| 92% |
With sulfuric acid; for 16h;Reflux; |
A solution of 15 g (0.0926 mol, 1 eq) 2H-indazole-3-carboxylic acid (1) and 0.5 ml (9.387 mmol, 0.1 eq) concentrated sulfuric acid in 300 mL of methanol were heated at reflux for 16 hours. The reaction mixture was concentrated in vacuo and then partitioned between ethyl acetate (300 mL) and water (300 mL), washed with aq. saturated sodium bicarbonate solution (100 mL x 2), the aqueous phase extracted with ethyl acetate (150 mL x 3), the combined organic layers were washed with brine (200 mL), dried (magnesium sulfate) and concentrated to give 15 g of 2 (92 % yield). |
| 90.1% |
|
Methyl lH-indazole-3-carboxylate (I): lH-indazole-3-carboxylic acid (2.4 g, 14.8 mmol) was dissolved in 100 mL methanol with 0.20 mL H2SO4 and heated to 80 C for 16 hours. Methanol was removed on rotary evaporator and the resulting residue was dissolved in 100 mL EtOAc. The organic solution was washed with water, saturatedNaHCC"3 and brine, dried over Na2S04 and concentrated to yield product (2.37g, 13.5 mmol, 90.1%). Product was identified by GC/MS. |
| 85% |
|
For the synthesis of RC-MC-30, methyl indazole-3-carboxylate was first formed.Acetyl chloride (7mL, excess) was added dropwise to ice-cooled methanol (2OmL) and the solution was stirred at the same temperature for 10 minutes. Commercially available indazole-3-carboxylic acid (2.3g, 14mmol) was then added to the solution in one lot and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed under vacuum, then the residual solid was dissolved in CHCl3 (10OmL), and washed with std. NaHCO3 solution. The aqueous layer was extracted with CHCl3 and the combined organic extract was washed with brine and dried over anhydrous Na2SO4. Removal of solvent left the product as a light yellow solid. Yield = 2.05g (85%); m.p. = 168-170 0C; IH NMR (400MHz, CDCl3) D 8.25 (d, J = 8.8 Hz, IH), 7.89 (d, J = 8.8 Hz, IH), 7.50 (t, J = 7.8 Hz, IH), 7.37 (t, J = 7.8 Hz, IH), 4.10 (s, 3H). |
| 78% |
|
To a solution of indazole 3-carboxylic acid (0.3 g, 1.86 mmol) in MeOH (10 mL) was added sulfuric acid (0.2 mL) and the mixture was stirred under reflux for 4 h. The mixture was then concentrated under reduced pressure and the residue was taken up in EtOAc (20 mL), washed with aq. NaHCO3 (2×20 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by crystallization (n-hexane/EtOAc) as white crystals; yield 0.25 g 78%; m.p. 168-170 C.; 1H NMR (400 MHz, CDCl3, TMS, ppm) delta 4.07 (s, 3H), 7.35 (t, 1H, J=15.35 Hz), 7.48 (t, 1H, J=14.45 Hz), 7.59 (d, 1H, J=8.23 Hz), 8.23 (d, 1H J=8.36 Hz), 11.72 (s, 1H). |
| 48% |
With sulfuric acid; for 10h;Heating / reflux; |
Step [0120] A 500 mL round-bottomed flask was charged sequentially with A (20 g, 0.12 mole), methanol (350 mL), and H2S04 (50 mL). The mixture was heated at reflux with stirring by magnetic stirrer for 10 hrs. The reaction was monitored by TLC on silica gel plates. [0121] Upon complete consumption of A, the mixture was poured into ice water (1 L) and methyl ester precipitated out as light yellow solid. White crystals of the product B (10 g, 0.057 mole, 48% yield) were obtained by recrystallization from ethyl acetate. |
|
sulfuric acid;Heating / reflux; |
Following the procedure of Harada et al., Chemical & Pharmaceutical Bulletin 1995, 43, 1912-30, first, indazole-1H-3-carboxylic acid was converted to the methyl ester (>95% purity) by refluxing the acid in methanol containing several drops of concentrated sulfuric acid. (m/z): [M+H]+ 177.0; 1H-NMR spectroscopy (CD3OD; ? (ppm) 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 3.9 (3H, s)). This ester was treated with isopropyliodide and potassium tert-butoxide in refluxing THF, which afforded 1-isopropyl-1H-indazole-3-carboxylic acid methyl ester. TLC (Rf=0.45 in 3/1 hexane/EtOAc). 1H-NMR (CD3OD): ? (ppm) 8.1-8.0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 3.9 (s, 3H), 1.5 (6H, d). The N?-isopropyl methyl ester was hydrolyzed in 1M NaOH/THF at ambient temperature to provide the title intermediate. (m/z): [M+Na]+ 226.6. 1H-NMR (CD3OD): ? (ppm) 8.1-8.0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 1.5 (6H, d). |
|
With sulfuric acid; at 80℃; for 24h; |
Preparation 2: 1-isopropyl-1H-indazole-3-carboxylic Acid To indazole-3-carboxylic acid (40 g, 247 mmol) suspended in methanol (700 mL) was added concentrated H2SO4 (10 mL) slowly while stirring the mixture. The mixture was stirred and refluxed at 80 C. for 24 h. The mixture was cooled, filtered, and concentrated under reduced pressure to afford a pale yellow solid. The solid was suspended in water (700 mL), crushed to fine powder, collected by filtration, and rinsed with water (?400 mL). The product was suspended in toluene, and evaporated to dryness under reduced pressure, affording indazole-3-carboxylic acid methyl ester as a pale yellow solid (45 g, >95% pure). (m/z): [M+H]+ calcd for C9H8N2O2 177.07; found, 177.0. 1H-NMR (CD3OD, 300 MHz): delta (ppm) 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 3.9 (3H, s). |
|
With thionyl chloride; at 20℃; for 24h; |
To the methanol solution of 1H-indazole-3-carboxylic acid (31b) (162 mg, 1 mmol) was added SOCl2 (0.5 mL) and the mixture was stirred at the room temperature for 24 h. After evaporation of the volatiles, the mixture was partitioned between aqueous NaHCO3 solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layer was dried over sodium sulfate. The volatiles were removed, and the residue was filtered over silica gel to provide 123 mg of 1H-Indazole-3-carboxylic acid methyl ester (32b). |
|
With sulfuric acid; for 20h;Heating / reflux; |
0.5 ml of concentrated sulphuric acid (95%) is added dropwise, at a temperature of about 20 C., to a solution of 9.13 g of 3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for 20 hours, the reaction medium is concentrated under reduced pressure at a temperature of about 40 C. The aqueous residue obtained is extracted with dichloromethane. The organic phases are combined, washed with water until neutral, dried over magnesium sulphate and then concentrated under reduced pressure at a temperature of about 40 C. The yellow powder obtained is washed with ethyl ether. A white powder is obtained. The filtrate is concentrated under reduced pressure until a yellow powder is obtained. This yellow powder is washed again with ethyl ether until a white powder is obtained. The yellow filtrate is concentrated a third time under reduced pressure and the yellow powder collected is itself also washed with ethyl ether. All the fractions of white powder are combined. 7.08 g of methyl 3-indazolecarboxylate are thus obtained in the form of a white powder. |
|
With sulfuric acid; In water; at 80℃; for 24h; |
d. Preparation of l-isopropyl-lH-indazole-3-carboxylic acid; To indazole-3-carboxylic acid (40 g, 247 mmol) suspended in methanol (700 mL) was added concentrated H2SO4 (10 mL) slowly while stirring the mixture. The mixture was stirred and refluxed at 80 C for 24 h. The mixture was cooled, filtered, and concentrated under reduced pressure to afford a pale yellow solid. The solid was suspended in water (700 mL), crushed to fine powder, collected by filtration, and rinsed with water (-400 mL). The product was suspended in toluene, and evaporated to dryness under reduced pressure, affording indazole-3-carboxylic acid methyl ester as a pale yellow solid (45 g, >95% pure). (m/z) : [M+H] + calcd for C9H8N202 177.07 ; found, 177. 0.'H-NMR (CD30D, 300 MHz): b (ppm) 8. 0 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 3.9 (3H, s). To a solution of indazole-3-carboxylic acid methyl ester (40.7 g, 231 mmol) in anhydrous tetrahydrofuran (700 mL) cooled in an ice bath was added slowly solid potassium tert-butoxide (28. 3 g, 252 mmol). The mixture was stirred at the same temperature for 1 hr prior to the addition of 2-iododopropane (34.4 mL, 367 mmol). The final mixture was stirred for 12 h at ambient temperature, and refluxed for 12 h. After cooling to room temperature, the mixture was filtered, and the collected solid was rinsed with tetrahydrofuran (100 mL). The filtrates were combined, and concentrated to dryness under reduced pressure, affording crude l-isopropyl-lH-indazole-3-carboxylic acid methyl ester (49.7 g) as a pale yellow oil. The crude material was purified by flash silica gel chromatography eluting with hexane/ethyl acetate (9/1 to 3/1) to yield 1-isopropyl-lH-indazole-3-carboxylic acid methyl ester (43 g, 197 mmol, >99% pure). IH-NMR (CD30D, 300 MHz) : 8 (ppm) 8.1-8. 0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 3.9 (s, 3H), 1.5 (6H, d). To a solution of the methyl ester dissolved in tetrahydrofuran (400 mL) was added 1M NaOH (400 mL). The mixture was stirred for 24 h at ambient temperature. The reaction was terminated by washing with ethyl acetate (2 x 400 mL), saving the aqueous layer. The aqueous layer was acidified slowly by adding conc. HC1 (-40 mL) in an ice bath, which led to separation of a pale yellow oily product. The product was extracted with ethyl acetate (1000 mL), and the organic layer was dried over MgS04 and evaporated under reduced pressure to yield the title intermediate as a pale yellow to white solid (34 g, >98% pure), which was further purified by crystallization from ethyl acetate to provide the title intermediate as colorless needles. (m/z) : [M+Na] + calcd for C11H12N202 226.07 ; found, 226. 6. lH-NMR (CD30D, 300 MHz):) : 8 (ppm) 8.1-8. 0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 1.5 (6H, d). |
|
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; |
Example 207; To the methanol solution of 1 H-indazole-3-carboxylic acid (162 mg, 1 mmol) was added 4N HCI in dioxane (2 mL) and the mixture was stirred at the room temperature for 24 h. After evaporation of the volatiles, the mixture was partitioned between aqueous NaHC03 solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2 X 15 mL), and the combined organic layer was dried over sodium sulfate. The volatiles were removed, and the residue was filtered over silica gel to provide 1 H-Indazole-3-carboxylic acid methyl ester (123 mg). LCMS m/z: 177 (M+1)+. |
| 22.76 g |
With sulfuric acid; at 60℃; |
[0017] Sulfuric acid (18 ml) was added to a solution of indazole-3-carboxylic acid (19.3 g, 0.119mol) in methanol andthe solution was stirred at 60C overnight. The solvent was removed in vacuo and the residue dissolved in ethyl acetate(500ml) and washed with water (200ml). The aqueous layer was extracted with ethyl acetate (2 x100 ml) and the combinedorganic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give (22.76g) of Methyl 1H-indazole-3-carboxylate as a cream coloured solid |
|
With sulfuric acid; for 4h;Reflux; |
To a solution of indazole-3-carboxylic acid (1.155 g, 7.12 mmol) in MeOH (14.24 mL) was added sulfuric acid (0.038 mL, 0.712 mmol), and the mixture was heated to reflux. After 4 h, LCMS indicated complete conversion to the methyl ester. As such, the mixture was concentrated in vacuo, dissolved in DCM and washed with NaHCO3. It was then dried over Na2SO4and concentrated in vacuo to yield the initial methyl 1H-indazole-3-carboxylate. The material was then dissolved in MeOH (11.53 mL) and hydrazine monohydrate (1.019 mL, 13.62 mmol) was added. The mixture was heated at 80oC for 6 h after which a white solid precipitated formed. The precipate was filtered and washed with heptanes:EtOAc (1:1) (50 mL) and dried under vacuum to yield 1H-indazole-3-carbohydrazide (0.85g, 4.82 mmol, 67% yield). The initial material was carried forward directly without further purification.. |
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