* 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.
With water; sodium hydroxide In methanol for 1 h; Reflux
To a stirred solution of methyl l_f/-indazole-5-carboxylate (6.5 g, 1.0 eq) in 200 mL MeOH was added a solution of NaOH (4.4 g, 3.0 eq) in 150 mL H20. The mixture was refluxed for 1 h. The organic solvent was removed in vacuo, the remaining aqueous solution was washed with EtOAc, acidified with 3 N HC1 to pH = 5~6, and the precipitate was collected by filtration, and washed with water, to give the desired product as a yellow solid (6.2 g, 98percent).
93%
Stage #1: With water; sodium hydroxide In methanol at 60℃; for 14 h; Stage #2: With hydrogenchloride In water
Step 3. 1H-Indazole-5-carboxylic acid A solution of methyl 1H-indazole-5-carboxylate (6.2 g, 35.19 mmol) and NaOH (5.6 g, 140.01 mmol) in methanol (100 mL) and water (10 mL) was stirred 14 hours at 60° C., the resulting mixture was concentrated in vacuo to provide a residue, which was dissolved in water (80 mL) and adjusted to pH 6 with HCl (3N). The solids were collected by filtration to afford 1H-indazole-5-carboxylic acid (5.3 g, 93percent) as a yellow solid. LC/MS (ES, m/z): [M+H]+ 163.2 1H-NMR (300 MHz, DMSO) δ 13.33 (s, 1H), 12.73-12.88 (m, 1H), 8.46 (d, J=0.6 Hz, 1H), 8.25 (s, 1H), 7.90-7.94 (m, 1H), 7.59 (d, J=8.7 Hz, 1H)
93%
With water; sodium hydroxide In methanol at 60℃;
To a solution of 3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine (100 mg, 0.57 mmol) in diphenyl ether (3 ml) was added ethyl 3-(lH-l ,2,3-benzotriazol-5-yl)-3- oxopropanoate (300 mg, 1.29 mmol) and 4-methylbenzene-l -sulfonic acid (5 mg, 0.02 mmol). After stirring 1 h at 170°C, the solids were collected by filtration, washed with ethyl acetate (2 x 10 ml), methanol (3 x 10 ml) and dried to give 5- (lH-benzo[if|[l,2,3]triazol-5-yl)-2-(pyridin-2-yl)-[l,2,4]triazolo[l,5-fl]pyrimidin- 7(4H)-one as a off-white solid (36.7 mg, 18percent). LC/MS (ES, m/z): [M+H]+ 331.0 *H NMR (300 MHz, DMSO) δ 8.70 (s, 1H), 8.40 (s, 1H), 8.22 (d, / = 7.8 Hz, 1H), 7.73 - 7.97 (m, 3H), 7.443 - 7.47 (t, J = 6.9 Hz, 1H), 6.25 (s, 1H)
Reference：
[1] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0261
[2] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 40
[3] Patent: WO2014/66743, 2014, A1, . Location in patent: Paragraph 0146
[4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8219 - 8248
2
[ 67-56-1 ]
[ 61700-61-6 ]
[ 473416-12-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 65 - 70℃; for 3 h;
A mixture of commercially available 1H-indazole-5-carboxylic acid (1, 3.0 g, 18.5 mmol; Aldrich) and sulfuric acid (10 mol-percent) in methanol (30 mL) was heated for 3 h at 65–70 °C. After complete conversion, the reaction was cooled to room temperature, hydrolyzed dropwise with a saturated sodium carbonate solution (10 mL), and extracted three times with ethyl acetate (30 mL). The combined organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to afford methyl 1H-indazole-5-carboxylate (3.19 g, 98percent) as a white crystalline solid (not shown in the Scheme above); mp 196.2–197.8 °C. 1H NMR (500 MHz, DMSO-d6) δ = 3.87 (s, OCH3, 3H), 7.61 (d, J = 8.83 Hz, 1H), 7.91 (dd, J = 1.58/8.83 Hz, 1H), 8.24 (s, 1H), 8.49 (s, 1H), 13.38 (s, NH, 1H). 13C (125 MHz, DMSO-d6) δ = 52.1 (OCH3), 110.4, 122.1, 122.7, 124.0, 126.4, 135.5, 141.8, 166.7 (CO2Me); LC/ESI-MS (m/z): negative mode 175.16 [M-H]–, positive mode 177.27 [M+H]+.
88%
at 70℃;
To a suspension of 1H-indazole-5-carboxylic acid (470 mg, 2.9 mmol) in MeOH (5 mL) H2SO4 (0.2 mL) was added. The mixture was heated to 70 °C and stirred at this temperature overnight. The mixture was left to reach room temperature, H2O (10 mL), NaHCO3 saturated aqueous solution (5 mL) and ethyl acetate (30 mL) were added. The phases were separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and evaporated to dryness to give methyl 1H-indazole-5-carboxylate (466 mg, 2.65 mmol, 88 percent yield) as a pale pink-yellow solid. MS found for C9H8N2O2 as (M+H)+ 176.9.
32%
at 100℃; for 0.0833333 h; Microwave irradiation
A solution of lH-indazole-5-carboxylic acid 0.25g (1.54 mmol) in methanol (2.5 mL) and cone. H2SO4 (0.1ml) was heated at 100 °C in an Emrys microwave reactor for 5 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with saturated NaHC03 and brine (30 mL), dried (MgSC^) and the volatiles were removed in vacuo to yield of lH-indazole-5-carboxylic acid methyl ester 0.086g (32percent) 4 as a pale yellow solid. 1H-NMR(CDC13, δ 8.58 (dd, IH, ArH), 8.21 (d, IH, ArH), 8.11 (dd, IH, ArH), 7.54 (d, 2H, ArH), 3.98 (s, 3H, CH3). LC-MS: m/z 177 M + H+.
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 470 - 492
[2] Patent: WO2013/78237, 2013, A1, . Location in patent: Page/Page column 81; 82
[3] Patent: WO2016/196776, 2016, A2, . Location in patent: Paragraph 00725
[4] Patent: WO2013/96496, 2013, A2, . Location in patent: Page/Page column 26
3
[ 239075-26-4 ]
[ 473416-12-5 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 0.166667 h;
The obtained acetyl indazole (1.2 g, 5.50 mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (1/1, 20 mL) and then 6N sodium hydroxide aqueous solution (1.8 mL) was added dropwise thereto. The mixture was stirred for 10 minutes at room temperature and acidified with 6N hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane. The extract was dried with anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound (1.0 g, 47percent). [1228] NMR: 1H-NMR (400HMz, CDCl3); δ 9.72 (br, s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.14 (dd, J = 1.2 Hz, 1H), 7.60 (d, 1H), 3.97 (s, 3H)
Stage #1: With hydrogenchloride; ammonium tetrafluoroborate; sodium nitrite In water for 0.583333 h; Stage #2: With 18-crown-6 ether; potassium acetate In chloroform; water at 20℃; for 2 h;
Step 3. Methyl 1H-indazole-5-carboxylate To a solution of methyl 4-amino-3-methylbenzoate (21 g, 133.18 mmol) in HCl (15 mL) and water (85 mL) was added NH4BF4 (20 g) and NaNO2 (10 g, 144.93). The mixture was stirred for 35 minutes, and the solids were collected by filtration and added in one portion to a stirred mixture of KOAc (16 g, 163.03 mmol) and 18-crown-6 (500 mg, 1.89 mmol) in CHCl3 (170 mL). After stirring for 2 hours at room temperature, the mixture was washed with water (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 30percent ethyl acetate in petroleum ether to afford methyl 1H-indazole-5-carboxylate as a white solid (14.5 g, 62percent). LC/MS (ES, m/z): [M+H]+ 177.0 1H-NMR (300 MHz, CDCl3) δ 8.58-8.59 (m, 1H), 8.23 (s, 1H), 8.09-8.13 (m, 1H), 7.54 (d, J=9.0 Hz, 1H), 3.98 (s, 3H)
55%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0 - 20℃; for 4 h; Stage #2: With 18-crown-6 ether; potassium acetate In chloroform; water at 0 - 20℃; for 3 h; Inert atmosphere
NaN02 (20 g, 0.29 mol) was added portion wise to a solution of methyl 4-amino-3- methylbenzoate (38 g, 0.23 mol) in aqueous HBF4 (48 wt, 200 mL) at 0°C. The reaction was allowed to stir for 4 h at room temperature. The solids were collected by filtration and washed with 3x200 mL of ether. The solids were dried in an oven under reduced pressure. Under an inert atmosphere of nitrogen, was placed CH3COOK (45 g, 0.46mol), 18-crown-6 (3 g, 0.012mol), and chloroform (200 mL). This was followed by the portion wise addition of the dried solid at 0°C. The reaction was stirred for 3 h at room temperature. Then 1 L of H20 was added and the resulting solution was extracted with 5x100 mL of DCM. The organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo to afford a residue which was purified by silica gel column chromatography with 1percent methanol in CH2Cl2 to afford of methyl lH-indazole-5-carboxylate as a yellow solid (22 g, 55percent). LCMS (ES, m/z): [M+H]+ 177.1 *H NMR (300 MHz, DMSO) δ 13.41 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.94 - 7.90 (dd, / = 1.50, 8.70 Hz, 1H), 7.64 (d, / = 8.70 Hz, 1H), 3.90 (s, 3H)
30%
With acetic acid; sodium nitrite In water at 20℃; for 5 h;
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5percent aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30percent).1H-NMR (DMSO-d6) δ; 3.86 (3H, s), 7.61 (1H, d, J=8.8Hz), 7.91 (1H, d, J=8.8Hz), 8.25 (1H, s), 8.48 (1H, brs), 13.41 (1H, brs).
Reference：
[1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[3] Patent: EP1403255, 2004, A1, . Location in patent: Page 43-44
[4] Patent: WO2013/97773, 2013, A1,
[5] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[6] Patent: WO2014/129796, 2014, A1,
[7] Patent: WO2014/143666, 2014, A1, . Location in patent: Paragraph 00190
With iodine; potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
General procedure: To a cooled (0°C) DMF solution indazole (1.0equiv) and K2CO3 or KOH (∼3equiv) was added I2 (2–4equiv) in one portion. The reaction was stirred with cooling or rt for several h and then was treated with xs 10percent aq NaHSO3 and subsequently diluted with H2O. In the majority of examples a filtration and washing (H2O) of the precipitate provided the desired material with the required purity.
65%
With potassium <i>tert</i>-butylate; iodine In tetrahydrofuran at 0 - 20℃; for 3 h;
To a solution of methyl lH-indazole-5-carboxylate (132a) (5 g, 28.4 mmol) in THF (40 mL) was added I2 (10.81 g, 42.6 mmol) and KOtBu (7.96 g, 71.0 mmol) at 0 °C, the resulting mixture was stirred for 3h at room temperature. The reaction mixture was diluted with 10percent aqueous sodium thiosulfate and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water, brine, dried and concentrated in vacuum. The obtained solid was washed with MeOH (20 mL) to give methyl 3-iodo-lH-indazole-5-carboxylate (132b) (5.6 g, 18.54 mmol, 65percent yield) as a yellow solid; 1H MR (300 MHz, DMSO-^e) δ 13.87 (s, 1H), 8.08 - 8.03 (m, 1H), 7.97 (dd, J= 8.8, 1.6 Hz, 1H), 7.65 (dd, J= 8.8, 0.7 Hz, 1H), 3.88 (s, 3H); MS (ES+): 303.2 (M+l); MS (ES-): 301.2 (M-l).
13 g
With potassium <i>tert</i>-butylate; iodine In tetrahydrofuran at 0 - 20℃; for 2 h;
To a solution of methyl lH-indazole-5-carboxylate (105) (10 g, 1 eq.) in THF (100 mL) was added iodine (21.6 g, 1.5 eq.) and potassium tert-butoxide (16 g, 2.5 eq.) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with 10percent sodium thiosulfate in water and extracted twice with EtOAc. The combined organic extracts were washed with brine and evaporated to dryness. The resultant solid was slurried with MTBE, filtered and dried to afford 106 (13 g).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h;
Potassium carbonate (60 g, 0.0.44 mol) was added to a solution of methyl 1H- indazole-5-carboxylate (22 g, 0.13 mol) in N,N-dimethylformamide (200 mL) followed by the dropwise addition of CH3I (62 g, 0.44 mol). Then the reaction was stirred for 5 h at room temperature. The reaction was then quenched by the addition of 200 mL of water, extracted with 4x200 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. Purification by silica gel column chromatography with 2percent ethyl acetate in petroleum ether afforded methyl 1 -methyl- lH-indazole-5- carboxylate as an orange solid (13 g, 55percent). LCMS (ES, m/z): [M+H]+ 191.0 *H NMR (300 MHz, DMSO) δ 8.48 (s, 1H), 8.24 (s, 1H), 7.97 - 7.94 (dd, / = 1.50, 8.70Hz, 1H), 7.77 - 7.72 (m, 1H), 4.09 (s, 3H), 3.88 (s, 3H)
38%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; oil at 20℃; for 1 h; Stage #2: at 20℃;
Acid Preparation 11; 1 -Methyl-1 H-indazole-5-carboxvlic acid; To a stirred suspension of 60percent NaH oil dispersion (87 mg, 2.2 mmol) in DMF (4 mL) was added methyl 1 H-indazole-5-carboxylate (264 mg, 1.50 mmol). The mixture was stirred at room temperature for 1 hour before the dropwise addition of iodomethane (0.11 mL, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and the residue was purified by Biotage chromatography (4OS column, 15percent acetone/heptane) to afford methyl 1 -methyl-1 H-indazole-5-carboxylate (107 mg, 38percent).
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7286 - 7293
[2] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[3] Patent: WO2009/144554, 2009, A1, . Location in patent: Page/Page column 48
14
[ 473416-12-5 ]
[ 74-88-4 ]
[ 1092351-82-0 ]
[ 1092351-86-4 ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃;
Acid Preparation 13; 2-Methyl-2H-indazole-5-carboxylic acid; To a solution of methyl 1 H-indazole-5-carboxylate (2.5 g, 14 mmol) in DMF (45 ml_) was added K2CO3 (4.90 g, 35.5 mmol) followed by iodomethane (1.77 ml_, 28.4 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 50 aC overnight. The mixture was concentrated, dissolved in EtOAc and washed with saturated aqueous NaCI. The organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 25-45percent EtOAc/heptane) to provide methyl 1- methyl-1 H-indazole-5-carboxylate (1.07 g, 40percent) and methyl 2-methyl-2H-indazole-5- carboxylate (227 mg, 8.4percent).
With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃;
Acid Preparation 13; 2-Methyl-2H-indazole-5-carboxylic acid; To a solution of methyl 1 H-indazole-5-carboxylate (2.5 g, 14 mmol) in DMF (45 ml_) was added K2CO3 (4.90 g, 35.5 mmol) followed by iodomethane (1.77 ml_, 28.4 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 50 aC overnight. The mixture was concentrated, dissolved in EtOAc and washed with saturated aqueous NaCI. The organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 25-45percent EtOAc/heptane) to provide methyl 1- methyl-1 H-indazole-5-carboxylate (1.07 g, 40percent) and methyl 2-methyl-2H-indazole-5- carboxylate (227 mg, 8.4percent).
With N-Bromosuccinimide In tetrahydrofuran at 20℃;
A mixture of compound 1 (1.7 g, 0.01 mol) and NBS (2.1 g, 0.012 mol) in THF (10 ml) was stirred at r.t. overnight. The mixture was concentrated to yield a residue, to which was added DCM (5 ml). After stirring for 30 min, the solution was filtered to yield compound 2 (1.9 g, 80percent) as a light yellow solid.
With water; sodium hydroxide; In methanol; for 1h;Reflux;
To a stirred solution of methyl l_f/-indazole-5-carboxylate (6.5 g, 1.0 eq) in 200 mL MeOH was added a solution of NaOH (4.4 g, 3.0 eq) in 150 mL H20. The mixture was refluxed for 1 h. The organic solvent was removed in vacuo, the remaining aqueous solution was washed with EtOAc, acidified with 3 N HC1 to pH = 5~6, and the precipitate was collected by filtration, and washed with water, to give the desired product as a yellow solid (6.2 g, 98%).
93%
Step 3. 1H-Indazole-5-carboxylic acid A solution of methyl 1H-indazole-5-carboxylate (6.2 g, 35.19 mmol) and NaOH (5.6 g, 140.01 mmol) in methanol (100 mL) and water (10 mL) was stirred 14 hours at 60 C., the resulting mixture was concentrated in vacuo to provide a residue, which was dissolved in water (80 mL) and adjusted to pH 6 with HCl (3N). The solids were collected by filtration to afford 1H-indazole-5-carboxylic acid (5.3 g, 93%) as a yellow solid. LC/MS (ES, m/z): [M+H]+ 163.2 1H-NMR (300 MHz, DMSO) delta 13.33 (s, 1H), 12.73-12.88 (m, 1H), 8.46 (d, J=0.6 Hz, 1H), 8.25 (s, 1H), 7.90-7.94 (m, 1H), 7.59 (d, J=8.7 Hz, 1H)
93%
With water; sodium hydroxide; In methanol; at 60℃;
To a solution of 3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine (100 mg, 0.57 mmol) in diphenyl ether (3 ml) was added ethyl 3-(lH-l ,2,3-benzotriazol-5-yl)-3- oxopropanoate (300 mg, 1.29 mmol) and 4-methylbenzene-l -sulfonic acid (5 mg, 0.02 mmol). After stirring 1 h at 170C, the solids were collected by filtration, washed with ethyl acetate (2 x 10 ml), methanol (3 x 10 ml) and dried to give 5- (lH-benzo[if|[l,2,3]triazol-5-yl)-2-(pyridin-2-yl)-[l,2,4]triazolo[l,5-fl]pyrimidin- 7(4H)-one as a off-white solid (36.7 mg, 18%). LC/MS (ES, m/z): [M+H]+ 331.0 *H NMR (300 MHz, DMSO) delta 8.70 (s, 1H), 8.40 (s, 1H), 8.22 (d, / = 7.8 Hz, 1H), 7.73 - 7.97 (m, 3H), 7.443 - 7.47 (t, J = 6.9 Hz, 1H), 6.25 (s, 1H)
Example 243 : Synthesis of (1E,6E)-1-(4-hydroxyphenyl)-7-(1H-indazol-5-yl)hepta-1,6-diene-3,5-dione (CU349); (1) Synthesis of 1H-indazole-5-carboxaldehyde; To a solution of <strong>[473416-12-5]methyl 1H-indazole-5-carboxylate</strong> (300 mg, 1.69 mmol, prepared according to the procedure described in JP-11-228513) in 8.5 mL of dry toluene was added diisobutylaluminum hydride (1 mol/L in n-hexane, 3.4 mL) under nitrogen at -78C. After the reaction mixture was stirred at the same temperature for 3 h, saturated Na2SO4 aqueous solution was added carefully at 0C. After the solution was stirred at room temperature, a sufficient amount of Na2SO4 was added with additional stirring for drying. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol = 98/2 to 85/15) to obtain (1H-indazol-5-yl)methanol (125 mg, 50%).
38%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;
A solution of <strong>[473416-12-5]methyl 1H-indazole-5-carboxylate</strong> (825 mg, 4.68 mmol) in tetrahydrofuran (20 ml) was added to a solution of lithium aluminum hydride (580 mg, 14.1 mmol) in tetrahydrofuran (16 ml) at 0C and stirred at 0C for 1 hour. A mixture of tetrahydrofuran (10 ml) and water (10 ml) was added to the reaction solution and the resulting mixture was filtered. The filtrate was concentrated and the resulting residue was diluted with chloroform and washed with a 1N-aqueous sodium hydroxide solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 1H-indazole-5-ylmethanol (260 mg, 38%) was obtained.1H-NMR (DMSO-d6) delta; 4.55 (1H, d, J=5.5Hz), 5.14 (1H, t, J=5.5Hz), 7.30 (1H, dd, J=1.1, 8.4Hz), 7.47 (1H, d, J=8.4Hz), 7.46 (1H, s), 8.01 (1H, s), 12.97 (1H, brs).
Reference Example 8 (1H-indazol-5-yl)methanol To a tetrahydrofuran solution (1.00 L) of <strong>[473416-12-5]methyl indazole-5-carboxylate</strong> methyl ester (6.91 g) that was synthesised based on the method disclosed in the document of J. Med. Chem. vol. 43, p. 41 (2000), lithium aluminum hydride (2.98 g, manufactured by Wako Pure Chemical Industries, Ltd.) was added at 0 C. The resultant mixture was stirred for 2.5 hours at room temperature. After the stirring was ended, 2N sodium hydroxide aqueous solution (39.22 mL, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the mixture at 0 C., and the resultant blend was filtered by using Celite. The filtrate was dried, and the solvent was distilled away under a reduced pressure. Subsequently, chloroform was added to the residue and the resultant mixture was filtered. Drying was performed, so that 4.12 g of the titled compound was obtained.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of <strong>[473416-12-5]methyl 1H-indazole-5-carboxylate</strong> (12-S1, 1 equiv) in THF (10 vol) at 0 C was added LAH (2 equiv). The reaction mixture was stirred at room temperature for 2 hours and then cooled at 0 C. The resulting mixture was quenched 10% NaOH solution, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford compound 12-S2.
Step 3. Methyl 1H-indazole-5-carboxylate To a solution of methyl 4-amino-3-methylbenzoate (21 g, 133.18 mmol) in HCl (15 mL) and water (85 mL) was added NH4BF4 (20 g) and NaNO2 (10 g, 144.93). The mixture was stirred for 35 minutes, and the solids were collected by filtration and added in one portion to a stirred mixture of KOAc (16 g, 163.03 mmol) and 18-crown-6 (500 mg, 1.89 mmol) in CHCl3 (170 mL). After stirring for 2 hours at room temperature, the mixture was washed with water (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 30% ethyl acetate in petroleum ether to afford methyl 1H-indazole-5-carboxylate as a white solid (14.5 g, 62%). LC/MS (ES, m/z): [M+H]+ 177.0 1H-NMR (300 MHz, CDCl3) delta 8.58-8.59 (m, 1H), 8.23 (s, 1H), 8.09-8.13 (m, 1H), 7.54 (d, J=9.0 Hz, 1H), 3.98 (s, 3H)
55%
NaN02 (20 g, 0.29 mol) was added portion wise to a solution of methyl 4-amino-3- methylbenzoate (38 g, 0.23 mol) in aqueous HBF4 (48 wt, 200 mL) at 0C. The reaction was allowed to stir for 4 h at room temperature. The solids were collected by filtration and washed with 3x200 mL of ether. The solids were dried in an oven under reduced pressure. Under an inert atmosphere of nitrogen, was placed CH3COOK (45 g, 0.46mol), 18-crown-6 (3 g, 0.012mol), and chloroform (200 mL). This was followed by the portion wise addition of the dried solid at 0C. The reaction was stirred for 3 h at room temperature. Then 1 L of H20 was added and the resulting solution was extracted with 5x100 mL of DCM. The organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo to afford a residue which was purified by silica gel column chromatography with 1% methanol in CH2Cl2 to afford of methyl lH-indazole-5-carboxylate as a yellow solid (22 g, 55%). LCMS (ES, m/z): [M+H]+ 177.1 *H NMR (300 MHz, DMSO) delta 13.41 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.94 - 7.90 (dd, / = 1.50, 8.70 Hz, 1H), 7.64 (d, / = 8.70 Hz, 1H), 3.90 (s, 3H)
30%
With acetic acid; sodium nitrite; In water; at 20℃; for 5h;
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5% aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30%).1H-NMR (DMSO-d6) delta; 3.86 (3H, s), 7.61 (1H, d, J=8.8Hz), 7.91 (1H, d, J=8.8Hz), 8.25 (1H, s), 8.48 (1H, brs), 13.41 (1H, brs).
With acetic acid; isopentyl nitrite; at 20 - 80℃; for 6h;
Isoamyl nitrite (26.8 g, 22.8 mmol) was added to a mixture of methyl 4-amino-3-methylbenzoate (3.4 g, 20.8 mmol) in acetic acid (AcOH, (20 mL). The reaction mixture was stirred at room temperature for lh then at 80 C for 5 h. It was concentrated and the residue was purified by silica gel column chromatography (Hexanes/EtOAc 10: 1 to 2: 1) to give pure methyl lH-indazole-5-carboxylate.
With diazomethane; In tetrahydrofuran; diethyl ether; at 0℃; for 1h;
Under ice-cooling, to a solution of 910 mg of <strong>[61700-61-6]1H-5-indazolecarboxylic acid</strong> in 60 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 50 ml of ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 923 mg of the title compound as pale yellow crystals.1H-NMR (400 MHz, DMSO-D6) d 3.87 (3H, s), 7.62 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 8.8 Hz), 8.26 (1H, s), 8.49 (1H, s), 13.42 (1H, s).
NaOH (3.72 g, 93.0 mmol) was added to a solution of methyl 1 H-indazole-5-carboxylate (4.1 g, 23.3 mmol) in dry DMF (60 mL) and the solution was stirred for 5 min. A solution of iodide (13.0 g, 51 .2 mmol) in dry DMF (20 mL) was added and the mixture was stirred at RT for 1 h. Water, 10% aqueous Na2S203 solution and EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water (3x), dried over Na2S04 and evaporated affording the target compound as white solid. Yield: 6.32 g (90%). MS: m/z: [M+H]+ = 303 (MW calc. 302.02)
81%
With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: To a cooled (0C) DMF solution indazole (1.0equiv) and K2CO3 or KOH (?3equiv) was added I2 (2-4equiv) in one portion. The reaction was stirred with cooling or rt for several h and then was treated with xs 10% aq NaHSO3 and subsequently diluted with H2O. In the majority of examples a filtration and washing (H2O) of the precipitate provided the desired material with the required purity.
65%
With potassium tert-butylate; iodine; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a solution of methyl lH-indazole-5-carboxylate (132a) (5 g, 28.4 mmol) in THF (40 mL) was added I2 (10.81 g, 42.6 mmol) and KOtBu (7.96 g, 71.0 mmol) at 0 C, the resulting mixture was stirred for 3h at room temperature. The reaction mixture was diluted with 10% aqueous sodium thiosulfate and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water, brine, dried and concentrated in vacuum. The obtained solid was washed with MeOH (20 mL) to give methyl 3-iodo-lH-indazole-5-carboxylate (132b) (5.6 g, 18.54 mmol, 65% yield) as a yellow solid; 1H MR (300 MHz, DMSO-^e) delta 13.87 (s, 1H), 8.08 - 8.03 (m, 1H), 7.97 (dd, J= 8.8, 1.6 Hz, 1H), 7.65 (dd, J= 8.8, 0.7 Hz, 1H), 3.88 (s, 3H); MS (ES+): 303.2 (M+l); MS (ES-): 301.2 (M-l).
With potassium hydroxide; iodine; In N,N-dimethyl-formamide; at 23℃; for 4h;
A mixture of methyl lH-indazole-5-carboxylate (12-2, 7.02 g, 39.7 mmol, 1 equiv), iodine (22.2 g, 87.4 mmol, 2.20 equiv) and potassium hydroxide (5.35 g, 95.4 mmol, 2.40 equiv) in DMF (75 mL) was stirred at 23 C for 4 h. The reaction mixture was partitioned between a 1: 1 aqueous mixture of saturated sodium chloride solution and saturated sodium thiosulfate solution and ethyl acetate (2 x 300 mL). The combined organic layers were washed with water then brine, dried over sodium sulfate and concentrated to give methyl 3-iodo-lEta-indazole-5-carboxylate (12-3) as a light red solid. LRMS m/z (M+H + CH3CN) 303.1 found, 303.0 required.
13 g
With potassium tert-butylate; iodine; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of methyl lH-indazole-5-carboxylate (105) (10 g, 1 eq.) in THF (100 mL) was added iodine (21.6 g, 1.5 eq.) and potassium tert-butoxide (16 g, 2.5 eq.) at 0 C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with 10% sodium thiosulfate in water and extracted twice with EtOAc. The combined organic extracts were washed with brine and evaporated to dryness. The resultant solid was slurried with MTBE, filtered and dried to afford 106 (13 g).
4-(methoxycarbonyl)-2-methylbenzenediazonium tetrafluoroborate[ No CAS ]
[ 473416-12-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
With 18-crown-6 ether; potassium acetate; In chloroform; at 20℃; for 24h;
A suspension of BF4 salt (12 g, 1.0 eq), potassium acetated (KOAc, 16.6 g, 2.5 eq) and 18-crown-6 (1.8 g, 0.1 eq) in CHCI3 (200 mL) was stirred at rt for 24 h, and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried with Na2S04 and concentrated to give the desired product (6.5 g, 55%).
With potassium acetate;18-crown-6 ether; In chloroform; at 23℃; for 5h;
A solution of sodium nitrite (4.60 g, 66.6 mmol, 1.10 equiv) in water (50 mL) was added slowly to a pre-cooled (-10 C) mixture of methyl 4-amino-3-methylbenzoate (12-1, 10.0 g, 60.5 mmol, 1 equiv) and concentrated aqueous hydrochloric acid solution (12 M, 15.1 mL, 182 mmol, 3.00 equiv) in water (75 mL) at a rate that kept the reaction mixture temperature below 0 C. Following the addition, the reaction mixture was stirred at -5 C for 30 min, then filtered. A solution of sodium tetrafluoroborate (20.0 g, 182 mmol, 3.00 equiv) in water (100 mL) was immediately added to the cold filtrate. The precipitate was filtered and washed with ice-cold water (70 mL). The remaining solid was air-dried to give 4-(methoxycarbonyl)-2-methylbenzenediazonium tetrafluoroborate as a white solid. A suspension of this product (16.0 g, 60.6 mmol, 1 equiv), potassium acetate (14.9 g, 152 mmol, 2.50 equiv) and 18- crown-6 (1.60 g, 6.06 mmol, 0.100 equiv) in chloroform (300 mL) was stirred at 23 C for 5 h. The reaction mixture was filtered and concentrated. The residue was partitioned between water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give methyl lH-indazole-5-carboxylate (12-2) as a light orange solid. LRMS m/z (M+Eta) 177.1 found, 177.1 required
4-[5-(1H-indazol-5-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 4-(N-hydroxycarbamimidoylmethoxy)piperidine-l-carboxylic acid tert- butyl ester (Preparation 3, 0.36mmol) in DMSO was added f-BuOK (0.44mmol). After sonication and heating a workable solution was obtained, and the mixture added to lH-indazole- 5-carboxylic acid methyl ester (0.4mmol). The reaction mixture was shaken at 6O0C for 15h. Once the reaction was complete it was neutralised with acetic acid (5 drops) and submitted for HPLC purification. The title compound was obtained as a colourless solid: MH+ 400.04, retention time 6.18min (Method 1).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
Potassium carbonate (60 g, 0.0.44 mol) was added to a solution of methyl 1H- indazole-5-carboxylate (22 g, 0.13 mol) in N,N-dimethylformamide (200 mL) followed by the dropwise addition of CH3I (62 g, 0.44 mol). Then the reaction was stirred for 5 h at room temperature. The reaction was then quenched by the addition of 200 mL of water, extracted with 4x200 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. Purification by silica gel column chromatography with 2% ethyl acetate in petroleum ether afforded methyl 1 -methyl- lH-indazole-5- carboxylate as an orange solid (13 g, 55%). LCMS (ES, m/z): [M+H]+ 191.0 *H NMR (300 MHz, DMSO) delta 8.48 (s, 1H), 8.24 (s, 1H), 7.97 - 7.94 (dd, / = 1.50, 8.70Hz, 1H), 7.77 - 7.72 (m, 1H), 4.09 (s, 3H), 3.88 (s, 3H)
38%
Acid Preparation 11; 1 -Methyl-1 H-indazole-5-carboxvlic acid; To a stirred suspension of 60% NaH oil dispersion (87 mg, 2.2 mmol) in DMF (4 mL) was added methyl 1 H-indazole-5-carboxylate (264 mg, 1.50 mmol). The mixture was stirred at room temperature for 1 hour before the dropwise addition of iodomethane (0.11 mL, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and the residue was purified by Biotage chromatography (4OS column, 15% acetone/heptane) to afford methyl 1 -methyl-1 H-indazole-5-carboxylate (107 mg, 38%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃;
Acid Preparation 13; 2-Methyl-2H-indazole-5-carboxylic acid; To a solution of methyl 1 H-indazole-5-carboxylate (2.5 g, 14 mmol) in DMF (45 ml_) was added K2CO3 (4.90 g, 35.5 mmol) followed by iodomethane (1.77 ml_, 28.4 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 50 aC overnight. The mixture was concentrated, dissolved in EtOAc and washed with saturated aqueous NaCI. The organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 25-45% EtOAc/heptane) to provide methyl 1- methyl-1 H-indazole-5-carboxylate (1.07 g, 40%) and methyl 2-methyl-2H-indazole-5- carboxylate (227 mg, 8.4%).
Methyl 1 H-indazole-5-carboxylate (1.5 g, 8.51 mmol) was added to a suspension of sodium hydride (442 mg, 1 1 .0 mmol, 1 .3 eq) in DMF (25 ml) cooled with an ice bath and the mixture was stirred under cooling for 1 h. Chloromethyl methyl ether (0.71 ml, 9.36 mmol, 1 .1 eq) was added and the mixture was stirred for 14 h upon warming to RT. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. The residue was purified by flash chromatography [hexane with 7% EtOAc]. Yield: 1.2 g (64%).
With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 3h;Cooling;
To a solution of 735 mg (4.17 mmol) of 5-carbomethoxyindazole dissolved in 20 ml of tetrahydrofuran are respectively added 824 muL (6.26 mmol) of triethylamine, 102 mg (0.834 mmol) of 4-dimethylamino-pyridine. The solution is cooled over an ice bath before adding 1.09 g (5 mmol) of di-tert-butyl dicarbonate. The reaction mixture is stirred at room temperature for 3h, then diluted with a saturated sodium chloride aqueous solution. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, and evaporated. The residue is triturated in a minimum amount of methanol and the solid is filtered to yield 650 mg (57%) of l-tert-butyl-5-methyl-lH-indazole-l,5-dicarboxylate in the form of a brown solid.1H-NMR: deltaEta pm 400 MHz, DMSO: 8.56-8.52 (2H, m, CH^), 8.18-8.15 (2H, m, CT ), 3.90 (3H, s, CH3), 1.65 (9H, s, 3 x CH3).
Step-1: Methyl 1-cyclopropyl-1H-indazole-5-carboxylateA mixture of <strong>[473416-12-5]methyl 1H-indazole-5-carboxylate</strong> (970 mg, 5.5 mmol), cyclopropylboronic acid (946 mg, 11 mmol), cupper (II) acetate, [2,2']bipyridyl (860 mg, 5.5 mmol) in 1,2-dichloroethane (50 mL) was heated at 70 oC for 2 hrs. The mixture was added saturated aqueous NH4Cl (70 mL) followed by the addition of DCM (30 mL) and water (30 mL), extracted with DCM (30 mL x 2), dried over Na2SO4, filtered through a pad of Celite (registered trademark) the filtrate was concentrated to give a pale brown solid, which was purified by column chromatography on silica gel (hexane/EtOAc = 8/1) to give 840 mg (71% yield) of the titled compound as a off-white solid.
Step 4. Methyl 1-(methoxymethyl)-1H-indazole-5-carboxylate To a solution of <strong>[473416-12-5]methyl 1H-indazole-5-carboxylate</strong> (14 g, 79.5 mmol) in DMF (100 mL) was added sodium hydride (1.75 g, 72.92 mmol), and 15 minutes later, MOM-Br (3.5 mL) was added. After stirring for 2 hours at room temperature, the reaction was quenched water (100 mL), extracted with dichloromethane (3*150 mL), dried over 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 methyl 1-(methoxymethyl)-1H-indazole-5-carboxylate as a white solid (6 g, 34%). LC/MS (ES, m/z): [M+H]+ 221.0 1H-NMR (300 MHz, CD3Cl) delta 8.52-8.55 (m, 1H), 8.06-8.15 (m, 2H), 7.58 (d, J=8.7 Hz, 1H), 5.74 (s, 2H), 3.97 (s, 3H), 3.34 (s, 3H)
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of Methanesulfonic acid 3-isobutoxy-6-methyl-pyridin-2-ylmethyl ester (1.54 mmole) and lH-Indazole-5-carboxylic acid methyl ester (0.247g, 1.4 mmole) in DMF (8ml) was added cesium carbonate (0.548g, 1.68 mmole) and the mixture stirred at ambient temperature for 18h. The mixture was evaporated to dryness and the residue partitioned between water (20ml) and ethyl acetate (2 x 20ml). The combined organics were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed using silica gel eluting with a 1 :2 mixture of ethyl acetate/ isohexane to give in the early fractions the title compound (0.240g, 48%) as a white solid. The corresponding 2-yl-indazole isomer eluted in the later column fractions. 1H-NMR(CDC13, 300 MHz) delta 8.49 (s, 1H, ArH), 8.09 (s, 1H, ArH), 8.01 (dd, 1H, ArH), 7.56 (d, 1H, ArH), 7.03 (s, 2H, ArH), 5.73 (s, 2H, CH2), 3.94 (s, 3H, CH3), 3.62 (d, 2H, CH2), 2.49 (s, 3H, CH3), 1.94 (m, 1H, CH), 0.89 (d, 6H, 2xCH3). LC-MS: m/z 354 M + H+.
A mixture of commercially available <strong>[61700-61-6]1H-<strong>[61700-61-6]indazole-5-carboxylic acid</strong></strong> (1, 3.0 g, 18.5 mmol; Aldrich) and sulfuric acid (10 mol-%) in methanol (30 mL) was heated for 3 h at 65-70 C. After complete conversion, the reaction was cooled to room temperature, hydrolyzed dropwise with a saturated sodium carbonate solution (10 mL), and extracted three times with ethyl acetate (30 mL). The combined organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to afford methyl 1H-indazole-5-carboxylate (3.19 g, 98%) as a white crystalline solid (not shown in the Scheme above); mp 196.2-197.8 C. 1H NMR (500 MHz, DMSO-d6) delta = 3.87 (s, OCH3, 3H), 7.61 (d, J = 8.83 Hz, 1H), 7.91 (dd, J = 1.58/8.83 Hz, 1H), 8.24 (s, 1H), 8.49 (s, 1H), 13.38 (s, NH, 1H). 13C (125 MHz, DMSO-d6) delta = 52.1 (OCH3), 110.4, 122.1, 122.7, 124.0, 126.4, 135.5, 141.8, 166.7 (CO2Me); LC/ESI-MS (m/z): negative mode 175.16 [M-H]-, positive mode 177.27 [M+H]+.
88%
With sulfuric acid; at 70℃;
To a suspension of <strong>[61700-61-6]1H-<strong>[61700-61-6]indazole-5-carboxylic acid</strong></strong> (470 mg, 2.9 mmol) in MeOH (5 mL) H2SO4 (0.2 mL) was added. The mixture was heated to 70 C and stirred at this temperature overnight. The mixture was left to reach room temperature, H2O (10 mL), NaHCO3 saturated aqueous solution (5 mL) and ethyl acetate (30 mL) were added. The phases were separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and evaporated to dryness to give methyl 1H-indazole-5-carboxylate (466 mg, 2.65 mmol, 88 % yield) as a pale pink-yellow solid. MS found for C9H8N2O2 as (M+H)+ 176.9.
32%
With sulfuric acid; at 100℃; for 0.0833333h;Microwave irradiation;
A solution of lH-<strong>[61700-61-6]indazole-5-carboxylic acid</strong> 0.25g (1.54 mmol) in methanol (2.5 mL) and cone. H2SO4 (0.1ml) was heated at 100 C in an Emrys microwave reactor for 5 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with saturated NaHC03 and brine (30 mL), dried (MgSC^) and the volatiles were removed in vacuo to yield of lH-<strong>[61700-61-6]indazole-5-carboxylic acid</strong> methyl ester 0.086g (32%) 4 as a pale yellow solid. 1H-NMR(CDC13, delta 8.58 (dd, IH, ArH), 8.21 (d, IH, ArH), 8.11 (dd, IH, ArH), 7.54 (d, 2H, ArH), 3.98 (s, 3H, CH3). LC-MS: m/z 177 M + H+.
A solution of lH-Indazole-5-carboxylic acid methyl ester (0.154g, 0.88 mmole) in DMF (5ml) was treated with sodium hydride (60% dispersion in oil) (0.042g, 1 mmole) then stirred at ambient temperature under a nitrogen atmosphere for lh. A solution of methanesulfonic acid 2-isobutoxy-5-trifluoromethoxy-benzyl ester (0.3g, 0.88 mmole) in DMF (5ml) was then added and the mixture stirred at ambient temperature for 18h. The mixture was evaporated to dryness and the residue partitioned between water (20ml) and dichloromethane (2 x 20ml). The combined organics were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed using silica gel eluting with a gradient of 5 - 20% ethyl acetate/ isohexane to give in the early fractions the title compound (0.217g, 59%>) as a white solid. The corresponding 2-yl-indazole isomer eluted in the later column fractions. H-NMR(CDC13, 300 MHz) 58.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.01 (dd, 1H, ArH), 7.41 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.88 (d, 1H, ArH), 6.71 (s, 1H, ArH), 5.61 (s, 2H, CH2), 3.99 (s, 3H, CH3), 3.78 (d, 2H, CH2), 2.05 - 2.19 (m, 1H, CH), 1.04 (d, 6H, 2xCH3).
With N-Bromosuccinimide; In tetrahydrofuran; at 20℃;
A mixture of compound 1 (1.7 g, 0.01 mol) and NBS (2.1 g, 0.012 mol) in THF (10 ml) was stirred at r.t. overnight. The mixture was concentrated to yield a residue, to which was added DCM (5 ml). After stirring for 30 min, the solution was filtered to yield compound 2 (1.9 g, 80%) as a light yellow solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
To a solution of methyl lH-indazole-5-carboxylate (15 g, 56.8 mmol) in DMF (300 mL) was added potassium carbonate (15.6 g, 1 13.6 mmol) and isopropyl iodide (19.3 g, 113.6 mmol), and the resulting mixture was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 0 (200 mL), and extracted with ethyl acetate (3 x 100 mL). The organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to afford the residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford methyl 1 -isopropyl- lH-indazole-5-carboxylate as a orange solid (8 g, 47%). (ES, m/z): [M+H]+ 219.0 *H NMR (300 MHz, DMSO) 58.48 (s, 1H), 8.27 (s, 1H), 7.96 - 7.92 (dd, /= 1.50, 9.00Hz, 1H), 7.81 (d, / = 9.00Hz, 1H), 5.09 - 5.00 (m, 1H), 3.88 (s, 3H), 1.50 (d, J = 6.60 Hz, 6H)
With potassium hydroxide; In dimethyl sulfoxide; at 25℃;
A mixture of 1 (591 mg, 3.366 mmol), 4-(2-chloroethyl)morpholine (1.0 mg, 6.72 mmol), KOH (376 mg, 6.72 mmol) in DMSO (10 ml) was stirred at 25 C. overnight. The mixture was extracted with EA. The combined organic layers were washed with water and brine, dried, and concentrated to give a residue, which was purified by column (PE/EA=1/1) to give compound 2 (600 mg, 78%) as a white solid
With potassium hydroxide; In dimethyl sulfoxide; at 25℃;
A mixture of compound 1 (591 mg, 3.366 mmol), 4-(2-chloroethyl)morpholine (1.0 mg, 6.72 mmol), KOH (376 mg, 6.72 mmol) in DMSO (10 ml) was stirred at 25 C. overnight. The mixture was extracted with EA. The resulting combined organic layers were washed with water and brine, dried, and concentrated to a residue, which was purified by column chromatography (PE/EA=1/1) to give compound 2 (246 mg, 19%) as a white solid
2-isopropyl-2H-indazole-5-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%; 26%
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃; for 8h;
1H-indole-5-carboxylic acid methyl ester (1 g, 5.71 mmol) was dissolved in dimethylformamide (20 mL), and isopropyl iodide (1.14 mL, 11.42 mmol) and sodium hydride (205 mg, 8.56 mmol) were slowly added dropwise thereto at 0. The mixture was stirred at 50 for 8 hours, added with 1N hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.1 g, 89%).According to the method described in Preparation Example 1-1, <strong>[473416-12-5]1H-<strong>[473416-12-5]indazole-5-carboxylic acid methyl ester</strong></strong> (1.0 g, 5.68 mmol) obtained from Preparation Example 80-1 and isopropyl iodide (1.7 mL, 17.03 mmol) were used to obtain 1-isopropyl-<strong>[473416-12-5]1H-<strong>[473416-12-5]indazole-5-carboxylic acid methyl ester</strong></strong> (680 mg, 55%) which passed firstly through column chromatography and 2-isopropyl-2H-<strong>[473416-12-5]indazole-5-carboxylic acid methyl ester</strong> (320 mg, 26%) which passed secondly through column chromatography.[1232] NMR: 1H-NMR (400HMz, CDCl3); delta 8.51 (s, 1H), 8.11 (s, 1H), 8.02 (dd, J = 1.6 Hz, 1H), 7.45 (d, 1H), 4.90-4.84 (m, 1H), 3.95 (s, 3H), 1.61 (d, 6H)[1233] NMR: 1H-NMR (400HMz, CDCl3); delta 8.50 (s, 1H), 8.10 (s, 1H), 7.90 (d, 1H), 7.71 (d, 1H), 4.85-4.79 (m, 1H), 3.94 (s, 3H), 1.68 (d, 6H)
With sodium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 0.166667h;
The obtained acetyl indazole (1.2 g, 5.50 mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (1/1, 20 mL) and then 6N sodium hydroxide aqueous solution (1.8 mL) was added dropwise thereto. The mixture was stirred for 10 minutes at room temperature and acidified with 6N hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane. The extract was dried with anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound (1.0 g, 47%). [1228] NMR: 1H-NMR (400HMz, CDCl3); delta 9.72 (br, s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.14 (dd, J = 1.2 Hz, 1H), 7.60 (d, 1H), 3.97 (s, 3H)
methyl 1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylate[ No CAS ]
methyl 2-((5-fluoropyridin-3-yl)methyl)-2H-indazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 65℃; for 3h;
To a solution of methyl lH-indazole-5-carboxylate (694mg, 3.94 mmol) in DMF (20 mL) was added 3-(chloromethyl)-5-fluoropyridine (3.94mmol, 1.2eq, prepared from the alcohol with SOCI2) and CS2CO3 (3.85g) at room temperature. After stirring 3h at 65C, the reaction mixture was quenched with aqueous ammonium chloride. The mixture (combined with a small scale reaction) was diluted with H20, extracted with dichloromethane, washed with sat. NaHC03 and brine. It was then dried over Na2S04> filtered, and concentrated. The residue was purified by column chromatography (Hexanes:EtOAc 7: 1 to 0: 1) to give regioisomeric products methyl l-((5-fluoropyridin-3-yl)methyl)-lH-indazole-5-carboxylate (422mg) and methyl 2-((5-fluoropyridin-3-yl)methyl)-2H-indazole-5-carboxylate (230mg), the former being carried forward in this synthetic protocol, the latter being used to form regioisomer N- (2-aminophenyl)-2-((5-fluoropyridin-3-yl)methyl)-2H-indazole-5-carboxamide A14.
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