
51%
at 17℃; for 14 h; Sealed tube; Inert atmosphere
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.
43%
With hydrazine In ethylene glycol at 165℃;
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.
43%
at 165℃; for 15 h;
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.
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 1 h; Stage #2: With hydrogenchloride; tin(II) chloride hydrate In water at 20℃;
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,
With acetic acid; sodium nitrite In water for 4.5 h;
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: C8H7BrN2 Exact Mass: 209.98 Molecular Weight: 21 1 .06 [00211] A solution of 4-bromo-2-ethylaniline (5.00 mL, 35.3 mmol) in glacial acetic acid (300 mL) was treated with a solution Of NaNO2 (2.43 g, 35.2 mmol) in water (10 mL). After stirring for 4.5 hours, the mixture was concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/Me0H, 100:0 to 97:3) provided the title compound (4.24 g, 57percent) as a dark red semi-solid: 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 1.5 Hz, IH), 7.45 (dd, J = 9.0, 1.5 Hz, IH), 7.31 (d, J = 9.0, IH), 2.56 (s, 3H); ESI MS m/z 211 [M+ H]+
44%
at 20℃; for 2.5 h;
Step 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 NaN02 (570 mg, 8.14 mmol). After stirring for 2.5 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1percent methanol in dichloromethane to afford 5-bromo-3-methyl-7H- indazole as a light red solid (700 mg, 44percent).'H-NMR (300 MHz, CDC13) δ 8.35 (s, 1H), 7.45 - 7.49 (m, 1H), 7.33 (d, / = 8.7 Hz, 1H), 2.59 (s, 3H)
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Patent: WO2014/106763, 2014, A1,
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[5] Patent: WO2007/126964, 2007, A2,
5
[ 93777-26-5 ]
[ 552331-16-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[4] Patent: WO2007/126964, 2007, A2,
6
[ 2142-63-4 ]
[ 552331-16-5 ]
Reference：
[1] Patent: CN102898374, 2016, B,
7
[ 41877-24-1 ]
[ 552331-16-5 ]
Reference：
[1] Patent: CN102898374, 2016, B,
8
[ 552331-16-5 ]
[ 74-88-4 ]
[ 552331-30-3 ]
Yield
Reaction Conditions
Operation in experiment
67%
With NaH In N,N-dimethyl-formamide
Example 112A 5-Bromo-1,3-dimethyl-1H-indazole Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60percent NaH (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO4), evaporated, and isolated by flash chromatography (1:1 Et2O:hexane) to give the desired product (360 mg; 67percent).
67%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 20℃; for 2 h;
Example 112A 5-Bromo-1,3-dimethyl-1H-indazole Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60percent NaH (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO4), evaporated, and isolated by flash chromatography (1:1 Et2O:hexane) to give the desired product (360 mg; 67percent).
67%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.25 h; Inert atmosphere
To a stirred solution of 5-bromo-3-methyl- 1H-indazole (2.51 g, 11.6 mmol), dissolved in N,N-dimethylformamide (30 mL) and cooled to 0°C under nitrogen, was added portionwise sodium hydride (60percent dispersion in mineral oil; 596 mg, 14.9 mmol).The dark brown, effervescing solution was stirred for 70 minutes prior to addition of iodomethane (0.87 mL, 14 mmol). The reaction mixture was stirred at 0°C for 15 minutes before warming to r.t. A brown-orange solid was formed and the mixture was stirred for 3 h prior to the addition of water (30 mL) and EtOAc (30 mL). The mixture was stirred for 40 minutes before leaving to stand overnight. Further EtOAc (20 mL) andwater (20 mL) were added, then the organic layer was separated. The aqueous layer was re-extracted with further EtOAc (2 x 50 mL). The organic layers were combined, dried with anhydrous sodium sulfate and filtered under reduced pressure, then the solvent was removed in vacuo. The resulting brown oil was purified by flash column chromatography on silica (gradient elution with 0-100percent EtOAc/isohexane) to afford the title compound (1.75 g, 67percent) as an orange oil. oH (DMSO-d6, 300 MHz) 7.94 (dd, J 1.7, 0.7 Hz, 1H), 7.55 (dd,J8.8, 0.7 Hz, 1H), 7.46 (dd,J8.9, 1.8 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H). LCMS (ES+) [M+H] 227.0, RT 2.00 minutes (method 3).
39%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h; Stage #2: at 0℃; for 4 h;
To a stirred suspension of NaH (60percent oil dispersion, 136 mg,2.83 mmol) in DMF (10 mL) was added a solution of 24 (400 mg,1.89 mmol) in DMF (2 mL) at 0 C, and the mixture was stirred atthe same temperature for 30 min. MeI (400 lL, 2.83 mmol) wasadded and the resulting mixture was stirred at 0 C for 4 h. Thereaction mixture was quenched with water and extracted withEtOAc. The combined EtOAc layers were washed with brine, driedover Na2SO4, and concentrated. The residue was purified by columnchromatography (silica gel, hexane/EtOAc = 80/20) to givethe title compound (200 mg, 39percent) as a yellow oil. 1H NMR(400 MHz, DMSO-d6) d 2.45 (3H, s), 3.95 (3H, s), 7.46 (1H, dd,J = 8.9, 1.8 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.94 (1H, d, J = 1.5 Hz). MS(ESI/APCI) m/z = 225.0 [M+H]+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Patent: US2003/187026, 2003, A1,
[3] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2017/55305, 2017, A1, . Location in patent: Page/Page column 53
[5] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 11, p. 2504 - 2518
5-bromo-3-methyl-1H-indazole (500 mg, 2.38 mol), zinc cyanide (418 mg, 3.57 mmol), Pd2(dba)3 (194mg, 0.238mmol) and X-Phos (227 mg, 0.476 mol) was added to a microwave tube. After purging with nitrogen to remove oxygen, the mixture was heated for 1 hour, and then was subject to column chromatography to obtain 5-cyano-3-methyl-1H-indazole (430 mg, 98percent). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.61 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 2.66 (s, 3H); MS m/z (ESI): 158 [M+H]+.
[1-(5-bromo-pyridin-3-yloxymethyl)-2-(2-methyl-1<i>H</i>-indol-3-yl)-ethyl]-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
[1-[5-(3-methyl-1<i>H</i>-indazol-5-yl)-pyridin-3-yloxymethyl]-2-(2-methyl-1<i>H</i>-indol-3-yl)-ethyl]-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
[00201] 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 170C for 5 hours. After this period, the reaction mixture was allowed to cool to room temperature, and the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 mL water was poured into the resulting solid and the water was then filtered off. The solid was washed with 400 mL water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 mL EtOAc and washed with 300 mL water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly in the next step without further purification.
94%
With hydrazine; at 117℃; for 5h;Heating / reflux;
Compound (4c) (66.0 g, 304 mmol) and 350ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The <.-- EPO <DP n="25"/>--> letapsujtiugj ijbetaapsfipn mixture was^efluxed at 117 0C for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification.
73%
With hydrazine hydrate; at 130℃; for 20h;
A solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (10 g, 46 mmol) in hydrazine hydrate (80 mL) was heated at reflux (130 9C) for 20 hours. The reaction mixture was cooled to room temperature, excess hydrazine hydrate was removed and the crude residue was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet- ether as eluents to obtain 5-bromo-3-methyl-1 H-indazole (7.09 g, 73%) as a solid. 1H NMR (CDCI3): delta 10.2-10.6 ( br, 1 H), 7.8-7.9 (s, 1 H), 7.4-7.5 (d, 1 H), 7.2-7.4 (d, 1H),2.5-2.7 (s, 3H).
71%
With hydrazine; for 24h;Heating / reflux;
Hydrazine (20 ml) and the product from Step B (5.1 g, 24.0 mmol) were heated to reflux and held for 24 h. The mixture was then cooled to room temperature and quenched with water (250 ml). A precipitate formed; this was isolated by filtration, washing with water, and then the solids were dissolved in ethyl acetate. The organic mixture was dried over sodium sulfate then concentrated, providing the indazole (3.54 g, 71%) as a beige solid; 1H NMR (300 MHz, CDCl3) delta 9.95 (br s, 1H), 7.83-7.82 (dd, J=1.7, 0.4 Hz, 1H), 7.47-7.44 (dd, J=8.7, 1.8 Hz, 1H), 7.33-7.31 (d, J=8.7 Hz, 1H), 2.56 (s, 3H); ES-MS: (M+H)=211, 213 m/z.
64%
With hydrazine hydrate; at 50℃; for 20h;
N2H4'H20 (50 mL) was added to a solution of l-(5-bromo-2-fluorophenyl)ethanone (10 g, 1.00 eq.). The reaction mixture was stirred for 20 h at 50C. Then it was cooled to room temperature and concentrated in vacuo. The product was purified by silica gel column chromatography with ethyl acetate/hexane (1:90). This afforded 6.2 g (64%) of 5-bromo-3-methyl-lH-indazole as a white solid. 'H-NMR: (300 MHz, DMSO-d6, ppm): delta 12.82 (s, 1H), 7.96 (s, 1H), 7.43 (m, 2H), 2.48 (s, 3H)
60%
With hydrazine; for 9h;Heating / reflux;
Example 102C 5-Bromo-3-methyl-1H-indazole A mixture of 102B (10 g, 46 mmol) and 98% hydrazine (25 mL) was heated to reflux for 9 hours, and poured over ice. The precipitate was collected and purified by flash chromatography (1:1 Et2O:hexane) to give the desired product as a white solid (5.8 g, 60%).
51%
With hydrazine hydrate; at 17℃; for 14h;Sealed tube; Inert atmosphere;
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 17C. 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 %) of 5-bromo-3- methyl-1 H-indazole as a yellow solid.
43%
With hydrazine; In ethylene glycol; at 165℃;
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×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, 43%) as a yellow solid. LC/MS (+APCI) 211, 213 m/z.
43%
In ethylene glycol; at 165℃; for 15h;
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×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, 43%) as a yellow solid. LC/MS (+APCI) 211, 213 m/z.
With hydrazine; for 10h;Heating / reflux;
To 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) was added anhydrous hydrazine (240 mL, 7.65 mol.). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5- bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol.) which was used without further purification.
With hydrazine;
3. Preparation of 5-bromo-3-meth l-1H-indazole Scheme 3 5-Bromo-3-methyl-1 H-indazole was synthesized via the reaction where 1-(5-bromo-2- fluorophenyl)ethanone was condensed with hydrazine. The reaction was carried out according to available literature28. H NMR (300 MHz, DMSO-d6) delta ppm 12.80 (br s, 1 H), 7.94 (s, 1 H), 7.44 (d, J = 9.12 Hz, 1 H), 7.41 (d, J = 9.12 Hz, 1 H), 2.47 (s, 3H). MS (ESI): m/z (M+H)+ 21 1.
With hydrazine; at 20℃; for 26h;Heating / reflux;
Step C; To 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) was added anhydrous hydrazine (240 mL, 7.65 mol). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature <n="91"/>and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5-bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol) which was used without further purification.
Example 112A 5-Bromo-1,3-dimethyl-1H-indazole Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60% NaH (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO4), evaporated, and isolated by flash chromatography (1:1 Et2O:hexane) to give the desired product (360 mg; 67%).
67%
Example 112A 5-Bromo-1,3-dimethyl-1H-indazole Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60% NaH (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO4), evaporated, and isolated by flash chromatography (1:1 Et2O:hexane) to give the desired product (360 mg; 67%).
67%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 0.25h;Inert atmosphere;
To a stirred solution of 5-bromo-3-methyl- 1H-indazole (2.51 g, 11.6 mmol), dissolved in N,N-dimethylformamide (30 mL) and cooled to 0C under nitrogen, was added portionwise sodium hydride (60% dispersion in mineral oil; 596 mg, 14.9 mmol).The dark brown, effervescing solution was stirred for 70 minutes prior to addition of iodomethane (0.87 mL, 14 mmol). The reaction mixture was stirred at 0C for 15 minutes before warming to r.t. A brown-orange solid was formed and the mixture was stirred for 3 h prior to the addition of water (30 mL) and EtOAc (30 mL). The mixture was stirred for 40 minutes before leaving to stand overnight. Further EtOAc (20 mL) andwater (20 mL) were added, then the organic layer was separated. The aqueous layer was re-extracted with further EtOAc (2 x 50 mL). The organic layers were combined, dried with anhydrous sodium sulfate and filtered under reduced pressure, then the solvent was removed in vacuo. The resulting brown oil was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc/isohexane) to afford the title compound (1.75 g, 67%) as an orange oil. oH (DMSO-d6, 300 MHz) 7.94 (dd, J 1.7, 0.7 Hz, 1H), 7.55 (dd,J8.8, 0.7 Hz, 1H), 7.46 (dd,J8.9, 1.8 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H). LCMS (ES+) [M+H] 227.0, RT 2.00 minutes (method 3).
39%
To a stirred suspension of NaH (60% oil dispersion, 136 mg,2.83 mmol) in DMF (10 mL) was added a solution of 24 (400 mg,1.89 mmol) in DMF (2 mL) at 0 C, and the mixture was stirred atthe same temperature for 30 min. MeI (400 lL, 2.83 mmol) wasadded and the resulting mixture was stirred at 0 C for 4 h. Thereaction mixture was quenched with water and extracted withEtOAc. The combined EtOAc layers were washed with brine, driedover Na2SO4, and concentrated. The residue was purified by columnchromatography (silica gel, hexane/EtOAc = 80/20) to givethe title compound (200 mg, 39%) as a yellow oil. 1H NMR(400 MHz, DMSO-d6) d 2.45 (3H, s), 3.95 (3H, s), 7.46 (1H, dd,J = 8.9, 1.8 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.94 (1H, d, J = 1.5 Hz). MS(ESI/APCI) m/z = 225.0 [M+H]+.
With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h;
Preparative Example 7; Preparation of 5-bromo-3-methyl-1-ftrimethylsilyl)ethoxymethyl-1H-indazole 116; To a solution of <strong>[552331-16-5]<strong>[552331-16-5]5-bromo-3-methyl-1H-indazol</strong>e</strong> 104 (0.4 g, 1.89 mmol) in anhydrous DMF (4 mL) at 0 0C was added sodium hydride (0.068 g, 2.85 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.377 g, 2.26 mmol). The reaction mixture was stirred at 0 0C fro 1 hour. Ethyl acetate (100 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column <n="96"/>chromatography to yield the desired 5-bromo-3-methyl-1-(trimethylsilyl)ethoxymethyl- 1H-indazole 116 (0.369 g, 1.08 mmol).
Example 102C 5-Bromo-3-methyl-1H-indazole A mixture of 102B (10 g, 46 mmol) and 98% hydrazine (25 mL) was heated to reflux for 9 hours, and poured over ice. The precipitate was collected and purified by flash chromatography (1:1 Et2O:hexane) to give the desired product as a white solid (5.8 g, 60%).
37
[ 552331-16-5 ]
[ 76513-69-4 ]
[ 903875-46-7 ]
[ 903875-45-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
Preparation of 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116.; Scheme 9To a solution of <strong>[552331-16-5]5-bromo-3-methylindazole</strong> 104 (2 g, 9.48 mmol) in anhydrous DMF (20 ml_), cooled in ice bath, was added sodium hydride (60% w/w, 0.57 g, 14.25 mmol)' and (2-trimethylsilylethoxy)methyl chloride (2.5 ml_, 14.16 mmol) in a dropwise manner. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. Ethyl acetate (200 ml_) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (2.95 g, 8.65 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
Preparation of 5-bromo-N-(4-methoxybenzvO-3-methylindazole 105.; EPO <DP n="71"/>Scheme 3To a solution of <strong>[552331-16-5]5-bromo-3-methylindazole</strong> 104 (0.2 g, 0.948 mmol) in anhydrous THF (3 ml_), cooled in ice bath, was added potassium f-butoxide (0.127 g, 1.13 mmol) and 4-methoxybenzyl chloride (0.14 ml_, 1.04 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 16 hours. Ethyl acetate (100 ml_) was added and the organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-N-(4-methoxybenzyl)-3- methylindazole 105 (0.29 g, 0.932 mmol) as a mixture of the 1 H- and 2H- indazole regioisomers. Preparation of 5-cvano-N-(4-rnethoxybenzyl)-3-methylindazole 106.
tetrakis(triphenylphosphine) palladium(0); In toluene; at 95℃; for 6h;
Example 102D 3-Methyl-5-trimethylstannanyl-1H-indazole A mixture of Example 102C (10.08 g, 47.8 mmol), hexamethyl-di-tin 2 (18 g, 55 mmol) and tetrakis(triphenylphosphine)palladium (5.5 g, 4.8 mmol) in toluene (100 ml) was stirred at 95 C. for 6 h. The mixture was then evaporated and the residue was taken into ethyl acetate (300 ml), washed with saturated sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluding with 1:4 ethyl acetate/hexanes to give 11.2 g desired product (80%). MS: (ESI) m/z 409 (M+H)+.
tetrakis(triphenylphosphine) palladium(0); In toluene; at 95℃; for 4h;
Preparation of 3-methyl-5-trimethylstannanylindazole 152.; EPO <DP n="89"/>Scheme 20104 152To a solution of <strong>[552331-16-5]5-bromo-3-methylindazole</strong> 104 (2.0 g, 9.48 mmol.) in anhydrous toluene (20 ml_) was added tetrakis(triphenylphosphine)palladium (1.1 g, 0.95 mmol.) and hexamethylditin (3.1 g, 9.46 mmol.). The reaction mixture was heated at 950C for 4 hours. Ethyl acetate (200 mL) was added. The organic layer was washed with water and brine. The organic layer was filtered through Celite and dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 3-methyl-5- trimethylstannanylindazole 152 (1.85 g, 6.27 mmol.) EPO <DP n="90"/>
11.2 g desired product (80%)
tetrakis(triphenylphosphine) palladium(0); In ethyl acetate; toluene;
Example 102D 3-Methyl-5-trimethylstannanyl-1H-indazole A mixture of Example 102C (10.08 g, 47.8 mmol), hexamethyl-di-tin 2 (18 g, 55 mmol) and tetrakis(triphenylphosphine)palladium (5.5 g, 4.8 mmol) in toluene (100 ml) was stirred at 95 C. for 6 h. The mixture was then evaporated and the residue was taken into ethyl acetate (300 ml), washed with saturated sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluding with 1:4 ethyl acetate/hexanes to give 11.2 g desired product (80%). MS: (ESI) m/z 409 (M+H)+.
With tetrakis(triphenylphosphine) palladium(0);
4. Preparation of 3-meth l-5-(trimethylstannyl)-1H-indazole Scheme 4 3-Methyl-5-(trimethylstannyl)-1 /- -indazole was synthesized via the reaction of 5-bromo-3- methyl-1 r7-indazole with hexamethyldistannane and Pd(PPh3)4. The reaction was carried out according to available literature29. 1H NMR (300 MHz, DMSO-d6) delta ppm 12.52 (s, 1 H), 7.79 (s, 1 H), 7.44 (d, J = 8.13 Hz, 1 H), 7.38 (d, J = 8.13 Hz, 1 H), 2.49 (s, 3H), 0.29 (t, J = 27.70 Hz, 9H). MS (ESI): m/z (M+H)+ 293. 5.
tetrakis(triphenylphosphine) palladium(0); In toluene; at 95℃; for 6h;
Preparative Example 2; Preparation of 3-methyl-5-trimethylstannanyl-1 /-/-indazole 105.; To a solution of 5-bromo-3-methyl-1 H-indazole 104 (20 g, 0.095 mol) in anhydrous toluene (200 ml_) was added tetrakis(triphe?ylphosphine)palladium (11 g, 0.0095 mol) and hexamethylditin (36 g, 0.11 mol). The reaction mixture was heated at 95 0C for 6 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate (300 ml_) was added and filtered. The filtrate was washed with sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 3-methyl-5- trimethylstannanyMW-indazole 105 (17.7 g, 0.06 mo.).
With triethylamine;dmap; In tetrahydrofuran; at 20℃;
To a stirred mixture of indazole from step B (4.06 g, 19.2 mmol), triethylamine (2.32 g, 3.20 mL, 23.0 mmol) in anhydrous THF (80 mL) was added di-tert-butyl-dicarbonate (5.02 g, 23.0 mmol) at ambient temperature, followed by DMAP (cat., about 0.1 g). The reaction was stirred overnight, evaporated to dryness, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL×2). The combined extracts were dried, filtered and concentrated to give a solid. Solid from a ethyl acetate/hexane trituration (1:10) was filtered and dried to afford 4.94 g of the desired product. The mother liquid was chromatographed on silica (5% EtOAc/Hex) to give 0.80 g of product (96% total yield).
95%
With dmap; triethanolamine; In acetonitrile;
Example 203A 5-Bromo-3-methyl-indazole-1-carboxylic Acid Tert-Butyl Ester A solution of Example 102C (1.0 g; 4.7 mmol), TEA (526 mg; 5.2 mmol), DMAP (200 mg; 1.6 mmol) and di-tert-butyldicarbonate (1.1 g; 5.0 mmol) in CH3CN (15 mL) was stirred at r.t. for 3 hrs, evaporated, and isolated by flash chromatography (30% Et2O/hexane) to give the desired product as a white solid (1.4 g; 95%).
95%
With dmap; triethylamine; In acetonitrile; at 20℃; for 3h;
Example 203A 5-Bromo-3-methyl-indazole-1-carboxylic Acid Tert-Butyl Ester A solution of Example 102C (1.0 g; 4.7 mmol), TEA (526 mg; 5.2 mmol), DMAP (200 mg; 1.6 mmol) and di-tert-butyldicarbonate (1.1 g; 5.0 mmol) in CH3CN (15 mL) was stirred at r.t. for 3 hrs, evaporated, and isolated by flash chromatography (30% Et2O/hexane) to give the desired product as a white solid (1.4 g; 95%).
With dmap; In dichloromethane; at 20℃; for 3h;
-Bromo-3 -methyl- lH-indazole (5.11 g, 24.2 mmol) and catalytic dimethylaminopyridine (~30 mg) were dissolved in methylene chloride (100 mL). Di-tert- butyl dicarbonate (5.9 g, 27.0 mmol) was added, and the mixture was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with 1 N sodium hydroxide (twice), 0.1 N hydrochloric acid, and brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound. MS (ESI+) m/z 210.8 (M-Boc)+.
(+/-)-[1-(2-methyl-1H-indol-3-ylmethyl)-2-(5-trimethylstannanyl-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester[ No CAS ]
[ 552331-64-3 ]
Yield
Reaction Conditions
Operation in experiment
28%
With triethylamine;tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 80℃; for 5h;
Example 225G (+-)-[2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2-methyl-1H-indol-3-ylmethyl)-ethyl]-carbamic Acid Tert-Butyl Ester Bromo-methylindazole (71 mg, 0.33 mmol), Example 225F (200 mg, 367 mmol), Pd2 dba3 (61 mg, 0.7 mmol), and P(o-tol)3 (41 mg, 0.14 mmol) were combined in a 10 mL round bottom flask with a stirbar. DMF (2 mL) was added and the atmosphere of the flask evacuated and replaced with argon twice. Et3N (0.09 mL, 0.67 mmol) was added and the reaction mixture warmed to 80 C. for 5 h and then cooled to room temperature. EtOAc was added and the resulting mixture filtered through Celite. The filtrate was washed twice with H2O and once with brine. Silica gel was added and the volatiles removed on a rotary evaporator. Flash chromatography (70-85-100% EtOAc/hexanes) gave 48 mg (28%) of as a yellow solid. Rf=0.30 (EtOAc); MS m/z 512 (M+H)+; 1H NMR (300 MHz, DMSO-D6) delta ppm 1.36 (s, 9H) 2.31 (s, 3H) 2.54 (s, 3H) 2.90 (m, 2H) 4.05 (m, 3H) 6.93 (m, 3H) 7.20 (m, 2H) 7.58 (m, 3H) 8.06 (s, 1H) 8.20 (d, J=2.71 Hz, 1H) 8.53 (d, J=1.70 Hz, 1H) 10.72 (s, 1H) 12.72 (s, 1H).
N-(6-(3-methyl-1H-indazol-5-yl)naphthalen-2-yl)thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With potassium carbonate;Fibercat palladium catalyst; In 1,4-dioxane; water; at 85℃; for 0.333333h;Microwave irradiation;
5-bromo-3-methyl-lH-indazole (30.7 mg, 0.145 mmol), N-(6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (110.3 mg, 0.291 mmol), Fibercat palladium catalyst (Johnson-Matthey, 59.3 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1 ,4-dioxane (1.6 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3 x 10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13% EtOAc / hexanes -> 100% EtOAc). This crude material was then purified via HPLC (10% -> 95% MeCN / water with 0.1 % TFA) to afford title compound (14.0 mg, 25%). MS (ESI pos. ion) m/z: 384 (M+H). Calc'd Exact Mass for C23H17N3OS: 383.
<strong>[552331-16-5]5-Bromo-3-methyl-1H-indazole</strong> (13.24 g, 62.75 mmol), bis(pinacolato)diboron (16.74 g, 65.89 mmol), potassium acetate (18.5 g, 188.25 mmol) and anhydrous 240 mL DMSO were charged into a 500 mL round bottom flask. After degassing the resulting reaction mixture with nitrogen for 15 minutes, 1,1-[Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (2.56 g, 3.14 mmol) was added. The reaction was then heated to 86 C. under nitrogen. After stirring for 20 hours, the black reaction mixture was cooled to room temperature and slowly poured into 1.2 L of diethyl ether. The resulting mixture was transferred to a 2 L separation funnel, and the lower layer was discarded. The upper layer was washed with 1.0 M magnesium sulfate (500 mL×2) and brine solution, dried over sodium sulfate, and concentrated to dryness. The residue was subjected to a silica gel column chromatography purification with hexane-EtOAc (4:1) as the eluant to afford the desired compound 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (10.0 g, 61.7%) as a colorless solid. LCMS (API-ES) m/z (%): 259.2 (100%, M++H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 85℃; for 6h;
Step 2. 3-Methyl-5-(tetramethyl-l ,3,2-dioxaborolan-2-yl)-7H-indazoleTo a solution of 5-bromo-3-methyl-7H-indazole (400 mg, 1.90 mmol) in DMSO (10 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l ,3,2-dioxaborolane (959 mg, 3.78 mmol), KOAc (400 mg, 4.08 mmol), Pd(dppf)Cl2 (100 mg). After stirring for 6h at 85C, the mixture was dissolved in water (50 mL), extracted with ethyl acetate (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford 3-methyl-5-(tetramethyl-l ,3,2-dioxaborolan-2-yl)-7H-indazole as a off-white solid (700 mg, crude).
2.5 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 95℃;Inert atmosphere;
Under an Ar atmosphere, a mixture of 5-bromo-3-methyl-lH-indazole (3 g, 14.2 mmol), bis(pinacolato)diboron (7.2 g, 28.4 mmol), [l , l-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.16 g, 1.42 mmol) and AcOK (2.79 g, 28.4 mmol) in 1 ,4-dioxane was heated at 95 C overnight. After cooling down to the room temperature, the mixture was concentrated and the residue was purified by flash column to give 3-methyl-5-(4,4,5,5- tetramethyl-[l ,3,2]dioxaborolan-2-yl)-lH-indazole (2.5 g) as yellow oil.
To an Argon flushed flask of anhydrous THF (81 mL) cooled to -78 C. was added a 1.7M solution of tert-butyllithium in n-pentane (27 mL, 45.6 mmol). After stirring the solution at -78 C. for 15 minutes, a solution of <strong>[552331-16-5]5-Bromo-3-methyl-1H-indazole</strong> (3 g, 14.2 mmol) in THF (42 mL) was added dropwise such that the temperature of the solution did not exceed -70 C. After stirring the solution at -78 C. for 30 minutes, anhydrous DMF (3.15 g, 43.09 mmol) was added dropwise. The reaction mixture was then stirred at -78 C. for 30 minutes, warmed to room temperature and stirred for 1.5 hours. The reaction mixture was cooled down to 0 C. and it was added carefully water (36 mL) and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc 6:4 v/v) to afford white solid (1.6 g, 70%).1H NMR (400 MHz, CDCl3) delta10.09 (br s, 1H), 10.07 (s, 1H), 8.24 (s, 1H), 7.95 (dd, 1H), 7.52 (d, 1H), 2.66 (s, 3H).LC/MS (m/z) [M+1]+ 161.1 (calculated for C9H8N2O, 160.06).(compound described: WO 2008071451)
To chilled tetrahydrofuran (600 mL) at -780C1 under Argon, was added 200 mL of a 1.7M solution of tert-butyllithium in n-pentane. After 15 minutes at -78C, a solution of 22.4 g (106.13 mmol) 5-bromo-3-methyl-1 H-indazole (commercially available, or see WO 2006/081230, 68-69) in 300 mL tetrahydrofuran was added dropwise at such a rate that the temperature of the solution did not exceed -7O0C. The mixture was stirred for 30 minutes before 24.5 mL N,N-dimethylformamide was added dropwise. After 20 minutes the cooling bath was removed and stirring contimued for 1 hour before 41 mL water was added carefully. A further 201 mL water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvents were distilled off to give 18.5 g crude 3-methyl-1 H- indazole-5-carbaldehyde, which was used without purification. 1 H-NMR (DMSO-d6): delta = 13.13 (br s, 1 H)1 10.01 (s, 1H), 8.40 (s, 1 H), 7.81 (d, 1 H), 7.58 (d, 1 H), 2.56 (s, 3H) ppm. MS (ES+): 161.34 (M++1 , 100%).
Example IAS-Methyl-lH-indazole-S-carbaldehydeTetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of ferf-butyllithium in ?-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-lH-indazole in TEtaF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -700C. The mixture was stirred for 30 minutes before N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl- lH-indazole-5-carbaldehyde, which was used in the next step without further purification.1H-NMR (DMSOd6): delta = 13.13 (br. s, IH), 10.01 (s, IH), 8.40 (s, IH), 7.81 (d, IH), 7.58 (d, IH), 2.56 (s, 3H) ppm.
Example IA 3-Methyl-lH-indazole-5-carbaldehydeTetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of /ert-butyllithium in H-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-lH-indazole in TEtaF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -700C. The mixture was stirred for 30 minutes before NN-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-lH- indazole-5-carbaldehyde, which was used in the next step without further purification.1H-NMR (DMSO-d6): delta = 13.13 (br. s, IH), 10.01 (s, IH), 8.40 (s, I H), 7.81 (d, I H), 7.58 (d, I H), 2.56 (s, 3H) ppm.
Tetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-lH-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -70C. The mixture was stirred for 30 minutes before NN-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-lH-indazole-5- carbaldehyde, which was used in the next step without further purification. 'H-NMR (DMSO-dg): delta = 13.13 (br. s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 7.81 (d, 1H), 7.58 (d, 1H), 2.56 (s, 3H) ppm.
Tetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-lH-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -70C. The mixture was stirred for 30 minutes before NN-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-lH-indazole-5- carbaldehyde, which was used in the next step without further purification. Tl-NMR (DMSO-dg): delta = 13.13 (br. s, 1Eta), 10.01 (s, 1Eta), 8.40 (s, 1Eta), 7.81 (d, 1Eta), 7.58 (d, 1Eta), 2.56 (s, 3Eta) ppm.
Tetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of teri-butyllithium in «-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5 -bromo-3 -methyl- lH-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -70C. The mixture was stirred for 30 minutes before NN-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-lH-indazole-5- carbaldehyde, which was used in the next step without further purification. 'H-NMR (DMSO-dg): delta = 13.13 (br. s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 7.81 (d, 1H), 7.58 (d, 1H), 2.56 (s, 3H) ppm.
1. To a solution of 5-bromo-3-methyl-lH-indazole (2.11 g, 10.0 mmol) in 50 mL of THF, was added 6.3 mL of n-BuLi solution in hexanes (1.7 M) at -78 C. After 10 minutes, 17.6 mL of t-BuLi solution in pentane (1.6 M) at -78 C. After 1 hr, DMF (10 mL) was added. After 10 minutes, the reaction was allowed to warm up to RT. After 10 minutes, the reaction was quenched with saturated ammonium chloride, and extracted with EtOAc. The organic layer was washed with brine (x2), dried (MgS04), and concentrated to give crude 3 -methyl- 1H- indazole-5-carbaldehyde (quant.) as a brownish solid. *H NMR (399 MHz, DMSO-d6) delta ppm 13.08 (1 H, br. s.), 9.98 (1 H, s), 8.36 (1 H, s), 7.78 (1 H, dd, 7=8.6, 1.2 Hz), 7.55 (1 H, d, 7=8.6 Hz), 2.53 (3 H, s)
Example IA3 -Methyl- 1 H-indazole-5-carbaldehyde Tetrahydrofuran (600 ml) was cooled down to -78C under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in /j-pentane (200 ml) was added dropwise. After 15 minutes at -78C, a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-lH-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed -70 C. The mixture was stirred for 30 minutes before NN-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-lH- indazole-5-carbaldehyde, which was used in the next step without further purification.1H-NMR (DMSO-Cl6): ? = 13.13 (br. s, IH), 10.01 (s, IH), 8.40 (s, IH), 7.81 (d, IH), 7.58 (d, IH), 2.56 (s, 3H) ppm.
With acetic acid; sodium nitrite; In water; for 4.5h;
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: C8H7BrN2 Exact Mass: 209.98 Molecular Weight: 21 1 .06 [00211] A solution of 4-bromo-2-ethylaniline (5.00 mL, 35.3 mmol) in glacial acetic acid (300 mL) was treated with a solution Of NaNO2 (2.43 g, 35.2 mmol) in water (10 mL). After stirring for 4.5 hours, the mixture was concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/Me0H, 100:0 to 97:3) provided the title compound (4.24 g, 57%) as a dark red semi-solid: 1H NMR (500 MHz, CDCl3) delta 7.82 (d, J = 1.5 Hz, IH), 7.45 (dd, J = 9.0, 1.5 Hz, IH), 7.31 (d, J = 9.0, IH), 2.56 (s, 3H); ESI MS m/z 211 [M+ H]+
44%
With acetic acid; sodium nitrite; at 20℃; for 2.5h;
Step 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 NaN02 (570 mg, 8.14 mmol). After stirring for 2.5 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% methanol in dichloromethane to afford 5-bromo-3-methyl-7H- indazole as a light red solid (700 mg, 44%).'H-NMR (300 MHz, CDC13) delta 8.35 (s, 1H), 7.45 - 7.49 (m, 1H), 7.33 (d, / = 8.7 Hz, 1H), 2.59 (s, 3H)
1-(5-bromo-3-methyl-1H-indazol-1-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
5 -Bromo-3 -methyl- 1 H-indazole (838 mg, 3.97 mmol) was dissolved in methylene chloride (15 mL) and diisopropylethylamine (0.7 mL). Acetic anhydride (500 uL, 5.29 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1 N sodium hydroxide followed by 1 N hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the title compound. MS (ESI+) m/z 252.7 (M+H)+.
3-methyl-5-(2-(trimethylsilyl)ethynyl)-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride;Heating / reflux;
[00289] 3-Methyl-5-(2-(trimethylsilyl)ethynyl)-lH-indazole: 5-Bromo-3-methyl- lH-indazole (1.72 g, 8.2 mmol), PdCl2(PPh)2 (1.14 g, 1.64 mmol), CuI (155 mg, 0.82 mmol) and ethynyltrimethylsilane (3.5 mL, 24.6 mmol) were dissolved in 180 mL Et3N and refluxed over night. The mixture was cooled to room temperature, filtered and evaporated. The residue was taken up in MeOH (100 mL), filtered again and evaporated. The product thus obtained was purified on glass column chromatography (20% EtOAc in hexane). The title compound was obtained as a dark solid. LCMS (API-ES) m/z (%): 229.0 (100%, M++H).
[00202] 3-Methyl-lH-indazole-5-carboxlic acid: A three necked round bottom flask equipped with an internal thermometer and an overhead stir motor was charged with 600 mL of THF and chilled to -78 0C. t-BuLi (1.7 M in THF, 200 mL, 0.340 mol) was added to the flask, and the mixture was stirred for 15 minutes. 5-Bromo-3 -methyl- IH- indazole (22.4 g, 0.106 mol) in 200 mL THF was then added dropwise via an addition funnel. The rate of addition was closely monitored to make sure that the internal temperature remained below -70 0C. The resulting orange solution was stirred for 30 minutes, at which point CO2 was bubbled through the mixture. A white precipitate was observed. After 20 minutes, the ice bath was removed and the temperature was allowed to warm to room temperature. The resulting mixture was stirred for an additional 30 minutes. Water was then added to the mixture (40 mL initially followed by a further 200 mL). The biphasic mixture was partially concentrated under reduced pressure, removing about 75% of the original organic portion. The biphasic solution was then transferred to an addition funnel, and the organic phase was extracted with 100 mL of 2M NaOH. The combined aqueous extracts were washed with ether and then acidified to pH = 2.0 with concentrated HCl. A precipitate began to form, and the mixture was cooled to 00C to complete the precipitation. The resulting solid was filtered, washed with I M HCl, and dried under reduced pressure at 160C over phosphorus pentoxide, affording 3-methyl- lH-indazole-5-carboxlic acid (18.1 g, 96 % yield) as a pink/beige solid. LCMS (API-ES) <n="98"/>m/z (%): 177.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) delta ppm 2.61 (s, 3H) 3.33 (b, 2H), 7.52 (d, J = 6.0 Hz, IH), 8.05 (d, J = 6.0 Hz, IH), 8.50 (s, IH).
96%
A three necked round bottom flask equipped with an internal thermometer and an overhead stir motor was charged with 600 mL of TEtaF and chilled to -78 0C. t-BuLi (1.7 M in TEtaF, 200 mL, 0.340 mol) was added to the flask, and the mixture was stirred for 15 min. 5-Bromo-3-methyl-lH-indazole (4d) (22.4 g, 0.106 mol) in 200 mL TEtaF was then added dropwise via an addition funnel. The rate of addition was closely monitored to insure that the internal temperature remained below -70 C. The resulting orange solution was stirred for 30 min, at which point CO2 was bubbled through the mixture. A white precipitate was observed. [0090] After 20 min, the ice bath was removed and the temperature allowed to warm to room temperatures (rt), and stir for an additional 30 min. Water was then added, 40 mL initially followed by a further 200 mL. The biphasic mixture was partially concentrated under reduced pressure, removing ~75% of the original organic portion. The biphasic solution was then transferred to an addition funnel, and the organic phase was extracted with 100 mL of 2M NaOH. The combined aqueous extracts were then washed with ether and then acidified to pEta = 2.0 with cone. HCl. A precipitate began to form and the mixture was cooled to 0 0C to complete the precipitation. The resulting solid was filtered, washed with 1 M HCl, and dried under reduced pressure at 160C over phosphorus pentoxide, affording 3-methyl-lH-indazole-5-carboxlic acid (4e) (18.1 g, 96 % yield) as a pink/beige solid. 1H NMR 400MEtaz (d4 MeOH) 2.61 (3 H, s), 3.33 (2 H, s), 7.52 (1 H, d, J = 6.0 Hz), 8.05 (1 H, t, J = 5.2 Hz)5 8.50 (1 H, s). MS (API-ES) m/z (%): 177 (100%, M++H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; at 100℃; under 15201.0 Torr;
To a solution of 5-bromo-3-methyl-lH-indazole (6.2 g, 1.0 eq) in methanol (700 mL) was added triethylamine (5.9 g, 2.0 eq) and Pd(dppf)Cl2 (1.2 g, 0.05 eq), and the reaction was placed under an atmosphere of CO (g) at 20 atm. The resulting reaction was stirred overnight at 100C. Then the mixture was concentrated in vacuo to afford a residue, which was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1/50) to afford methyl 3- methyl-lH-indazole-5-carboxylate (5.2 g, 93%) as a white solid. 'H-NMR: (DMSO, ppm): delta 12.99 (s, 1H), 8.40 (s, 1H), 7.90 (dd, = 1.2 Hz, J2 = 9.0 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 2.54 (s, 3H)
83%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; under 3800.26 Torr; for 14h;
To a 50 mL steel tank reactor purged and maintained with an atmosphere of carbon monoxide (5 atm), were added 5-bromo-3-methyl-1 H-indazole (1.00 g, 4.74 mmol), Pd(dppf)CI2.CH2Cl2 (400 mg, 0.49 mmol), potassium acetate (1.40 g, 14.3 mmol), N,N- dimethylformamide (5 mL) and methanol (25 mL). The solution was stirred for 14 h at 80C. The reaction mixture was concentrated under vacuum. The residue was dissolved in water and extracted 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 ethyl acetate/petroleum ether (3:7). This resulted in 750 mg (83%) of 3-Methyl-1 H-indazole-5-carboxylic acid methyl ester as a yellow solid.
80%
With sodium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; under 3102.97 Torr; for 20h;
To a solution of <strong>[552331-16-5]<strong>[552331-16-5]5-bromo-3-methyl-1H-indazol</strong>e</strong> (10 g, 47.6 mmol) in MeOH (160 mL), PdCI2dppf (5.57 g, 7.62 mmol), NaOAc (11.7 g, 142.85 mmol) and DMF (5 mL) were added and degassed (using N2 gas 3-times). The mixture was sealed, charged with CO gas (60 psi) and heated at 80 gC for 20 hours. The reaction mixture was concentrated to obtain a residue, which was diluted with water (100 mL), acidified with 10% aqueous citric acid and extracted using ethyl acetate (3x200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 1 H-indazole-5-carboxylic acid methyl ester (7.23 g, 80%) as a solid. 1H NMR (CDCI3): delta 9.6-10.2 ( br, 1 H), 8.4-8.6 (s, 1 H), 8.0-8.2 (d, 1 H), 7.4-7.5 (d, 1 H), 3.9-4.05 (s, 3H), 2.55-2.7 (s, 3H).
50%
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; for 24h;
Step 1. Methyl 3-methyl-1H-indazole-5-carboxylate A mixture of <strong>[552331-16-5]<strong>[552331-16-5]5-bromo-3-methyl-1H-indazol</strong>e</strong> (11.0 g, 52.12 mmol), Pd(dppf)Cl2 (1.9 g, 2.60 mmol) and TEA (10.53 g, 104.06 mmol) in methanol (40 ml) was stirred for 24 hours at 100 C. under an atmosphere of CO (g). The resulting mixture was concentrated in vacuo to provide a residue, which was purified by a silica gel column chromatography with 3% ethyl acetate in petroleum ether to afford methyl 3-methyl-1H-indazole-5-carboxylate as a gray solid (5.0 g, 50%). LC/MS (ES, m/z): [M+H]+ 191.0 1H-NMR (300 MHz, DMSO) delta 12.99 (s, 1H), 8.41 (s, 1H), 7.89-7.93 (m, 1H), 7.52-7.55 (m, 1H), 4.08 (s, 3H), 2.55 (s, 3H)
To a 0 C. stirred solution of <strong>[552331-16-5]5-bromo-3-methyl-indazole</strong> (from Preparation 1, 1.00 g, 4.33 mmol) in anhydrous DMF (30 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.21 g, 5.19 mmol). After 30 min, benzyl chloromethyl ether (60%, 1.47 g, 5.63 mmol) was added vial syringe in about 1 min. Stirring was continued for 1 h. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give an oil that was purified by chromatography on silica gel (hexane/ethyl acetate 10:1) to give the title compound (0.72 g, 50%) that was pure by NMR.
5-bromo-1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrabutylammomium bromide; potassium hydroxide; In tetrahydrofuran; for 1h;
(A) A vigorously stirred solution of 5-bromo-3-methyl-1Hindazole6 (633 mg; 3 mmol) and 4-chloro-2-trifluoromethylbenzylbromide (984 mg; 3.6 mmol) in THF (15 mL) was added pulverizedKOH (234 mg; 3.6 mmol) followed by tetrabutylammonium bromide(192 mg; 0.6 mmol). After 1 h, the mixture was diluted withether (30 mL), filtered and concentrated. Purification of the residueby silica gel chromatography (20-40%) DCM/hexanes afforded 5-bromo-1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazole7 (1.01 g, 84%) as a white solid (slight yellow tint), which wasused directly.(B) A mixture of bromoindazole 7 (1.01 g; 2.5 mmol), potassiumferrocyanide (233 mg; 0.55 mmol), Na2CO3 (266 mg; 1.9 mmol) andpalladium (II) acetate (12 mg; 0.053 mmol) in dimethylacetamide(7 mL) was purged with nitrogen and then heated at 105 C. After3 h, the mixture was cooled to room temperature, diluted withether (20 mL) and filtered. The ethereal solutionwas extracted withwater, dried (K2CO3), concentrated under reduced pressure andpurified by silica gel chromatography (20e100%) DCM/hexanes toafford 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-carbonitrile 8 (629 mg, 72%) as a white solid, which was useddirectly.(C) To a mixture of cyanoindazole 8 (629 mg; 1.8 mmol), formicacid (40 mL) and water (4 mL) was added aluminum-nickel (50:50)catalyst (900 mg) and the reactionwas heated to a mild reflux. After2 h, additional catalyst (400 mg) was added and heating wascontinued for 1 h after which time the heating source was removedand the reaction was allowed to partially cool. The warm mixturewas filtered through Celite; the filtered inorganics were washedwith warm MeCN and the combined filtrate was concentrated. Theresidue thus obtained was purified by silica gel chromatographyeluting with DCM to provide 1-[4-chloro-2-(trifluoromethyl)-benzyl]-3-methyl-1H-indazol-5-carbaldehyde 9 as a colorless oil(600 mg, 95%). 1H NMR (400 MHz, CDCl3) delta 10.06 (s, 1 H), 8.26 (s,1 H), 7.91 (d, J 8.61 Hz, 1 H), 7.71 (d, J 1.96 Hz, 1 H), 7.33 (dd,J 8.61, 1.96 Hz, 1 H), 7.29 (d, J 8.61 Hz, 1 H), 6.66 (d, J 8.22 Hz,1 H), 5.74 (s, 2 H), 2.68 (s, 3 H).
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