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CAS No. : | 170487-40-8 | MDL No. : | MFCD07371612 |
Formula : | C9H8N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TUSICEWIXLMXEY-UHFFFAOYSA-N |
M.W : | 176.17 | Pubchem ID : | 286535 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.37 |
TPSA : | 54.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.9 cm/s |
Log Po/w (iLOGP) : | 1.14 |
Log Po/w (XLOGP3) : | 2.08 |
Log Po/w (WLOGP) : | 1.35 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 1.84 |
Consensus Log Po/w : | 1.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.62 |
Solubility : | 0.42 mg/ml ; 0.00238 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.86 |
Solubility : | 0.241 mg/ml ; 0.00137 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.98 |
Solubility : | 0.183 mg/ml ; 0.00104 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 16 h; | To a stirred solution of compound methyl lH-indazole-6-carboxylate (1.0 g, 5.676 mmol, leq) in tetrahydrofuran/rnethanol/H20 (1:1:1; lOmL) was added LIOH (476 mg, 11.353 mmol, 2 eq) at room temperature then stirred for 16h. The solvents were evaporated, residue diluted with water (lOmL) andacidified with 2N HCI (pH4-5) to get solid precipitate, filtered and dried to get compound 2 (900 mg,—97percent) as off white solid. TLC system: methanol/dichloromethane (1:9), Rf: 0.1.‘H NMR (300 MHz, DMSO-d6): ö 13,36 (s, 1H), 13.04 (s, lH), 8.24—8.08 (m, 2H), 7.85 (dd, J 8.5, 0.9 Hz, I H), 7.67 (dd, J = 8.4, 1.3 Hz, I H). |
87% | With lithium hydroxide; water In tetrahydrofuran at 50℃; for 4 h; | b) A solution of compound 26e2 (5.0 g, 28.4 mmol) in THF (56 mL) was treated with LiOH (21 mL of a 2M aqueous solution, 42 mmol), and the reaction mixture is stirred at 50 °C. After 4 hours, the reaction mixture was cooled to room temperature and diluted with water. The basic aqueous layer was rinsed with diethyl ether, acidified to pH 3-4 by the addition of 1 M HCI, and extracted with ethyl acetate. The aqueous layer was extracted further with ethyl acetate, and the combined organic layers were rinsed with brine, dried over MgS04, and concentrated to afford 4.0 g (87percent yield) of compound 26. 3.'H NMR (CD30D) 8 7.79-7. 87 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H) ; ES (+) MS m/e = 163 (M+1). |
85.6% | With water; lithium hydroxide In tetrahydrofuran at 50℃; for 4 h; | A mixture of intermediate (12) (44.0g, 0.25mol) was dissolved in tetrahydrofuran (a 500 mL) was added 2NLiOH aqueous solution (200mL, 0.40mol), the reaction was stirred at 50 4h. Cooling to room temperature, the tetrahydrofuran was evaporated under reduced pressure, the residue was added distilled water (200 mL), washed with 1NHCl acidified to pH 3.5, added with ethyl acetate (3 × 500mL) extraction, the combined organic layer was washed with brine (a 500 mL), no over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid intermediate (13) 34.7g, yield 85.6percent. |
85.6% | With water; lithium hydroxide In tetrahydrofuran at 50℃; for 4 h; | Intermediate (12) (44.0 g, 0.25 mol) was dissolved in tetrahydrofuran (500 mL), and an aqueous solution of 2N LiOH (200 mL, 0.40 mol) was added. The reaction mixture was stirred at 50°C for 4 h, and was then cooled to roomtemperature. Tetrahydrofuran was distilled off under reduced pressure, and the residue was diluted by adding distilledwater (200 mL). The resulting mixture was acidified to pH 3.5 with 1 N HCl, and was extracted with ethyl acetate (33500mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure to obtain intermediate (13) as a light yellow solid (34.7 g, yield:85.6percent).MASS (ESI+) m/z = 163 (M+H)+.1 H NMR (400 MHz, CD3OD): 7.79-7.87 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid; sodium nitrite In water at 20℃; for 5 h; Acidic aqueous solution | To a mixture of 3-amino-4-methyl-benzoic acid methyl ester (15g, 90.9 mmol) in HOAc (400 mL) was added a solution OfNaNO2 (6.27g, 90.9 mmol) in H2O (9OmL) dropwise. The mixture was stirred at ambient temperature for five hr. then concentrated in vacuo. The resulting solid was triturated with ethyl acetate (400 mL) and filtered. The filtrate was concentrated to afford the title compound (13.3g, 83percent). m/z (M+H) = 177.18 |
83% | With acetic acid; sodium nitrite In water at 20℃; Cooling with ice | Example 1 A Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethylcarbamoyl)-1H- indazol-3-yl)cyclohex-3-enecarboxylic acid (1A) Step 1: Preparation of methyl 1H-indazole-6-carboxylate (A-2). Methyl 3-amino-4-methylbenzoate (A-l) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added drop-wise to the solution of starting material under ice-cooling at room temperature. The ice bath was removed and the mixture was stirred overnight. The half of the solvents were evaporated, the mixture was diluted with water (80 mL) and extracted with EtOAc(3x30 mL). The collected organic phase was washed with water and brine (2x200 mL), dried and evaporated to afford 2 (4.4 g), yield 83percent. LCMS (ESI): calc'd for C9H8N202, [M+H]+: 177, found: 177. |
83% | With acetic acid; sodium nitrite In water at 0℃; | Step 1: Preparation of methyl 1H-indazole-6-carboxylate (A-2).Methyl 3-amino-4-methylbenzoate (A-i) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added drop-wise to the solution while stirring at 0 °C. The ice bath was removed and the mixture was stirred overnight. Solvents were evaporated, and the mixture was diluted with water (80 mL) and extracted with EtOAc(3x30 mL). The combined organics were washed with water and brine (2x200 mL),dried and evaporated to afford 2 (4.4 g), yield 83percent. LCMS (ESI): calc’d for C9H8N202, [M+H]: 177, found: 177. |
83% | With acetic acid; sodium nitrite In water at 20℃; Cooling with ice | Methyl 3-amino-4- methylbenzoate (i-8a) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added dropwise to the solution of starting material under ice-cooling at room temperature. The icebath was removed and the mixture was stirred overnight. Half of the solvents were then evaporated, the mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 30 mL). The collected organic phase was washed with water and brine ( 2 x 200 mL ), dried and evaporated to afford i-8b (4.4 g, 83percent). LCMS (ESI): calc'd for C9H8N202, [M+H]+: 177, found: 177. |
83% | With sodium nitrite In water; acetic acid at 20℃; Cooling with ice | Step 1. Preparation of methyl 1H-indazole-6-carboxylate (i-14b).Methyl 3-amino-4-methylbenzoate (i-14a) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added dropwise to the solution of starting material under ice-cooling at room temperature. The ice bath was removed and themixture was stirred overnight. Half of the solvent was evaporated, the mixture was diluted with water (80 mL) and extracted with EtOAc (3x30 mL). The collected organic phase was washed with water and brine (2x200 mL), dried and evaporated to afford the title compound (4.4 g), yield 83percent. LCMS (ESI): calc’d for C9H8N202, [M+H]: 177, found: 177. |
83% | With acetic acid; sodium nitrite In water at 20℃; Cooling with ice | Methyl 3-amino-4- methylbenzoate (i-8a) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added dropwise to the solution of starting material under ice-cooling at room temperature. The icebath was removed and the mixture was stirred overnight. Half of the solvents were then evaporated, and the mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 30 mL). The collected organic phase was washed with water and brine (2 x 200 mL), dried and evaporated to afford i-8b (4.4 g, 83percent). LCMS (ESI): calc’d for C9H8N2O2, [M+H]: 177, found: 177. |
83% | With acetic acid; sodium nitrite In water at 0 - 20℃; | Step 1: Preparation of methyl 1H-indazole-6-carboxylate (A-2) [0301] Methyl 3-amino-4-methylbenzoate (A-1) (5.0 g, 30.2 mmol) was dissolved in AcOH (140 mL). Sodium nitrite (2.1 g, 30.2 mmol) in water (3.5 mL) was added drop-wise to the solution while stirring at 0° C. The ice bath was removed and the mixture was stirred overnight. Solvents were evaporated, and the mixture was diluted with water (80 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with water and brine (2×200 mL), dried and evaporated to afford 2 (4.4 g), yield 83percent. LCMS (ESI): calc'd for C9H8N2O2, [M+H]+: 177. found: 177. |
80% | With acetic acid; sodium nitrite In water at 0 - 20℃; | 2.47 g (34.5 mmol) of sodium nitrite was dissolved in 3.8 ml of water, and it was added dropwise to a mixture of 5.64 g (34.1 mmol) of methyl 3-amino-4-methyl-benzoate and 140 ml of acetic acid under ice-cooling. After the temperature of the reaction mixture was allowed to warm to room temperature and the mixture was stirred overnight, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate and filtered. The solvent was distilled off to give 4.83 g (yield: 80percent) of methyl indazole-6-carboxylate. MASS(ESI+) m/z= 177 (M+H)+ |
80.8% | With acetic acid; sodium nitrite In water at 20℃; for 5 h; | A mixture of intermediate (11) (57.8g, 0.35mol) was dissolved in glacial acetic acid (1.5 L of) was slowly added dropwise NaNO2 (24.2g, 0.35mol) in distilled water (350 mL of) solution. The reaction was stirred at room temperature 5H, concentrated under reduced pressure, to the residue was added distilled water (a 500 mL), extracted with ethyl acetate (3 × 1.0L). The organic layer was washed with distilled water (1.5 L of) and brine (1.5 L of), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid intermediate (12) 49.5g, yield 80.8percent. |
80.8% | With acetic acid; sodium nitrite In water at 20℃; for 5 h; | Intermediate (11) (57.8 g, 0.35 mol) was dissolved in glacial acetic acid (1.5 L), and a solution of NaNO2 (24.2g, 0.35 mol) in distilled water (350 mL) was slowly added dropwise. The reaction mixture was stirred at room temperaturefor 5 h, and concentrated under reduced pressure. Distilled water (500 mL) was added to the residue, and the mixturewas extracted with ethyl acetate (331.0 L). The organic layer was washed with distilled water (1.5 L) and brine (1.5 L),dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtainintermediate (12) as a light yellow solid (49.5 g, yield: 80.8percent).MASS (ESI+) m/z = 177 (M+H)+.1 H NMR (400 MHz, CDCl3): 3.96 (s, 3H), 7.80-7.85 (m, 2H), 8.14 (s, 1H), 8.27 (s, 1H). |
73% | Stage #1: With acetic acid; sodium nitrite In water at 0 - 20℃; for 6 h; |
Step A: 1H-Indazole-6-carboxylic acid methyl ester To a stirred solution of methyl 3-amino-4-methylbenzoate (4.98 g, 30 mmol) in acetic acid (50 mL) was added sodium nitrite (2.29 g, 33.0 mmol) in water (5 mL) dropwise at 0° C. After 5 min a solid precipitated. The cooling bath was removed and the reaction mixture was brought to room temperature. More acetic acid (50 mL) was added to dissolve the precipitate; this was stirred for 2 h, and a clear dark solution appeared. After 4 h, acetic acid was evaporated and the residue was added to a saturated aqueous sodium bicarbonate solution; this was extracted with ethyl acetate (3*60 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated. The residue solidified upon standing at room temperature to give an amorphous solid (3.9 g, 73percent): MS (ES) m/z 177 (M+); 1H NMR (CDCl3): 10.05 (1H, br s), 8.29 (1H, s), 8.16 (1H, s), 7.86 (1H, d, J=8.0 Hz), 7.81 (1H, d, J=8.0 Hz), 3.97 (3H, s). |
67% | Stage #1: With hydrogenchloride; ammonium tetrafluroborate; sodium nitrite In water at 3℃; for 1 h; Stage #2: With potassium acetate In chloroform for 1.16667 h; |
a) A solution of compound 26.1 (12.4 g, 75 mmol) and NH4BF4 (10.5 g, 100 mmol) in water (85 mL) was treated with concentrated HC1 (15 mL), cooled to 3 °C, and treated dropwise over 25 minutes with a solution of NaN02 (5.18 g, 75 mmol) in water (12 mL). The resulting thick slurry was stirred for 35 minutes, and the solid was collected by filtration, rinsed with water, methanol, and ether, and dried under N2. The solid was added in one portion to a stirred mixture of KOAc (8.1 g, 82. 5 mmol) and 18-crown-6 (0.5 g, 1.9 mmol) in chloroform (170 mL). After 70 minutes, water (170 mL) was added, and the layers were separated. The aqueous phase was extracted with chloroform, and the combined organic layers were rinsed with water, dried, and concentrated. The residue was triturated with hexane and the resulting solid isolated by filtration to provide 8.85 g (67percent yield) of compound 26. 2 as a dull yellow powder.'H NMR (CDCl3) 8 3.96 (s, 3H), 7. 80-7. 85 (m, 2H), 8.14 (s, 1H), 8. 27 (s, 1H); ES (+) MS m/e = 177 (M+1). |
71.6% | With sodium nitrite In water; acetic acid | (a) To a solution of 3-amino-4-methylbenzoic acid methyl ester (25 g, 0.15 mol) in 1 L of acetic acid cooled to 0° C. was added a solution of NaNO2 (12.5 g, 0.182 mol) in 50 ml of water and the mixture was warmed to room temperature with stirring over 4 hours. The solution was concentrated in vacuo, the residue was triturated with water, the solid was filtered and washed with water and hexane to afford 19 g (71.6percent) of methyl indazole-6carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate In N,N-dimethyl-formamide at 20℃; | To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100percent ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90percent). 1H NMR (400 MHz, CDCl3, δ): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H). |
90% | With sodium carbonate In N,N-dimethyl-formamide at 20℃; | Step 1. methyl 1H-indazole-6-carboxylate To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100percent ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90percent). 1H NMR (400 MHz, CDCl3, δ): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With hydrogenchloride; potassium acetate; sodium nitrite In hexane; chloroform; water | A. 6-Methoxycarbonylindazole. A solution of methyl 3-amino-4-methylbenzoate (12.39 g, 75 mmol) in water (85 mL) and concentrated hydrochloric acid (15 mL) was treated with ammonium fluoborate (10.48 g, 100 mmol) and cooled to -3° C. A solution of sodium nitrite (5.18 g, 75 mmol) in water (12 mL) was added dropwise over 25 min, producing a thick slurry. After stirring for 35 min more, the solid was collected by filtration, and was washed with water (100 mL), methanol (50 mL) and ether (50 mL), and dried. This material was added to a stirred mixture of potassium acetate (8.1 g, 82.5 mmol), 18-crown-6 (0.5 g, 1.9 mmol) and chloroform (170 mL) at room temperature, and stirring was continued for 70 min. Water (170 mL) was added and stirring was continued until the solid was dissolved. The layers were separated, and the aqueous phase was extracted with chloroform. The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated. The resulting solid was stirred in hexane overnight, collected by filtration, rinsed with hexane and dried to provide the title product (8.85 g, 67percent) as a dull yellow powder, which could be recrystallized from acetonitrile to give pale orange crystals, mp 142-144° C.: 1H NMR (CDCl3) d 11.17 (bs, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.83 (m, 2H), 3.97 (s, 3H); Mass spectrum (NH3-CI) m/z 177 (100percent, M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With diazomethyl-trimethyl-silane In diethyl ether; toluene | A solution of IH-indazole-6-carboxyIic acid 14C (1.73 g; 10.70 ramol) in toluene (80 ml) and methanol (30 niL) was treated with a solution of TMS-diazomethaiie (2 M soln in ether) until evolution of gas stopped. The reaction mixture was concentrated in vacuo and the residue was adsorbed on silica gel. The product was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent acetone in hexanes) to provide the product 14D (950 rag; 50 percent for two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.28 (IH, s), 8.16 (IH, s), 7.86 (IH, d, J = 8.54 Hz), 7.81 (IH, d, J = 8.54 Hz), 3.98 (3H, s). LR-MS (ESI): caldc for C9H9N2O2 [M+H]+ 177.07; found 177.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: With lithium triethylborohydride In tetrahydrofuran at -78℃; for 1 h; Stage #2: With sodium hydrogen sulfate; water In tetrahydrofuran |
Step E - Synthesis of Compound 17 F; 17E 17F; A solution of indazole 17E (460 mg; 1.66 mmol) in 16 mL of dry THF was cooled to -78 °C and treated with lithium triethylborohydride (2.5 eq, 4.15 mL of a 1 M soln in THF). The reaction mixture was stirred at -78 °C and followed by TLC (25 percent ethyl acetate in hexanes). The reaction was completed in about 1 h and quenched by addition of aqueous saturated sodium hydrogen sulfate (3 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to give the crude product as a colorless oil. The residue was chromatographed on a Biotage 40-S silica gel column (0 to 40 percent ethyl <n="114"/>acetate in hexanes) to give the following: des-Boc starting material (70 mg); alcohol product 17F (160 mg; 40 percent). 1H-NMR (CDCl3; 400 MHz): δ 8.19 (IH, s), 8.13 (IH, s), 7.67 (IH, d, J = 7.93 Hz), 7.30 (IH, d, J = 7.93 Hz), 5.13 (2H, s), 1.71 (9H, s). |
40% | Stage #1: With lithium triethylborohydride In tetrahydrofuran at -78℃; for 1 h; Stage #2: With sodium hydrogen sulfate; water In water |
Step E - Synthesis of Compound 19F; 19E 19F; A solution of indazole 19E (460 mg; 1.66 mmol) in 16 mL of dry THF was cooled to - 78 °C and treated with lithium triethylborohydride (2.5 eq, 4.15 mL of a 1 M soln in THF). The reaction mixture was allowed to stir at -78 °C and followed by TLC (25 percent ethyl acetate in hexanes). The reaction was completed in about 1 h and quenched by addition of aqueous saturated sodium hydrogen sulfate (3 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to provide the crude product as a colorless oil. The resulting residue was chromatographed on a Biotage 40- S silica gel column (0 to 40 percent ethyl acetate in hexanes) to provide the following: des-Boc starting material (70 mg); alcohol product 19F (160 mg; 40 percent). 1H-NMR (CDCl3; 400 MHz): δ 8.19 (IH, s), 8.13 (IH, s), 7.67 (IH, d, J = 7.93 Hz), 7.30 (IH, d, J = 7.93 Hz), 5.13 (2H, s), 1.71 (9H, s). |
40% | With lithium triethylborohydride In tetrahydrofuran at -78℃; for 1 h; | A solution of indazole 14E (460 mg; 1.66 mmol) in 16 tnL of dry THF was cooled to - 78 0C and treated with lithium triethylborohydride (2.5 eq, 4.15 mL of a 1 M soln in THF). The reaction mixture was stirred at -78 0C and followed by TLC (25 percent ethyl acetate in hexanes). The reaction was completed in about 1 h and quenched by addition of aqueous saturated sodium hydrogen sulfate (3 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to provide the crude product as a colorless oil. The residue was chromatographed on a Biotage 40-S silica gel column (0 to 40 percent ethyl acetate in hexanes) to provide the following: des-Boc starting material (70 mg); alcohol product 14F (160 mg; 40 percent). 1H-NMR (CDCl3; 400 MHz): δ 8.19 (IH, s), 8.13 (IH, s), 7.67 (IH, d, J = 7.93 Hz), 7.30 (IH3 d, J = 7.93 Hz), 5.13 (2H, s), 1.71 (9H. s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sulfuric acid In methanol; water | 1.B 1H-Indazole-6-carboxylic acid methyl ester A mixture of 7.59 g (46.8 mmol, 1.0 equiv) 1H-indazole-6-carboxylic acid in 500 mL CH3OH and 1 mL conc. H2SO4 was heated to reflux for 8 hours, then allowed to stir at room temperature for 18 hours. The mixture was concentrated to ~200 mL, diluted with 1 L ethyl acetate, and washed 1*250 mL saturated aqueous NaHCO3, 1*250 mL H2O, 1*250 mL brine, and dried over Na2SO4. The aqueous washes were extracted with two portions of ethyl acetate to recover additional product. The organic layers were combined, concentrated, and dried to give 6.75 g (82percent) of a yellow-orange-tan solid: 1H NMR (300 MHz, CDCl3) δ 10.8 (br s, 1H), 8.28 (dd, 1H, J=0.9, 1.9 Hz), 8.15 (d, 1H, J=1.0 Hz), 7.8 (m, 2H), 3.97 (s, 3H): MS (Cl, NH3) m/z 177 (M+H+, base). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; | To a solution of 26-S1 (2.5 g, 14.2 mmol) in DMF (30 mL) was added KOH (1.8 g, 31.9 mmol followed by iodine (5.4 g, 21.3 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with EtOAc twice. The combined organics were washed with 5percent aqueous Na2S2O4 solution and brine, dried, and concentrated to dryness to afford 26-S2 (4.0 g, 93.3percent yield) as a yellow solid, which was carried forward directly in the next synthetic step without further purification. LC/MS (ESI) m/z: 303 (M+H)+. |
78% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3 h; | To a solution of methyl 1H-indazole-6-carboxylate (865 mg, 4.91 mmol) in N,N-dimethylformamide (12 mL) was added potassium hydroxide (840 mg, 3.05 mmol) followed by iodine (1.54 g, 5.9 mmol). The mixture was stirred at room temperature for 3 hours. Sodium bisulfate (30 mL of 5percent aqueous) was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (5-65percent ethyl acetate/heptanes) to afford methyl 3-iodo-1H-indazole-6-carboxylate as a colorless solid (1.16 g, 78percent). 1H NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1H), 8.13 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 3.87 (s, 3H). |
78% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 2. methyl 3-iodo-1H-indazole-6-carboxylate To a solution of methyl 1H-indazole-6-carboxylate (865 mg, 4.91 mmol) in N,N-dimethylformamide (12 mL) was added potassium hydroxide (840 mg, 3.05 mmol) followed by iodine (1.54 g, 5.9 mmol). The mixture was stirred at room temperature for 3 hours. Sodium bisulfate (30 mL of 5percent aqueous) was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (5-65percent ethyl acetate/heptanes) to afford methyl 3-iodo-1H-indazole-6-carboxylate as a colorless solid (1.16 g, 78percent). 1H NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1H), 8.13 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 3.87 (s, 3H). |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 20℃; for 1 h; Cooling with ice | Step 2: Preparation of Methyl 3-iodo-1H-indazole-6-carboxylate (A-3). Methyl lH-indazole-6-carboxylate (A-2) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC(50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions under ice-cooling at room temperature. The ice bath was removed and the mixture was stirred at room temperature for lh. The reaction was monitored by TLC (25percent MeOH in chloroform) then it was slowly quenched with Na2S203 (sat. sol. in water, 100 mL), diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The organic phase was evaporated and triturated with n-hexane. The precipitated material was filtered and dried to afford a brown solid 3 (5.3 g), yield 62percent. LCMS(ESI): calc'd for C9H7IN202, [M+H]+: 303, found: 303. |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 0 - 20℃; for 1 h; | Step 2: Preparation of Methyl 3-iodo-1H-indazole-6-carboxylate (A-3).Methyl 1H-indazole-6-carboxylate (A-2) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC (50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol)were added in portions while stirring at 0 °C. The ice bath was removed and the mixture was stirred at room temperature for lh. The reaction was monitored by TLC (25percent MeOH in chloroform) then it was slowly quenched with Na2S2O3 (sat. sol. in water, 100 mL), diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The organic phase was evaporated and triturated with n-hexane. The precipitated material was filtered and dried toafford a brown solid 3 (5.3 g), yield 62percent. LCMS(ESI): calc’d for C9H71N202, [M+H]+: 303, found: 303. |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 20℃; Cooling with ice | Methyl 1H- indazole-6-carboxylate (i-8b) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC (50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions under ice-cooling at room temperature. The ice bath was removed and the mixture was stirred at room temperature for lh. The reaction was monitored by TLC (25percent MeOH in chloroform) then it was slowly quenched with Sat. Na2S203 aqueous (100 mL), diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic phase was evaporated and triturated with n-hexane. The precipitated material was filtered and dried to afford a brown solid i-8c (5.3 g, 62percent). LCMS (ESI): calc'd for C9H7IN202, [M+H]+: 303, found: 303. |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 20℃; for 1 h; Cooling with ice | Step 2. Preparation of Methyl 3-iodo-1H-indazole-6-carboxylate (i-14c). Methyl 1H-indazole-6-carboxylate (i-14b) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAc (50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions under ice—cooling at room temperature. The ice bath was removed and the mixture was stirred at room temperature for lh and then was slowly quenched withNa25203 (sat. sol. in water, 100 mL), diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The organic phase was evaporated and triturated with n-hexane. The precipitated material was filtered and dried to afford the title compound as a brown solid (5.3 g), yield 62percent. LCMS(ESI): calc’d for C9H7N202, [M+H]: 303, found: 303. |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 20℃; for 1 h; Cooling with ice | Methyl 1H- indazole-6-carboxylate (i-8b) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC (50mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions under ice-cooling at room temperature. The ice bath was removed and the mixture was stirred at room temperature for lh. The reaction was monitored by TLC (25percent MeOH in chloroform) then it was slowly quenched with sat. Na2S2O3 aqueous (100 mL), diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic phase was evaporatedand triturated with n-hexane. The precipitated material was filtered and dried to afford a brown solid i-8c (5.3 g, 62percent). LCMS (ESI): calc’d for C9H71N202, [M+H]+: 303, found:303. |
62% | With iodine; potassium hydroxide In N,N-dimethyl acetamide at 0 - 20℃; for 1 h; | Step 2: Preparation of Methyl 3-iodo-1H-indazole-6-carboxylate (A-3) [0302] Methyl 1H-indazole-6-carboxylate (A-2) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC (50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions while stirring at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC (25percent MeOH in chloroform) then it was slowly quenched with Na2S2O3 (sat. sol. in water, 100 mL), diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was evaporated and triturated with n-hexane. The precipitated material was filtered and dried to afford a brown solid 3 (5.3 g), yield 62percent. LCMS(ESI): calc'd for C9H7IN2O2, [M+H]+: 303. found: 303. |
15 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1 h; | 1 4a) Methyl 3-iodo- I H-indazole-6-carboxylatePotassium hydroxide (11 g, 19.69 mmol, 3.47 eq) and iodine (28.8 g, 11.35 rnmol, 2.0 eq) were added to a stirred solution of methyl IH-indazole-6-carboxylate (10 g, 5.68 mmol, 1.0 eq) in DMF (100 mL). Stirring was continued for I h at room temperature and the reaction mixture was then quenched with aqueous sodium thiosulfate solution (20percent, 20 mL). The precipitating solid was filtered off, washed withwater (20 mL) and dried. The target compound was obtained as white solid that was used within the next step without further purification. Yield: 15 g IH NMR (400 MHz, DMSO-d6, ö ppm): 13.86 (s, lH), 8.16 (s, IH), 7.75 (d, J = 8.6 Hz, 1H), 7.56 (d, J =8.6 Hz, 1K), 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran Stage #2: Heating / reflux |
Methyl 1H-indazole-6-carboxylate was prepared according to the procedure disclosed in J. Med. Chem. 2000, 43 (1), 41-58 (example 12b, page 49). Alkylation was done under standard conditions (sodium hexamethyldisilazide, THF, iodomethane, reflux) provided methyl 1-methyl-1 H-indazole-6- carboxylate (43percent). Saponification was done under standard conditions (1 N NaOH) afforded the title product (96percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 mg | Stage #1: With sodium hydride In mineral oil at 20℃; for 0.5 h; Cooling with ice |
S[00478] To an ice-cooled solution of methyl lH-indazole-6-carboxylate (566 mg, 3.21 mmol) was added NaH (154 mg, 3.85 mmol), the mixture was then stirred at room temperature for 30min. Methyl iodide (547 mg, 3.85 mmol) was added drop wise, and the reaction mixture was stirred overnight. Cooled to 0 °C, added water and extracted with ethyl acetate. The organic phase was concentrated and purified by gel chromatograph to provide 130 mg of methyl 1 -methyl- lH-indazole-6-carboxyl ate and 230 mg of methyl 2 -methyl -2H-indazole-6- carboxylate, 59percent.1H NMR for methyl 1 -methyl- lH-indazole-6-carboxylate: 1H NMR (400 MHz, CDC13): δ 3.97 (3H, s), 4.14 (3H, s), 7.74-7.82 (2H, m), 8.02 (1H, s), 8.17 (1H, d, J = 0.8 Hz). 1H NMR for methyl 2-methyl-2H-indazole-6-carboxylate: 1H NMR (400 MHz, CDC13): δ 3.94 (3H, s), 4.25 (3H, s), 7.65-7.72 (2H, m), 7.92 (1H, s), 8.47 (1H, d, J= 1.2 Hz). [M+H] Calc'd for C 10H10N2O2, 191; Found, 191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hexamethyldisilazane In tetrahydrofuranHeating / reflux | Methyl 1H-indazole-6-carboxylate was prepared according to the procedure disclosed in J. Med. Chem. 2000, 43 (1 ), 41-58 (example 12b, page 49). Alkylation under standard conditions (sodium hexamethyldisilazide, THF, iodomethane, reflux) provided methyl 2-methyl-2H-indazole-6-carboxylate (44percent). Saponification under standard conditions (1 N NaOH) afforded the title product (53percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 mg | Stage #1: With sodium hydride In mineral oil at 20℃; for 0.5 h; Cooling with ice |
S[00478] To an ice-cooled solution of methyl lH-indazole-6-carboxylate (566 mg, 3.21 mmol) was added NaH (154 mg, 3.85 mmol), the mixture was then stirred at room temperature for 30min. Methyl iodide (547 mg, 3.85 mmol) was added drop wise, and the reaction mixture was stirred overnight. Cooled to 0 °C, added water and extracted with ethyl acetate. The organic phase was concentrated and purified by gel chromatograph to provide 130 mg of methyl 1 -methyl- lH-indazole-6-carboxyl ate and 230 mg of methyl 2 -methyl -2H-indazole-6- carboxylate, 59percent.1H NMR for methyl 1 -methyl- lH-indazole-6-carboxylate: 1H NMR (400 MHz, CDC13): δ 3.97 (3H, s), 4.14 (3H, s), 7.74-7.82 (2H, m), 8.02 (1H, s), 8.17 (1H, d, J = 0.8 Hz). 1H NMR for methyl 2-methyl-2H-indazole-6-carboxylate: 1H NMR (400 MHz, CDC13): δ 3.94 (3H, s), 4.25 (3H, s), 7.65-7.72 (2H, m), 7.92 (1H, s), 8.47 (1H, d, J= 1.2 Hz). [M+H] Calc'd for C 10H10N2O2, 191; Found, 191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In tetrahydrofuran at 20℃; Cooling with ice | A. 1-tert-Butyl, 6-meth l lH-indazole-l,6-dicarboxylate [00470] To an ice-cooled solution of methyl lH-indazole-6-carboxylate (502 mg, 2.84 mmol), DMAP (69 mg, 0.57 mmol) and Et3N (431 mg, 4.26 mmol) in THF (10 mL) was added Boc20 (743 mg, 3.41 mmol) slowly. The reaction mixture was stirred overnight at room temperature. It was then concentrated, the residue was extracted with ethyl acetate, collected the organic phase, concentrated for gel chromatograph to provide 797 mg of the title compound (100percent). 1H NMR (400 MHz, CDC13): δ 1.74 (9H, s), 3.97 (3H, s), 7.77 (IH, dd, J = 0.4 Hz, J= 8.4 Hz), 7.95 (IH, dd, J= 1.2 Hz, J= 8.4 Hz), 8.21 (IH, d, J= 0.8 Hz), 8.90 (IH, s). [M+H] Calc'd for Ci4Hi6N204, 277, 221, 177; Found, 221. |
93% | at 60℃; for 3 h; | Step D - Synthesis of Compound 17E; 17D 17E; A solution of lH-indazole-6-carboxylic acid methyl ester 17D (840 mg; 4.76 mmol) in 25 mL of acetonitrile was treated with Boc-anhydride (1.05 eq, 1.09 g) and a catalytic amount of DMAP (tip of spatula). The mixture was stirred at 60 0C for 3 h. The mixture was concentrated to half its volume in rotavap and then diluted with ethyl acetate (100 mL) and washed with aqueous saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent ethyl acetate in hexanes) to give the product 17E (1.2 g; 93 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 8.91 (IH, s), 8.22 (IH, s), 7.99 (IH, dd, J = 1.22, 8.54 Hz), 7.78 (IH, d, J = 8.54 Hz), 3.97 (3H, s), 1.74 (9H, s). |
93% | at 60℃; for 3 h; | Step D - Synthesis of Compound 19E; 19D 19E; A solution of lH-indazole-6-carboxylic acid methyl ester 19D (840 mg; 4.76 mmol) in 25 mL of acetonitrile was treated with Boc-anhydride (1.05 eq, 1.09 g) and a catalytic amount of DMAP (tip of spatula). The mixture was allowed to stir at 60 °C for 3 hours. The mixture was concentrated to half its volume in rotavap and then diluted with ethyl acetate (100 mL) and washed with aqueous saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The resulting residue was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent ethyl acetate in hexanes) to provide the product 19E (1.2 g; 93 percent) as a colorless oil. 1H-NMR (CDCl3; 400 <n="188"/>MHz): δ 8.91 (IH, s), 8.22 (IH, s), 7.99 (IH, dd, J = 1.22, 8.54 Hz), 7.78 (IH, d, J = 8.54 Hz), 3.97 (3H, s), 1.74 (9H, s). |
93% | With dmap In acetonitrile at 60℃; for 3 h; | A solution of lH-indazole-6-carboxylic acid methyl ester 14D (840 mg; 4.76 mmol) in 25 niL of acetonitrile was treated with Boc-anhydride (1.05 eq, 1.09 g) and a catalytic amount of DMAP (tip of spatula). The mixture was stirred at 60 0C for 3 hours. The mixture was concentrated to half its volume in rotavap and then diluted with ethyl acetate (100 mL) and washed with aqueous saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent ethyl acetate in hexanes) to provide the product 14E (1.2 g; 93 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 8.91 (I H, S), 8.22 (IH, s), 7.99 (IH, dd, J = 1.22, 8.54 Hz), 7.78 (IH, d. J - 8.54 Hz), 3.97 (3H, s), 1.74 (9H, s). |
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