* 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; 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).
With potassium <i>tert</i>-butylate In dimethyl sulfoxide
To a stirred solution of potassium tert-butoxide (8.1 g, 73 mmol) in DMSO (30 mL) was added a solution of 3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid (1.9 g, 7.3 mmol) at RT. The mixture was stirred overnight, followed by the adition of ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was dicarded. The pH of the aqueous layer was adjusted to 4-5 with aqueous 1N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 800 mg (97percent) of 1H-indazole-6-carboxylic acid as a tan solid: 1H NMR (400 MHz. DMSO-d6) δ 13.4, 13.0, 8.2, 8.1, 7.9, 7.7.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8219 - 8248
[2] Patent: US2003/73707, 2003, A1,
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).
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.
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).
With potassium tert-butylate; In dimethyl sulfoxide;
To a stirred solution of potassium tert-butoxide (8.1 g, 73 mmol) in DMSO (30 mL) was added a solution of 3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid (1.9 g, 7.3 mmol) at RT. The mixture was stirred overnight, followed by the adition of ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was dicarded. The pH of the aqueous layer was adjusted to 4-5 with aqueous 1N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 800 mg (97percent) of 1H-indazole-6-carboxylic acid as a tan solid: 1H NMR (400 MHz. DMSO-d6) delta 13.4, 13.0, 8.2, 8.1, 7.9, 7.7.
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 16h;
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): oe 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 4h;
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 4h;
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 4h;
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).
85.6%
With water; lithium hydroxide; In tetrahydrofuran; at 50℃; for 4h;
Methyl 1H-indazole-6-carboxylate (44.0 g, 0.25 mol) was dissolved in tetrahydrofuran (500 mL).2N LiOH aqueous solution (200 mL, 0.40 mol) was added.The reaction solution was stirred at 50 ° C for 4 h.After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure and the residue was diluted with distilled water (200 mL) and acidified to pH 3.5 with 1N HCl.Ethyl acetate (3 × 500 mL) was added for extraction.The mixed organic layer was washed with brine (500 mL).Dry over anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure to give a pale yellowColor solid intermediate (13) 34.7g,The yield was 85.6percent.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); for 2h;
d) A solution of compound 26. 3 (7.8 g, 20.8 mmol), compound 26. 4 (3. 4 g, 20.8 mmol), 1-hydroxybenzotriazole hydrate ("HOBt", 3.5 g, 22.3 mmol), and diisopropylethylamine ("DIEA", 14 mL, 83.3 mmol) in DMF (100 mL) was treated with EDCI (4.4 g, 22.3 mmol). After 2 h, the reaction mixture was treated with 1 M HC1 and extracted with ethyl acetate. The combined organic extracts were rinsed with NaHC03 (sat'd), rinsed with brine, rinsed with water, dried over MgS04, and concentrated to afford 8.4 g (99percent yield) of the title compound. ES (+) MS m/e = 404 (M+1).
B N2-(4-t-Butylbenzoyl)-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine By methods substantially equivalent to those described in Example 9-C, N2-(4-t-butylbenzoyl)-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine (0.1 g, 5percent) was prepared from 4-methoxycarbonyl-N2-(4-t-butylbenzoyl)-1,2-benzenediamine and <strong>[704-91-6]6-indazolecarboxylic acid</strong>. 1H NMR FD-MS, m/e 438.3 (M+) Anal. for C26H22N4O3: Calc: C, 68.92; H, 5.57; N, 11.91. Found: C, 68.94; H, 5.62; N, 11.79.
With 1,2-dichloro-ethane; In methanol; ethyl acetate; N,N-dimethyl-formamide;
C N2-(4-t-Butylbenzoyl)-N1-(6-indazolylcarbonyl)-1,2-benzenediamine To a stirring solution of N2-(4-t-butylbenzoyl)-1,2-benzenediamine (830 mg, 3.1 mmol) and <strong>[704-91-6]6-indazolecarboxylic acid</strong> (European Pat. Appln. Pub. No. 242 167 A2, p 43) (500 mg, 3.1 mmol) in DMF (5 mL) was added EDC (1.19 g, 6.2 mmol). After 12 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with water and twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo, then chromatographed over silica gel, eluding with a solvent gradient of dichloromethane through 5percent methanol/dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 330 mg (26percent) of an off-white solid. 1H NMR FD-MS, m/e 412 (M+) Anal. for C24H24N4O2: Calc: C, 72.80; H, 5.87; N, 13.58. Found: C, 72.15; H, 5.80; N, 13.19.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In methanol; N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: A DMF solution of 3-(5-amino-1H-indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (1.0equiv), DIPEA (N,N-diisopropylethylamine, 3equiv) and RCO2H (1.05equiv) at 0°C was treated with TBTU (O-(Benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate) (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by preparative HPLC. Alternatively, a DMF solution of 3-(3-sulfamoylphenyl)-1H-indazole-5-carboxylic acid (1.0equiv), DIPEA (3equiv) and RR?NH (1.05equiv) at 0°C or rt was treated with TBTU (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by prepHPLC.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 23℃; for 14h;
A mixture of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (4-1, 1.11 g, 6.85 mmol, 1 equiv), N,N- diisopropylethylamine (2.65 g, 20.5 mmol, 3.00 equiv), (1H-l,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1- yl)rhohosphonium hexafluorophosphate (Pybop, 5.34 g, 10.3 mmol, 1.50 equiv) and methylamine (10.3 mL (2M in THF), 20.5 mmol, 3 .00 equiv) in DMF (10 mL) was stirred at 23 °C for 14 h. The reaction mixture was partitioned between a 1: 1 aqueous mixture of of sodium chloride solution and sodium bicarbonate solution and ethyl acetate (2 x 50 mL). The aqueous layer was then acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to EPO <DP n="64"/>100percent EtOAc, then 10percent MeOH in EtOAc) to give N-methyl-1H-indazole-6-carboxamide (4-2) as a light brown solid. LRMS m/z (M+H) 176.2 found, 176.1 required.
With sodium hydroxide; water; In ethanol; at 80℃; for 4h;
A mixture of 1H-indazole-6-carbonitrile (1-3, 1.50 g, 10.5 mmol, 1.00 equiv), and sodium hydroxide ( 1.26 g, 31.4 mmol, 3 equiv) in a 1 : 1 mixture of ethanol and IN aqueous sodium hydroxide (5 mL) was heated to 80 °C for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (4 x 50 mL). The organic layer was discarded and the aqueous layer was acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1H-indazole-6-carboxylic acid (4- 1) as an off-white solid. The LRMS m/z (M+H ) 163.1 found, 163.0 required.
With sodium hydroxide; In ethanol; water; at 80℃; for 4h;
A mixture of lH-indazole-6-carbonitrile (1-3, 1.50 g, 10.5 mmol, 1.00 equiv), and sodium hydroxide (1.26 g, 31.4 mmol, 3 equiv) in a 1:1 mixture of ethanol and IN aqueous sodium hydroxide (5 mL) was heated to 80 0C for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (4 x 50 mL). The organic layer was discarded and the aqueous layer was acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give lH-indazole-6-carboxylic acid (4-1) as an off-white solid. The LRMS m/z (M+H ) 163.1 found, 163.0 required.
With bromine; sodium hydrogensulfite; In acetic acid;
(b) To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99percent), mp >250°.
99%
With bromine; sodium hydrogensulfite; In acetic acid;
(b) To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99percent), mp >250°.
With bromine; acetic acid; at 25℃; for 16h;in the dark;
Bromine (0.385 mL, 7.48 mmol) was added dropwise to a solution of 1 H-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (1 g, 5.98 mmol) in acetic acid (30 mL) and the reaction mixture was stirred for 16 h at 25°C in the dark. The reaction was quenched by addition of a saturated aqueous solution of Na2S03 (12 mL) and brine (25 mL) and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2S04), filtered and concentrated. The material thus obtained was used without further purification in the next step. MS (UPLC/MS): 239.1/241.1 [M-H]-, 481.3/483.3 [2M-H]-; tR (UPLC conditions f): 1.59 min.
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone;
(a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2 O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2*100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone;
(a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2 x 100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
1.B 1H-Indazole-6-carboxylic acid methyl ester A mixture of 7.59 g (46.8 mmol, 1.0 equiv) <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> 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) delta 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).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 23℃; for 14h;
A mixture of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (4-1, 1.11 g, 6.85 mmol, 1 equiv), N,N-diisopropylethylamine (2.65 g, 20.5 mmol, 3.00 equiv), (lH-l,2,3-benzotriazol-l-yloxy)(tripyrrolidin-l-yl)phosphonium hexafluorophosphate (Pybop, 5.34 g, 10.3 mmol, 1.50 equiv) and methylamine (10.3 mL (2M in THF), 20.5 mmol, 3 .00 equiv) in DMF (10 mL) was stirred at 23 0C for 14 h. The reaction mixture was partitioned between a 1 : 1 aqueous mixture of of sodium chloride solution and sodium bicarbonate solution and ethyl acetate (2 x 50 mL). The aqueous layer was then acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 100percent EtOAc, then 10percent MeOH in EtOAc) to give N-methyl-lH-indazole-6-carboxamide (4-2) as a light brown solid. LRMS m/z (M+H) 176.2 found, 176.1 required.
With methanol; In diethyl ether; toluene;Product distribution / selectivity;
Step C - Synthesis of Compound 17 D; 17C 17D; A solution of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> 17C (1.73 g; 10.70 mmol) in toluene (80 mL) and methanol (30 mL) was treated with a solution of TMS-diazomethane (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 give the product 17D (950 mg; 50 percent for <n="113"/>two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): delta 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.
With methanol; In diethyl ether; toluene;Product distribution / selectivity;
19C 19D; A solution of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> 19C (1.73 g; 10.70 mmol) in toluene (80 mL) and methanol (30 mL) was treated with a solution of TMS-diazomethane (2 M soln in ether) until evolution of gas stopped. The reaction mixture was concentrated in vacuo and the resulting 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 19D (950 mg; 50 percent for two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): delta 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.
Step B - Synthesis of Compound 17 C; 17B 17C; To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 17B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was stirred for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were 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 17C as a slightly yellow solid which was used without further purification.
Step B - Synthesis of Compound 19C; 19B 19C; To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 19B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was allowed to stir for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x <n="187"/>50 mL) and the combined organic layers were 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 19C as a slightly yellow solid which was used without further purification.
With potassium tert-butylate; In dimethyl sulfoxide; for 6h;
To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 14B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was stirred for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were 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 14C as a slightly yellow solid which was used without further purification.
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): delta 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.
With sulfuric acid;
Preparation of tert -butyl 5-(hydroxymethyl)-lH-indazole- l -carboxylateThe title compound was synthesized by esterification of <strong>[704-91-6]indazole-6-carboxylic acid</strong> using methanol in presence of cone, sulphuric acid followed by reduction of the ester group using lithium aluminium hydride and its subsequent reaction with di-ter/-butyl dicarbonate anhydride; NMR (300 MHz, DMSO-c 6) delta 1.64 (s, 9H), 4.67 (d, J = 5.1 Hz, l H), 5.43 (br s, I H), 7.29 (d, .] = 7.8 Hz, I H), 7.80 (d, J = 8.1 Hz, 1 H), 8.12 (s, 1 H), 8.36 (s, 1 H).
With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (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, delta): 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-carboxylateTo a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (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, delta): 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).
5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride[ No CAS ]
[ 704-91-6 ]
[ 1401461-15-1 ]
Yield
Reaction Conditions
Operation in experiment
With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
Example 11 N-(1-(7-(3,4-Dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide Procedure:A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150.x.21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25percent acetonitrile/75percent water (0.1percent TFA V/V) initially, and then proceed to 50percent acetonitrile/50percent water (0.1percent TFA V/V) in a linear fashion after just 9 min.) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide (45 mg, 36percent) as white solid. 1H NMR (300 MHz, DMSO): delta 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J=6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.63-7.44 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 4.62-4.25 (m, 2H), 3.96-3.66 (m, 10H), 2.35-2.11 (m, 3H). LC-MS: 516.9 [M+H]+, tR=1.38 min. HPLC: 100percent at 214 nm, 100percent at 254 nm, tR=5.76 min.
With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
A mixture of 5-(3-aminopyrrolidin-l-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4- <i]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2S04. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150 x 21.2 mm; inject volume: 3ml/inj, flow rate: 20ml/min; wavelength: 214nm and 254 nm; the gradient conditions are: 25percent acetonitrile/75percent water (0.1percentTFA V/V) initially, and then proceed to 50percent acetonitrile/50percent water (0.1percentTFA V/V) in a linear fashion after just 9 min.) to give N-(l-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-<JJpyrimidin-5- yl)pyrrolidin-3-yl)- lH-indazole-6-carboxamide (45 mg, 36 percent) as white solid. 1H NMR (300 MHz, DMSO): delta 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J = 6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, = 8.4 Hz), 7.63 - 7.44 (m, 2H), 6.92 (d, 1H, = 9.0 Hz), 4.62 - 4.25 (m, 2H) , 3.96 - 3.66 (m, 10H), 2.35 - 2.11 (m, 3H). LC - MS: 516.9 [M + H]+, tR = 1.38 min. HPLC: 100 percent at 214 nm, 100 percent at 254nm, tR = 5.76 min.
2,6-dimethylbenzyl 3-chloro-1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
195 mg
To a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (343 mg) in acetonitrile (10 mL) was addedN-chlorosuccinimide (313 mg), and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then acetone (10 mL), potassium carbonate (883 mg) and 2,6-dimethylbenzyl chloride (724 mg) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (195 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.79 (1H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.1 Hz) 7.26-7.23 (1H, m), 7.14 (2H, d, J = 7.6 Hz), 7.06-7.02 (1H, m), 6.92 (2H, d, J = 7.6 Hz), 5.54 (2H, s), 5.40 (2H, s), 2.42 (6H, s), 2.25 (6H, s).
tert-butyl (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate[ No CAS ]
[ 704-91-6 ]
C20H26N4O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12h;
General procedure: The appropriate carboxylic acid (1 mmol) and N-tboc-bispidine 13 (248 mg, 1.1 mmol) were dissolved in dry CH2Cl2 (5 mL) and cooled to 0 °C. DMAP (6.1 mg, 0.05 mmol) and DCC (206 mg, 1 mmol) were added and the mixture was allowed to warm up and stir at rt. The precipitate was filtered off after 12 h and washed with cold CH2Cl2 (2 mL). The solvent of the filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (silica gel, mixtures of CH2Cl2 and MeOH?40:1. 20:1 or 9:1).
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a stirred solution of compound 3A (900 mg, 5.555 mmol, 1.0 eq) in dimethylformamide (30 mL) was added 1 -hydroxy-7-azabenzotriazole (37 mg, 0.277 mmol, 0.05 eq), N-(3-Dirnethylaminopropyl)-N?- ethylcarbodiirnide hydrochloride (1.1 g, 6.11 mmol, 1.1 eq) followed by morpholine (0.6mL, 6.666 rnmol, 1.2 eq), tetraethylammonium (1.5 mL, 11.11 mmol, 2.0 eq) and stirred at room temperature for 16h. The RM was diluted with water (50 mL), extracted with ethyl acetate (2 X 50 mL), washed withbrine (50 mL), dried over anhydrous Na2SO4 and evaporated to get compound INT-3B (1 g, crude) as colorless liquid. The compound 3 used for next step without purification. TLC system:methanol/dichlorornethane (1:9), Rf: 0.4.?H NMR: (300 MHz, DMSO-d6): oe 13.24 (s, IH), 8.13 (s, 1H), 7.83 (dd, J 8.2, 1.2 Hz, IH), 7.56 (s, 1H), 7.12 (dd, J = 8.3, 1.3 Hz, IH), 3.71?3.35 (m, 8H).
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(5-hydroxy-3-oxapent-1-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(5-hydroxy-3-oxapent-1-yloxy)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.1%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
To the intermediate was cooled to 0 (17-02H) (3.50g, 6.37mmol), intermediate (13) (1.14g, 7.01mmol) and DIPEA (2.47g, 19.11mmol) in DMF (50mL) was added HATU (2.67g, 7.01mmol). The reaction mixture was stirred at room temperature overnight, distilled water (100 mL), extracted with ethyl acetate (3 × 100mL), the combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was separated and purified by silica gel column to give a pale yellow solid intermediate (18-02H) 3.76g, yield 85.1percent.
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(3,6,9,12,15-pentaoxapentane-1-oxy)benzoyl]benzylamidopyrrolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(4,7,10-trioxadecan-1-yloxy)benzoyl]benzamideamido-4-(1H-indazole-6-formylamino)pyrrolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.2%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
To the intermediate was cooled to 0 (17-03M) (3.87g, 6.37mmol), intermediate (13) (1.14g, 7.01mmol) and DIPEA (2.47g, 19.11mmol) in DMF (50mL) was added HATU (2.67g, 7.01mmol). The reaction mixture was stirred at room temperature overnight, distilled water (100 mL), extracted with ethyl acetate (3 × 100mL), the combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was isolated as a pale yellow solid intermediate (18-03M) 4.27g silica gel column, yield 89.2percent.
89.2%
With 2-(7-azobenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
HATU (2.67 g, 7.01 mmol) was added to a solution of intermediate (17-03M) (3.87 g, 6.37 mmol), intermediate(13) (1.14 g, 7.01 mmol) and DIPEA(2.47 g, 19.11 mmol) in DMF (50 mL) which was cooled to 0°C. The reaction mixturewas stirred overnight at room temperature before distilled water (100 mL) was added, and was extracted with ethylacetate (33100 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated ona silica gel column to obtain intermediate (18-03M) as a light yellow solid (4.27 g, yield: 89.2percent).MASS (ESI+) m/z = 752 (M+H)+.
44%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
Cooling to 0 ° C(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(3,6,9,12,15-pentaoxapentan-1-yloxy)benzoyl ]Benzylaminopyrrolidine-1-carboxylic acid tert-butyl ester (JK-03M-06) (70.0 g, 100.7 mmol),1H-carbazole-6-carboxylic acid (JK-03M-07) (24.5 g, 151.1 mmol)Add HATU (46.0 g, 120.8 mmol) to a solution of DMF (800 mL).DIPEA (52.1 g, 402.8 mmol) was added dropwise for about 20 minutes.The reaction mixture was stirred at room temperature overnight.Add 1N aqueous ammonium chloride solution (2000 mL),Extracted with ethyl acetate (1000 mL × 3),Mixed organic layer dissolved in saturated ammonium chloride Washed with water (1000 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure.The residue was purified by silica gel column to give a pale yellow solid(JK-03M-08) 55.0 g (two-step total yield 44percent).
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yloxy)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.8%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
To the intermediate was cooled to 0 (17-06H) (4.62g, 6.37mmol), intermediate (13) (1.14g, 7.01mmol) and DIPEA (2.47g, 19.11mmol) in DMF (50mL) was added HATU (2.67g, 7.01mmol). The reaction mixture was stirred at room temperature overnight, distilled water (100 mL), extracted with ethyl acetate (3 × 100mL), the combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was separated and purified by silica gel column to give a pale yellow solid intermediate (18-02H) 4.53g, yield 81.8percent.
81.8%
With 2-(7-azobenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
HATU (2.67 g, 7.01 mmol) was added to a solution of intermediate (17-06H) (4.62 g, 6.37 mmol), intermediate(13) (1.14 g, 7.01 mmol) and DIPEA (2.47 g, 19.11 mmol) in DMF (50 mL) which was cooled to 0°C. The reaction mixturewas stirred overnight at room temperature before distilled water (100 mL) was added, and was extracted with ethylacetate (33100 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated ona silica gel column to obtain intermediate (18-02H) as a light yellow solid (4.53 g, yield: 81.8percent).MASS (ESI+) m/z = 870 (M+H)+.
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yloxy)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine hydrochloride[ No CAS ]
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.4%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
To the intermediate was cooled to 0 (17-07M) (4.99g, 6.37mmol), intermediate (13) (1.14g, 7.01mmol) and DIPEA (2.47g, 19.11mmol) in DMF (50mL) was added HATU (2.67g, 7.01mmol). The reaction mixture was stirred at room temperature overnight, distilled water (100 mL), extracted with ethyl acetate (3 × 100mL), the combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was isolated as a pale yellow solid intermediate (18-07M) 5.17g silica gel column, yield 87.4percent.
87.4%
With 2-(7-azobenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
HATU (2.67 g, 7.01 mmol) was added to a solution of intermediate (17-07M) (4.99 g, 6.37 mmol), intermediate(13) (1.14 g, 7.01 mmol) and DIPEA (2.47 g, 19.11 mmol) in DMF (50 mL) which was cooled to 0°C. The reaction mixturewas stirred overnight at room temperature before distilled water (100 mL) was added, and was extracted with ethylacetate (333100 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated ona silica gel column to obtain intermediate (18-07M) as a light yellow solid (5.17 g, yield: 87.4percent).MASS (ESI+) m/z = 928 (M+H)+.
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine hydrochloride[ No CAS ]
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(3,6-dioxanonane-1-yloxyl)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(3,6-dioxanonan-1-yloxyl)benzoyl]benzamido}-4-(1H-indazol-6-carboxamido)pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.1%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃;
To the intermediate was cooled to 0 (17-02P) (3.77g6.37mmol), intermediate (13) (1.14g, 7.01mmol) and DIPEA (2.47g, 19.11mmol) in DMF (50mL) was added HATU (2.67g, 7.01mmol). The reaction mixture was stirred at room temperature overnight, distilled water (100 mL), extracted with ethyl acetate (3 × 100mL), the combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was separated and purified by silica gel column to give a pale yellow solid intermediate (18-02H) 4.13g, yield 88.1percent.
tert-butyl (3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(5-hydroxy-3-oxapentan-1-oxy)benzoyl]benzamido pyrrolidine-1-carboxylate[ No CAS ]
[ 704-91-6 ]
tert-butyl (3R,4R)-3-{4-[2,3-difluoro-6-(5-hydroxy-3-oxapentan-1-oxy)]benzoyl}benzamido-4-(1H-indazole-6-carboxamido)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.1%
With 2-(7-azobenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
HATU (2.67 g, 7.01 mmol) was added to a solution of intermediate (17-02H) (3.50 g, 6.37 mmol), intermediate(13) (1.14 g, 7.01 mmol) and DIPEA (2.47 g, 19.11 mmol) in DMF (50 mL) which was cooled to 0°C. The reaction mixture was stirred overnight at room temperature before distilled water (100 mL) was added, and was extracted with ethylacetate (33100 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated ona silica gel column to obtain intermediate (18-02H) as a light yellow solid (3.76 g, yield: 85.1percent).MASS (ESI+) m/z = 694 (M+H)+.
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-oxy)]benzoyl }benzamido-4-(1H-indazole-6-carboxamido)pyrrolidine hydrochloride[ No CAS ]
(3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)benzoyl]benzamido}pyrrolidine-1-carboxylate tert-butyl ester[ No CAS ]
[ 704-91-6 ]
(3R,4R)-3-{4-[2,3-difluoro-6-(2,5,8,14,17,20-heptaoxadocosan-22-oxy)]benzoyl}benzamido-4-(1H-indazole-6-carboxamido)pyrrolidine hydrochloride[ No CAS ]
tert-butyl (3R,4R)-3-amino-4-{4-[2,3-difluoro-6-(3,6-dioxanonan-1-oxy)]benzoyl}benzamidopyrrolidine-1-carboxylate[ No CAS ]
[ 704-91-6 ]
tert-butyl (3R,4R)-3-{4-[2,3-difluoro-6-(3,6-dioxanonan-1-oxy)]benzoyl}benzamido-4-(1H-indazole-6-carboxamido)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.1%
With 2-(7-azobenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃;
HATU (2.67 g, 7.01 mmol) was added to a solution of intermediate (17-02P) (3.77 g, 6.37 mmol), intermediate(13) (1.14 g, 7.01 mmol) and DIPEA (2.47 g, 19.11 mmol) in DMF (50 mL) which was cooled to 0°C. The reaction mixturewas stirred overnight at room temperature before distilled water (100 mL) was added, and was extracted with ethylacetate (33100 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated ona silica gel column to obtain intermediate (18-02H) as a light yellow solid (4.13 g, yield: 88.1percent).MASS (ESI+) m/z = 736 (M+H)+,
With 3-Methylpyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 36h;
2-Chloro-1H-indole-6-carboxylic acid (1.95 g, 10 mmol) and p-methylbenzoylhydrazone(1.5 g, 10 mmol) was suspended in 40 mL of tetrahydrofuran,Then add EDC (3.2g),HOBt (2.1g) and 3-methyl pyridine (3.5mL),After stirring for 24 hours at room temperature,filter,The cake was washed with tetrahydrofuran to give an off-white solid.After drying, 3.05 g of dihydrazide was obtained.Used in the next step without purification.Referring to the method shown in Example 1, wherein "2-chloro-1H-indole-6-carboxylic acid" is replaced with <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong>.In this embodiment,1H- indazol-6-carboxylic acid (1.62g, 10mmol),p-Methylbenzoylhydrazone (1.5g, 10mmol),Stir the reaction at room temperature for 36 hours.After drying, 2.53 g of dihydrazide was obtained.In step b,Burgess reagent (3.1g),Raise the temperature and reflux for 3 hours.Recrystallization from anhydrous ethanol gave compound 1-4 (2.13 g) as a white solid product.Yield 90percent.
ethyl (S)-2-amino-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoate bis hydrochloride[ No CAS ]
[ 704-91-6 ]
ethyl (2S)-2-(1H-indazol-6-carbonylamino)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 2h;
Ethyl (S)-2-amino-9-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)nonanoate bis-HCl salt (50 mg, 0.123 mmol), <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (24 mg, 0.147 mmol), HATU (70 mg, 0.184 mmol) and N,N-diisopropylethylamine (75 uL, 0.43 mmol) were stirred in THF (5 mL) at room temperature for two hours. The reaction mixture was evaporated and purified by combiflash chromatography (2.0 M NH3-MeOH in DCM = 0-30percent) to give ethyl (2S)-2-(1H-indazole-6-carbonylamino)-9-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)nonanoate (35 mg, 59percent). LCMS [M+H+]: 478.3.
2-(4-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-3-one[ No CAS ]
[ 704-91-6 ]
8-(1H-indazole-6-carbonyl)-2-(4-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 40℃; for 20h;
General procedure: A mixture of intermediates 4a-e (0.60 mmol), EDCI (138 mg,0.72 mmol), corresponding carboxylic acid derivatives (0.60 mmol)and HOBt (97 mg, 0.72 mmol) in N,N-dimethylformamide (6.0 mL)was stirred for 20 h. The reaction mixture was diluted with ethylacetate and washed with brine, the organic layer was dried over magnesium sulfate and concentration in vacuo. The residue waspurified by silica gel column chromatography (5percent methanol/chloroform)to afford the title compounds 6a-t as a white solid.
Chemistry
Pharmaceutical Intermediates
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Material Science
For Research Only
110K+ Compounds
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