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CAS No. : | 98434-06-1 | MDL No. : | MFCD04113954 |
Formula : | C8H5NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MLWFYCMVBAIITM-UHFFFAOYSA-N |
M.W : | 179.13 | Pubchem ID : | 1090982 |
Synonyms : |
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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 |
---|---|---|
90% | Stage #1: With lithium hydroxide; water In tetrahydrofuran; methanol for 15 h; Stage #2: With hydrogenchloride In water |
To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (4.14 g) inTHF(130 mL) and methanol (25 mL) was slowly added IN lithiun hydroxide aqueous solution (80 mL). The resulting mixture was stirred for 15 hours, and then concentrated under reduced pressure. The remaining solution was acidified with IN hydrochloric acid to form a solid, and the solid was filtered, washed with distilled water, dried to give 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid (yield: 90 percent) as a white solid.[178] .H-NMR(acetone-d , 200MHz), ppm(δ): 7.90~7.86(m, IH), 7.19(d, IH), 7.00(s, IH), 6.77-6.73(1H IH) |
90% | Stage #1: With lithium hydroxide; water In tetrahydrofuran; methanol for 15 h; Stage #2: With hydrogenchloride In water |
4.14 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester was dissolved in 130 mL of THF 130 mL and 25 mL of methanol before the slow addition of 80 mL of aqueous 1N lithium hydroxide. Stirring for 15 hrs was followed by the removal of THF and methanol under reduced pressure. The residue was acidified with 1N HCl to produce a precipitate which was then filtered, washed with distilled water and dried to produce 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid as a white solid (Yield: 90percent). 1H-NMR (acetone-d6, 200 MHz), ppm(δ): 7.90~7.86 (m, 1H), 7.19 (d, 1H), 7.00 (s, 1H), 6.77~6.73 (m, 1H) |
90% | Stage #1: With lithium hydroxide; water In tetrahydrofuran; methanol for 15 h; Stage #2: With hydrogenchloride In water |
3) Step 3 : Preparation of 5-furan-2-yl-isoxazole-3-carboxylic acid4.14 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester was dissolved in 130 mL of THF 130 mL and 25 mL of methanol before the slow addition of 80 mL of aqueous IN lithium hydroxide. Stirring for 15 hrs was followed by the removal of THF and methanol under reduced pressure. The residue was acidified with IN HCl to produce a precipitate which was then filtered, washed with distilled water and dried to produce 3.22 g of 5-furan-2-yl-isoxazole-3- carboxylic acid as a white solid (Yield: 90 percent).IH-NMR (acetone-ds, 200MHz), ppm(δ): 7.90~7.86(m, IH), 7.19(d, IH), 7.00(s, IH), 6.77~6.73(m, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (4.14 g) inTHF(130 mL) and methanol (25 mL) was slowly added IN lithiun hydroxide aqueous solution (80 mL). The resulting mixture was stirred for 15 hours, and then concentrated under reduced pressure. The remaining solution was acidified with IN hydrochloric acid to form a solid, and the solid was filtered, washed with distilled water, dried to give 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid (yield: 90 %) as a white solid.[178] .H-NMR(acetone-d , 200MHz), ppm(delta): 7.90~7.86(m, IH), 7.19(d, IH), 7.00(s, IH), 6.77-6.73(1H IH) | |
90% | 4.14 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester was dissolved in 130 mL of THF 130 mL and 25 mL of methanol before the slow addition of 80 mL of aqueous 1N lithium hydroxide. Stirring for 15 hrs was followed by the removal of THF and methanol under reduced pressure. The residue was acidified with 1N HCl to produce a precipitate which was then filtered, washed with distilled water and dried to produce 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid as a white solid (Yield: 90%). 1H-NMR (acetone-d6, 200 MHz), ppm(delta): 7.90~7.86 (m, 1H), 7.19 (d, 1H), 7.00 (s, 1H), 6.77~6.73 (m, 1H) | |
90% | 3) Step 3 : Preparation of 5-furan-2-yl-isoxazole-3-carboxylic acid4.14 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester was dissolved in 130 mL of THF 130 mL and 25 mL of methanol before the slow addition of 80 mL of aqueous IN lithium hydroxide. Stirring for 15 hrs was followed by the removal of THF and methanol under reduced pressure. The residue was acidified with IN HCl to produce a precipitate which was then filtered, washed with distilled water and dried to produce 3.22 g of 5-furan-2-yl-isoxazole-3- carboxylic acid as a white solid (Yield: 90 %).IH-NMR (acetone-ds, 200MHz), ppm(delta): 7.90~7.86(m, IH), 7.19(d, IH), 7.00(s, IH), 6.77~6.73(m, IH) |
225 mg | With water; lithium hydroxide; In tetrahydrofuran; methanol; for 16h; | To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (0.5 g, 2.41 mmol) in THF (30 mL) and methanol (6 mL) was slowly added in lithium hydroxide aqueous solution (10 mL). The resulting mixture was stirred for 16 hrs. THF was concentrated under reduced pressure. The resulting residue was acidified with 1N HC1 and extracted with ethyl acetate (3 X 100 mL). Combined organic extracts were washed with distilled water, dried over anhydrous NaSCf and concentrated under reduced pressure to obtain 5-furan-2-yl-isoxazole-3-carboxylic acid (225 mg, 52 % as white solid). LCMS: 180 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of S-furan-l-yl-isoxazole-S-carboxylic acid(7 retag) and3-imidazol-l-yl-propylamine(0.005 mL) in DMF were added HOBt(8 retag), EDC(9 mg) and TEA(OOl 4 mL). The resulting solution was stirred at a room temperature for 18 hours, and then concentrated under reduced pressure. The resulting concentrate was purified with preparative HPLC to give 4 mg of S-furan-l-yl-isoxazole-S-carboxylic acid (3-imidazol-l-yl-propyl)-amide (yield: 35 %).[182] lH-NMR(acetone-d , 200MHz), ppm(delta): 8.16(bs, IH), 7.86~7.84(m, IH),7.65~7.61(m, IH), 7.19-7.12(m, 2H), 6.97-6.8^m, 2H), 6.78~6.71(m, IH), 4.18(t, 2H), 3.48(q, 2H), 2.24-2.07 (m, 2H) Exact Mass (calc): 286.11 LC-MS ESI+) m/e (M+ 1)+ : 287 |
35% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> (7 mg) and 3-imidazol-1-yl-propyl amine (0.005 mL) in DMF was added 8 mg of HOBt, 9 mg of EDC and 0.014 mL of TEA. After stirring at room temperature for 18 hrs, the reaction solution was concentrated in vacuo. The obtained concentrate was purified by preparative HPLC to afford 4 mg of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> (3-imidazol-1-yl-propyl)-amide (Yield: 35%). 1H-NMR (acetone-d6, 200 MHz), ppm(delta): 8.16 (bs, 1H), 7.86~7.84 (m, 1H), 7.65~7.61 (m, 1H), 7.19~7.12 (m, 2H), 6.97~6.89 (m, 2H), 6.78~6.71 (m, 1H), 4.18 (t, 2H), 3.48 (q, 2H), 2.24~2.07 (m, 2H) Exact Mass (calc.): 286.11 LC-MS (ESI+) m/e (M+1)+: 287. |
35% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4) Step 4: Preparation of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> (3-imidazol-l-yl- propyl)-amide (Derivative (I))To a solution of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong>(7 mg) and 3-imidazol-l-yl- propyl amine(0.005mL) in DMF was added 8mg of HOBt, 9mg of EDC and 0.014mL of TEA.After stirring at room temperature for 18 hrs, the reaction solution was concentrated in vacuo. The obtained concentrate was purified by preparative HPLC to afford 4 mg of 5-furan-2-yl- <n="37"/>isoxazole-3-carboxylic acid (3-imidazol-l-yl-propyl)-amide (Yield: 35 %). lH-NMR(acetone-d6, 200MHz), ppm(delta): 8.16(bs, IH), 7.86~7.84(m, IH), 7.65~7.61(m, IH), 7.19~7.12(m, 2H), 6.97~6.89(m, 2H), 6.78~6.71(m, IH), 4.18(t, 2H), 3.48(q, 2H), 2.24~2.07(m, 2H) Exact Mass (calc): 286.11 LC-MS (ESI+) m/e (M+l)+ : 287 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | To a solution of 2.0 g of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> and 6.2 mL of TEA in benzene was added 3.61 mL of DPPA at room temperature. After refluxing for 1.5 hrs, 30 mL of distilled water was added and then the resulting solution was refluxed for an additional 30 min. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel to obtain 0.6 g of 5-furan-2-yl-isoxazol-3-ylamine (Yield: 40%). NMR (acetone-d6, 200 MHz), ppm(delta): 7.75~7.73 (m, 1H), 6.91~6.88 (m, 1H), 6.66~6.61 (m, 1H), 6.15 (s, 1H), 5.18 (br s, 2H) | |
40% | With diphenyl phosphoryl azide; triethylamine; In benzene; at 20℃; for 1.5h;Heating / reflux; | 1 ) Step 1 : Preparation of 5-furan-2-yl-isoxazol-3-ylamineTo a solution of 2.0 g of S-furan^-yl-isoxazole-S-carboxylic acid and 6.2 mL of TEA in benzene was added 3.61 mL of DPPA at room temperature. After refluxing for 1.5 hrs, 30 mL of distilled water was added and then the resuting solution was refluxed for an additional 30 min. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel to obtain 0.6 g of 5-furan-2-yl-isoxazol-3-ylamine (Yield: 40%).NMR (acetone-dfo 200MHz), ppm(delta): 7.75~7.73(m, IH), 6.91~6.88(m, IH), 6.66~6.61(m, IH), 6.15(s, IH), 5.18(br s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | A solution of <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> (CAS 98434-06-1) (77.3 mg, 0.42 mmol) in methanol (2 ml) was cooled to 0 C. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) (135 mg, 0.46 mmol) was added and the mixture stirred at 0 C. for 10 minutes. Thereafter, a solution of (RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (85 mg, 0.38 mmol) in methanol (1 ml) was added and the reaction mixture stirred at 0 C. for 2 hours, then kept at 4 C. for 16 hours. For the workup, the reaction mixture was treated at 0 C. with sodium hydroxide (1 N, 6 ml). The yellow suspension was extracted with ethyl acetate (15 ml), then the aqueous layer re-extracted with ethyl acetate (10 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on a Silicycle-Si-amine phase using a gradient of dichloromethane and methanol=100/0 to 90/10 the <strong>[98434-06-1]5-furan-2-yl-isoxazole-3-carboxylic acid</strong> [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide was obtained as a white sold (16 mg, 11% of theory). Mass (calculated) C19H17FN4O4 [384.365]; (found) [M+H]+=385. | |
11% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 0 - 4℃; for 18h; | A solution of S-furan^-yl-isoxazole-S-carboxylic acid (CAS 98434-06-1) (77.3 mg, 0.42 mmol) in methanol (2 ml) was cooled to 0 0C. 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride hydrate (DMTMM) (135 mg, 0.46 mmol) was added and the mixture stirred at 0 0C for 10 minutes. Thereafter, a solution of (7?5J-5-(5-amino-2-fluoro- phenyl)-5-methyl-5,6-dihydro-2H-[l,4]oxazin-3-ylamine (85 mg, 0.38 mmol) in methanol (1 ml) was added and the reaction mixture stirred at 0 0C for 2 hours, then kept at 4 0C for 16 hours. For the workup, the reaction mixture was treated at 0 0C with sodium hydroxide (1 N, 6 ml). The yellow suspension was extracted with ethyl acetate (15 ml), then the aqueous layer re-extracted with ethyl acetate (10 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on a Silicycle-Si-amine phase using a gradient of dichloromethane and methanol = 100/0 to 90/10 the 5-falpharan-2-yl-isoxazole-3- carboxylic acid [3 -((RS) -5 -amino-3 -methyl- 3 ,6-dihydro-2H-[ 1 ,4]oxazin-3 -yl)-4-fluoro-phenyl] - amide was obtained as a white sold (16 mg, 11% of theory). Mass (calculated) C19Eta17FN4O4 [384.365]; (found) [M+H]+ = 385 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 18℃; for 1h;Inert atmosphere; | Step 3: Preparation of 5-(2-furyl)-N-[1-[[2-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]isoxazole-3-carboxamide A mixture of 1-[[2-(trifluoromethyl)phenyl]methyl]pyrazol-4-amine (0.108 g, 0.447 mmol), 5-(2-furyl)isoxazole-3-carboxylic acid (0.080 g, 447 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.203 g, 0.536 mmol) and diisopropylethylamine (0.233 mL, 1.34 mmol) in N,N-dimethylformamide (2 mL) was purged with nitrogen (3*). The reaction mixture was stirred at 18 C. for 1 h under nitrogen. The residue was purified by prep-HPLC (Agela Durashell C18 150*25 5 um column; 45-95% acetonitrile in an a 0.04% ammonium hydroxide, 12 min gradient) to afford 5-(2-furyl)-N-[1-[[2-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]isoxazole-3-carboxamide (0.088 g, 0.217 mmol, 49%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.55 (br. s, 1H), 8.07 (s, 1H), 7.72-7.66 (m, 2H), 7.60 (s, 1H), 7.53-7.45 (m, 1H), 7.44-7.36 (m, 1H), 7.05-6.96 (m, 2H), 6.92 (s, 1H), 6.58 (dd, J=2.0, 3.4 Hz, 1H), 5.54 (s, 2H); LCMS (ESI) m/z: 403.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: To a solution of aryl or alkyl acid (1 equiv) in CH2Cl2 (10 mL), was added oxalyl chloride (2.5 equiv) and DMF (0.01 equiv) at 0C and then stirring for 2h. To the resulting solid were added THF (10 mL) and 20 (1.2 equiv) after concentrating under reduced pressure, subsequent cooling to -10C, DIPEA (2.5 equiv) was added dropwise, and the reaction proceed for 3 h. The mixture was added H2O and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM=30/1) to afford the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: To a solution of 5-propylisoxazole-3-carboxylic acid (58mg, 0.375mmol) and methyl ((4-aminophenyl)sulfonyl)-l-prolinate 10 (70mg, 0.25mmol) in 5mL of DCM, HBTU (284mg, 0.75mmol) and DIPEA (220muL, 1.25mmol) were added. After stirring at rt. overnight, the mixture was extracted with DCM (20mL×3). The organic layer was washed with 1N NaHSO4 (aq.), saturated NaHCO3 (aq.), brine and dried over anhydrous Na2SO4. The resulting solution was evaporated, and the residue was purified by PTLC (DCM/MeOH=40/1) to give the desired product 11 (40mg, 38%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Example 104. Preparation of [5-(2-furyl)isoxazol-3-yl]-(3-phenoxyazetidin-1-yl)methanone (206) To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.120 g, 0.67 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (0.305 g, 0.80 mmol) in N,N'-dimethylformamide (3 mL) was added diisopropylethylamine (260 mg, 2.01 mmol) and 3-phenoxyazetidine hydrochloride salt (137 mg, 0.74 mmol). The mixture was stirred at 15 C. for 2 h. The mixture was purified by prep-HPLC (Waters X bridge 150*25 5 uM column; 35-65% acetonitrile in a 10 mM ammonium acetate solution in water, 11 min gradient) to afford [5-(2-furyl)isoxazol-3-yl]-(3-phenoxyazetidin-1-yl)methanone (52 mg, 0.17 mmol, 25%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 7.58 (s, 1H), 7.32 (t, J=7.9 Hz, 2H), 7.05-7.00 (m, 1H), 6.95 (d, J=3.5 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J=7.9 Hz, 2H), 6.56 (dd, J=1.8, 3.5 Hz, 1H), 5.08-4.97 (m, 2H), 4.66-4.58 (m, 2H), 4.30 (dd, J=4.2, 11.2 Hz, 1H); LCMS (ESI) m/z: 311.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | To stirred solution of 5-(furan-2-yl)isoxazole-3- carboxylic acid (lOOmg, 0.558mmol,l equiv) in DMF (lOml) add HATU (233 mg, 0.6l3mmol, 1.1 equiv) and stirred for half hours then add l-(3,5-bis(trifluoromethyl)-lH- pyrazol-4-amine (l72 mg, 0.558mmol, 1 equiv) and DIEA in it. Stirred reaction mixture for overnight at room temperature. Reaction monitored by LCMS. Reaction mixture was diluted with ethyl acetate (30 mL) and washed with water(50 mL). The organic layer dried over anhydrous sodium sulphate & concentrate to get crude product which is purified by stritulation using Isopropyl Alcohol (12 mg white solid). 'H NMR (400 MHz, DMSO-ri6) d ppm 5.56 (s, 2 H) 7.16 (s, 1H) 7.29 (d,.7=3.51Hz, 1H) 7.72 (s, 2 H) 7.95 (s, 2 H) 8.01 (s, 1H) 8.08 (br. s., 1H) 8.33 (s, 1H) 11.06 (s, 1H). LCMS: 471 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | To a solution 5-(furan-2-yl)isoxazole-3- carboxylic acid (100 mg, 0.558mmol, 1 equiv) in DMF (1 mL), were added HATU (212.8 mg, 0.558 mmol, 1 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with DIPEA (216.2 mg, 1.67 mmol, 3 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with a solution of the l-(2,4-bis(trifluoromethyl)phenyl)-3- methyl-lH-pyrazol-4-amine hydrochloride (192.7 mg, 0.558 mmol, 1 equiv) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. The reaction mixture was diluted water (50 mL).The resulting precipitate was filtered off. The crude material was purified by trituration with hexane (15 mg). LCMS: 471 [M+H] +. 'H NMR (400 MHz, DMSO-rir,) d 10.56 (s, 1H), 8.42 (s, 1H), 8.28 - 8.20 (m, 2H), 8.01 (d, J= 1.8 Hz,IH), 7.91 (d, = 8.3 Hz, 1H), 7.29 (d,.7= 3.6 Hz, 1H), 7.21 (s, 1H), 6.78 (dd, J= 3.5, 1.8 Hz, 1H), 2.3l(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | To a solution of 5-(furan-2- yl)isoxazole-3 -carboxylic acid (49.8 mg, 0.278 mmol, 1 equiv) in DMF (1 mL), were added HATU (106 mg, 0.278 mmol, 1 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with DIPEA (107.7 mg, 0.835 mmol, 3 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with a solution of the l-(2,4- bis(trifluoromethyl)benzyl)-3-methyl-lH-pyrazol-4-amine hydrochloride (100 mg, 0.278 mmol, 1 equiv) in DMF (1 mL). The reaction mixture was kept under stirring for 24 hrs. The reaction mixture was diluted water (50 mL).The resulting precipitate was filtered off and the solid was purified by trituration with hexane to yield the title compound as freee base (30 mg). LCMS: 485 [M+H] +. XH NMR (400 MHz, DMSO-ri6) d 10.36 (s, 1H), 8.12 - 8.04 (m, 2H), 8.01 (d,.7= 1.6 Hz, 1H), 7.74 (s,lH), 7.28 (d,.7= 3.6 Hz, 1H), 7.17 (s, 1H), 6.84 (d, = 8.2 Hz, 1H), 6.78 (dd, J= 3.5, 1.8 Hz, 1H), 5.58(s, 2H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | To a solution of 5- (furan-2-yl)isoxazole-3-carboxylic acid (49.8 mg, 0.278 mmol, 1 equiv) in DMF (1 mL), were added HATU (106 mg, 0.278 mmol, 1 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with DIPEA (107.7 mg, 0.835 mmol, 3 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with a solution of the l-(2,4- bis(trifluoromethyl)benzyl)-5-methyl-lH-pyrazol-4-amine hydrochloride (100 mg, 0.278 mmol, 1 equiv) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. The reaction mixture was diluted water (50 mL). The reaction mixture was kept under stirring for 24 hrs. The reaction mixture was diluted water (50 mL).The resulting precipitate was filtered off and the solid was purified by trituration with isopropyl alcohol to yield the title compound as freee base (20 mg). LCMS: 485 [M+H] +. 'H NMR (400 MHz, DMSO-ri6) d 10.37 (s, 1H), 8.21 (s, 1H), 8.09 (d, J= 9.5 Hz, 2H), 8.01 (s, 1H), 7.28(d, J= 3.6 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J= 8.2 Hz, 1H), 6.83 - 6.74 (m, 1H), 5.57 (s, 2H), 2.19 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | To a solution of 5-furan-2-yl-isoxazole-3- carboxylic acid (200 mg, 1.11 mmol, 1 equiv) in DMF (1 mL), were added HATU (467 mg, 1.22 mmol, 1.1 equiv). The mixture was treated drop wise with DIPEA (461 mg, 3.57 mmol, 3.2 equiv). After stirring at RT for l5minutes, the mixture was treated drop wise with a solution of the l-{l[2,4bis(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-amine (360 mg, 1.11 mmol, 1 equiv) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. Product formation was confirmed with TLC & LCMS and reaction mixture was diluted EtOAc (50 mL) & washed with water (50 mL X 2). Organic layer dried over Na2S04 & concentrated under reduced pressure to obtain crude which was further purified by flash column chromatography to obtain pure product /V-(l-(l -(2,4- bis(trifluoromethyl)phenyl)ethyl)-lH-pyra/ol-4-yl)-5-(thiophen-2-yl)isoxa/ole-3- carboxamide. (70 mg, 28% as off white solid) ' H NMR (400 MHz, DMSO-d6) d 11.04 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.89(d, J = 5.0 Hz, 1H), 7.84 (d, J = 3.7 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.32 - 7.21 (m, 1H), 5.93 (q, J =6.9 Hz, 1H), 1.87 (d, J = 6.9 Hz, 3H). LCMS: 501 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | To a solution of 5-(furan-2- yl)isoxazole-3 -carboxylic acid (200 mg, 1.11 mmol, 1 eq) in DMF (1 mL), were added HATU (467 mg, 1.22 mmol, 1.1 eq). The mixture was treated drop wise with DIPEA (461 mg, 3.57 mmol, 3.2 eq). After stirring at RT for l5minutes, the mixture was treated drop wise with a solution of the l-{l[2,4bis(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-amine (360 mg, 1.11 mmol, 1 eq) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. Product formation was confirmed with TLC & LCMS and reaction mixture was diluted EtOAc (50 mL) & washed with water (50 mL X 2). Organic layer dried over Na2S04 & concentrated under reduced pressure to obtain crude which was further purified by flash column chromatography to obtain pure product A-(1 -(1 -(2.4- bis(trifluoromethyl)phenyl)ethyl)-lH-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. (150 mg, 27% as off white solid). LCMS: 484 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a stirred solution of 5-(furan-2-yl) isoxazole- 3-carboxylic acid (200 mg, leq, 1.111 mmole), HATU (423.33 mg, 1.111 mmole, and leq) and DIPEA (430 mg, 3eq, and 3.33 mmole) in 5 ml of DMF at RT was added l-(2,3-dihydro- lH-inden-l-yl)-lH-pyrazol-4-amine hydrochloride (393.33 mg, leq, 1.111 mmole). Resulting reaction mixture was stirred at RT for 24 hr. Reaction mixture was diluted with water and extracted with ethyl acetate, organic layer dried over anhydrous sodium suplahte, concentrated under vacuum to obtain crude which was triturated with IP A: Hexane (1:9) to obtain N-(l-(2, 3-dihydro-lH-inden-l-yl)-lH-pyrazol-4-yl)-5-(furan-2-yl) isoxazole-3- carboxamide. LCMS: 360 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | [0333] To a solution of 5 -(furan-2-yl)isoxazole-3 -carboxylic acid (100 mg, 0.55 mmol, 1 equiv) in DMF (1 mL), were added HATU (233 mg, 0.61 mmol, 1.1 equiv). The mixture was treated drop wise with DIPEA (230 mg, 1.78 mmol, 3.2 equiv). After stirring at RT for 15 minutes, the mixture was treated drop wise with a solution of the 4-((4-amino-lH-pyrazol-l- yl)methyl)benzonitrile (110 mg, 0.55 mmol, 1 equiv) in DMF (1 mL). The reaction mixture was kept under stirring for 24 at RT. Product formation was confirmed with TLC & LCMS and reaction mixture was diluted EtOAc (50 mL) & washed with water (50 mL X 2). Organic layer dried over Na2S04 & concentrated under reduced pressure to obtain crude The crude product which was purified by prep purification to obtain solid N-(l-(4-cyanobenzyl)-lH- pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. (30 mg, 18% as off white solid). 'H NMR (400 MHz, DMSO-ri6) d 11.06 (s, 1H), 8.25 (s, 1H), 8.00 (d, J= 1.8 Hz, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.70 (s, 1H), 7.36 (d, = 8.0 Hz, 1H), 7.29 (d, = 3.5 Hz, 1H), 7.16 (s, 1H), 6.77 (dd, J= 3.4, 1.8 Hz, 1H), 5.46 (s, 2H), 2.92 (q, J= 7.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To stirred solution of 5-(furan-2-yl)isoxazole-3- carboxylic acid (200 mg, 0.647 mmol,l equiv) in DMF (10 ml) add HATU (270 mg, 0.7l lmmol, 1.1 equiv) was added DIPEA (267 mg, 2.07 mmol, 3.2 equiv). After Stirling at RT for 15 minutes, then add 1 -(2, 4-bis(trifluoromethyl)benzyl)-lH-imidazol -4-amine (115 mg, 0.647 mmol,l equiv). Stirred reaction mixture for overnight at room temperature. Reaction monitored by LCMS. Reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (50 mL). The organic layer dried over anhydrous sodium sulphate & concentrate to get crude product which is purified by using column chromatography (100 mg, 32% as white solid). 1H NMR (400MHz, DMSO-d6) d = 11.21 (br. s., 1H), 8.17 - 8.05 (m, 2 H), 8.00 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.24 (br. s., 3 H), 6.76 (br. s., 1H), 5.57 (br. s., 2 H). LCMS: 471 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-(furan-2-yl) isoxazole-3-carboxylic acid (200 mg, leq, l. H7mmole) was taken in 5 mL of DMF. To it, HATU (424.5 mg, l. H7mmole, and leq) was added. To it DIPEA (0.288 mg. 2eq, and 2.234 m mole) was added. Reaction mixture was kept under stirring for 20 min. To it, l-(2, 3-dihydro-lH-inden-2-yl)-lH- pyrazol-4-amine (222.3, leq, l. H7mmole) was added. Resulting reaction mixture was kept under stirring for 24 hr. Work up was done by Adding water and recovered with ethyl acetate.Crude was triturated with IPA : Hexane (1 :9) kept stirring overnight and filtered. Residue obtained as product N-(l -(2, 3-dihydro-lH-inden-2-yl)-lH-pyrazol-4-yl)-5-(furan-2-yl) isoxazole-3-carboxamide. XH NMR (400 MHz, DMSO-r/6) d 10.98 (s, 1H), 8.01 (d, J= 7.5 Hz, 2H), 7.66 (s, 1H), 7.31 - 7.12 (m,6H), 6.77 (dd, J= 3.4, 1.8 Hz, 1H), 5.29 - 5.17 (m, 1H), 3.43 (dd, J= 16.2, 7.8 Hz, 2H), 3.27 (dd,.7=16.1, 5.9 Hz, 2H). LCMS: 360 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-(furan-2-yl) isoxazole-3 -carboxylic acid (lOOmg, leq, 0.502 m mole) was taken in 5 ml of DMF. To it HATU (l90.9 mg, 0.502mmole, and leq) was added. To it DIPEA (0. l7ml, 2eq, and 1.005 m mole) was added. Reaction mixture was kept under stirring for 20 min. To it l-(2, 3-dihydro-lH-inden-l-yl)-lH-pyrazol-4-amine (4) (89.9 mg, leq, 0.502 m mole) was added. Resulting reaction mixture was kept under stirring for 24 hr. Work up was done by adding water and recovered with ethyl acetate. Crude was triturated with IP A: Hexane (1:9) kept stirring overnight and filtered. Residue obtained as product N-(l -(2, 3-dihydro-lH-inden-l-yl)-lH-pyrazol-4-yl)-5-(furan-2-yl) isoxazole-3- carboxamide. *H NMR (400 MHz, DMSO-ri6) d 11.01 (s, 1H), 8.01 (d, J= 4.3 Hz, 2H), 7.67 (s, 1H), 7.35 (d, J= 7.6Hz, 1H), 7.32 - 7.24 (m, 2H), 7.19 (t, J= 7.4 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J= 7.5 Hz, 1H), 6.80 - 6.74(m, 1H), 5.92 (t, = 7.1Hz, 1H), 3.12 (ddd, J= 14.6, 8.7, 5.1Hz, 1H), 2.93 (dt, J= 15.7, 7.5 Hz, lH),2.6l (dtd, J= 13.1, 8.2, 5.1Hz, 1H), 2.35 (dq, J= 13.4, 6.6 Hz, 1H). LCMS: 360 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-(furan-2-yl) isoxazole-3-carboxylic acid (lOOmg, leq, 0.558 m mole) was taken in 3 ml of DMF. To it HATU (212.8 mg, 0.558 m mole, and leq) was added. To it DIPEA (l44T3 mg, 2eq, and 1.117 m mole) was added. Reaction mixture was kept under stirring for 20 min. To it l-(2, 6-dichlorobenzyl)-lH-pyrazol-4-amine.HCl (186.3 mg, 1.2 eq, 0.670mmole) was added. Resulting reaction mixture was kept under stirring for 24 hr. Work up was done by adding water and recovered with ethyl acetate. And resulting crude was purified by PREP. Obtained product was N-(l-(2, 6-dichlorobenzyl)-lH-pyrazol- 4-yl)-5-(furan-2-yl) isoxazole-3-carboxamide. ' H NMR (400 MHz, DMSO-<76) d 11.00 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 7.56 (d, J= 8.1Hz, 2H), 7.45 (t, J= 8.1Hz, 1H), 7.28 (d, J= 3.5 Hz, 1H), 7.13 (s, 1H), 6.77 (dd, J= 3.4, 1.8 Hz, lH),5.55 (s, 2H), 5.32 (s, OH), 3.97 (s, OH), 1.23 (s, 1H), 0.89 - 0.81 (m, OH). LCMS: 402 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | To stirred solution of 5-(furan-2-yl)isoxazole- 3-carboxylic acid (lOOmg, 0.563mmol,l eq) in DMF (lOml) add HATU (235 mg, 0.619 mmol, 1.1 eq) and stirred for half hours then add 4-((4-amino-lH-pyrazol-l-yl)methyl)-2- (trifluoromethyl)benzonitrile (l50 mg, 0.563 mmol, 1 eq) and DIEA in it. Stirred reaction mixture for overnight at room temperature. Reaction monitored by LCMS. Reaction mixture was diluted with ethyl acetate(30 mL) and washed with water(50 mL). The organic layer dried over anhydrous sodium sulphate & concentrate to get product which is further purified by reversed phase chromatography. (10 mg white solid). 'H NMR (400 MHz, DMSO-ri6) d ppm 5.57 (s, 2 H) 6.78 (br. s., 1H) 7.17 (s, 1H) 7.29 (d,.7=3.51Hz, 2 H) 7.73 (s, 1H) 7.88 (s, 1H) 8.01 (s, 1H) 8.16 (d,.7=7.45 Hz, 1H) 8.31 (s, 1H) 11.09 (s, 1H). LCMS: 428 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | To stirred solution of 5-(furan-2-yl)isoxazole-3- carboxylic acid (60 mg, 0.338mmol, 1 eq) in DMF (lOml) add HATU (141 mg, 0.0.372mmol, 1.1 eq) and stirred for half hours then add l-(2,4-bis(trifluoromethyl)-lH-pyrazol-4-amine (lOOmg, 0.338mmol, 1 eq) and DIEA(0. l8 mL,l.08lmmol,3.2eq) in it. Stirred reaction mixture for overnight at room temperature. Reaction monitored by LCMS. Reaction mixture was diluted with ethyl acetate(30 mL) and washed with water(50 mL). The organic layer dried over anhydrous sodium sulphate & concentrate to get product (12 mg). 1H NMR (400 MHz, DMSO-r/e) d ppm 6.79 (br. s., 2 H) 7.21 (s, 2 H) 7.31 (br. s., 1H) 8.06 (s, 1H) 8.02 (s, 1H) 8.27 (br. s., 1H) 8.49 (br. s., 1H) 11.30 (br. s., 1H). LCMS: 457 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.126 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Step 3: Preparation of N-[1-[(3-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.100 g, 0.558 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.254 g, 0.670 mmol), 1-[(3-fluorophenyl)methyl]pyrazol-4-amine (0.117 g, 0.614 mmol) and diisopropylethylamine (292 mL, 1.67 mmol) at 15 C. The mixture was stirred at 15 C. for 2 h. The residue was purified by prep-HPLC (YMC-Actus Triart C18 100*30 mm*5 mum; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B %: 40%-60%, 12 min) to afford N-[1-[(3-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.126 g, 0.36 mmol, 64%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.60 (br. s, 1H), 8.08 (s, 1H), 7.61 (br. d, J=11.0 Hz, 2H), 7.38-7.28 (m, 1H), 7.12-6.81 (m, 5H), 6.58 (br. s, 1H), 5.30 (s, 2H); LCMS (ESI) m/z: 353.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.5 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 16h; | Step 3: Preparation of 5-(furan-2-yl)-N-(1-[4-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazol-4-yl)-1,2-oxazole-3-carboxamide To a solution of <strong>[98434-06-1]5-(furan-2-yl)-1,2-oxazole-3-carboxylic acid</strong> (0.05 g, 0.279 mmol), 1-[4-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazol-4-amine (67.5 mg, 0.279 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (106 mg, 0.279 mmol) in N,N'-dimethylformamide (1.1 mL) at 25 C. was added diisopropylethylamine (97.1 muL, 0.558 mmol) dropwise. The reaction mixture was stirred at 25 C. for 16 h. The reaction mixture was quenched with water (1 mL). The aqueous layer was extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (ISCO, 12 g silica, eluting with 0-80% ethyl acetate/hexanes for 20 min) to afford 5-(furan-2-yl)-N-(1-[4-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazol-4-yl)-1,2-oxazole-3-carboxamide (48.5 mg, 0.120 mmol, 50%) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) delta 8.77 (d, J=5.1 Hz, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.68 (d, J=0.7 Hz, 1H), 7.63-7.46 (m, 2H), 7.01 (dd, J=3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.59 (dd, J=3.5, 1.8 Hz, 1H), 5.56 (s, 2H); LCMS (ESI) m/z: 404.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.177 g; 0.04 g | A mixture of 1-[(3,4-dichlorophenyl)methyl]-3-methyl-pyrazol-4-amine (0.107 g, 0.419 mmol), 1-[(3,4-dichlorophenyl)methyl]-5-methyl-pyrazol-4-amine (0.214 g, 0.837 mmol), 5-(2-furyl)isoxazole-3-carboxylic acid (0.150 g, 838 mmol), diisopropylethylamine (438 mL, 2.51 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.381 g, 1.00 mmol) in N,N-dimethylformamide (3 mL) was purged with nitrogen (3*) and then the mixture was stirred at 18 C. for 2 hour under nitrogen. The reaction mixture was washed with water (10 mL) and then extracted with ethyl acetate (5 mL*2). The combined organic layers were washed with brine (5 mL*2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=7/3, then by prep-HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (0.04% ammonia)-acetonitrile]; B %: 35%-85%, 12 min) to produce firstly N-[1-[(3,4-dichlorophenyl)methyl]-3-methyl-pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.177 g, 0.409 mmol, 49%) as a brown solid. 1H NMR (400 MHz, Chloroform-d) delta=8.22 (s, 1H), 8.07 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.07 (dd, J=2.0, 8.4 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.92 (s, 1H), 6.59 (dd, J=1.6, 3.5 Hz, 1H), 5.19 (s, 2H), 2.33 (s, 3H); LCMS (ESI) m/z: 417.2 [M+H]+. and secondly N-[1-[(3,4-dichlorophenyl)methyl]-5-methyl-pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.040 g, 0.0957 mmol, 11%) as a white solid. 1H NMR (400 MHz, Chloroform-d) delta=8.07 (s, 1H), 7.83 (s, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.00 (d, J=3.2 Hz, 1H), 6.96 (dd, J=1.6, 8.3 Hz, 1H), 6.94 (s, 1H), 6.59 (dd, J=2.0, 3.3 Hz, 1H), 5.26 (s, 2H), 2.21 (s, 3H); LCMS (ESI) m/z: 417.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 12h; | Example 7. Preparation of N-(1-benzyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (4) The mixture of 5-(furan-2-yl)isoxazole-3-carboxylic acid (0.090 g, 0.502 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.191 g, 0.502 mmol) and diisopropylethylamine (0.176 mL, 1.00 mmol) in N,N-dimethylformamide (1 mL) at 0 C. was added <strong>[28466-62-8]1-benzyl-1H-pyrazol-4-amine</strong> (0.087 g, 0.502 mmol). The reaction mixture was stirred at 15 C. for 12 h. The residue was purified by prep-HPLC (column: Luna C8 100*30 5 u; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B %: 36%-66%, 12 min gradient) to give N-(1-benzyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (0.055 g, 0.162 mmol, 32%) as a pink solid. 1H NMR (400 MHz, Chloroform-d) delta 8.47 (br. s., 1H), 8.02 (s, 1H), 7.61 (d, J=6.6 Hz, 2H), 7.40-7.31 (m, 3H), 7.26 (br. s., 1H), 6.99 (d, J=3.5 Hz, 1H), 6.91 (s, 1H), 6.65-6.53 (m, 1H), 5.31 (s, 2H); LCMS (ESI) m/z: 335.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.083 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Step 3: Preparation of N-[1-[[5-fluoro-2-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.150 g, 0.837 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.381 g, 1.00 mmol), diisopropylethylamine (0.438 mL, 2.51 mmol), and 1-[[5-fluoro-2-(trifluoromethyl)phenyl]methyl]pyrazol-4-amine (0.239 g, 0.921 mmol) at 15 C. The mixture was stirred at 15 C. for 2 h. The residue was purified by prep-HPLC (YMC-Actus Triart C18 150*30 5 u; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B %: 50%-70%, 10 min) to give N-[1-[[5-fluoro-2-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.083 g, 0.20 mmol, 24%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.61 (s, 1H), 8.12 (s, 1H), 7.74-7.67 (m, 2H), 7.60 (d, J=1.1 Hz, 1H), 7.11-7.04 (m, 1H), 6.99 (d, J=3.5 Hz, 1H), 6.93 (s, 1H), 6.65 (dd, J=1.9, 9.4 Hz, 1H), 6.58 (dd, J=1.8, 3.5 Hz, 1H), 5.53 (s, 2H); LCMS (ESI) m/z: 421.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 18℃; for 2h;Inert atmosphere; | Step 3: Preparation of N-[1-[(2-chloro-5-fluoro-phenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide A mixture of 1-[(2-chloro-5-fluoro-phenyl)methyl]pyrazol-4-amine (0.101 g, 0.447 mmol), 5-(2-furyl)isoxazole-3-carboxylic acid (0.080 g, 447 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.203 g, 0.536 mmol) and diisopropylethylamine (0.233 mL, 1.34 mmol) in N,N-dimethylformamide (2 mL) was purged with nitrogen (3*) and then the mixture was stirred at 18 C. for 2 h under nitrogen. The residue was purified by prep-HPLC (Waters Xbridge C18 150*25 mm*5 um column; 37-67% acetonitrile in a 10 mM ammonium acetate solution in water, 11 min gradient) to give N-[1-[(2-chloro-5-fluoro-phenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.075 g, 0.192 mmol, 43%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta=8.58 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=5.2, 8.8 Hz, 1H), 7.05-6.95 (m, 2H), 6.93 (s, 1H), 6.69 (dd, J=3.2, 8.9 Hz, 1H), 6.58 (dd, J=1.6, 3.2 Hz, 1H), 5.41 (s, 2H); LCMS (ESI) m/z: 387.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.03 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Step 3: Preparation of 5-(2-furyl)-N-[1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]isoxazole-3-carboxamide To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.090 g, 0.502 mol) in N,N-dimethylformamide (2 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.286 g, 0.754 mmol), diisopropylethylamine (0.263 mL, 1.51 mmol), and 1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-amine (0.133 g, 0.553 mmol). The reaction mixture was stirred at 15 C. for 2 h. The crude residue was purified by prep-HPLC (YMC-Actus Triart C18 100*30 mm*5 um; 40-60% acetonitrile in a 10 mM ammonium acetate solution in water, 12 min gradient) to give 5-(2-furyl)-N-[1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]isoxazole-3-carboxamide (0.030 g, 0.073 mmol, 14%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.50 (br. s, 1H), 8.07 (s, 1H), 7.62 (s, 1H), 7.59-7.55 (m, 2H), 7.52-7.43 (m, 2H), 7.42-7.38 (m, 1H), 6.98 (d, J=3.3 Hz, 1H), 6.90 (s, 1H), 6.57 (dd, J=1.5, 3.3 Hz, 1H), 5.35 (s, 2H); LCMS (ESI) m/z: 403.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.077 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Step 3: Preparation of N-[1-[(4-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.090 g, 0.50 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.229 g, 0.60 mmol), 1-[(4-fluorophenyl)methyl]pyrazol-4-amine (0.106 g, 0.55 mmol), diisopropylethylamine (263 mL, 1.51 mmol) at 15 C. The mixture was stirred at 15 C. for 2 h. The mixture was purified by prep-HPLC (Waters X bridge 150*25 5 mum column; 30-65% acetonitrile in a 10 mM ammonium acetate solution in water, 10 min gradient) to give N-[1-[(4-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.077 g, 0.21 mmol, 43%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.51 (s, 1H), 8.04 (s, 1H), 7.60 (s, 2H), 7.27-7.23 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.99 (d, J=3.5 Hz, 1H), 6.91 (s, 1H), 6.58 (dd, J=1.8, 3.5 Hz, 1H), 5.27 (s, 2H); LCMS (ESI) m/z: 353.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.075 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Step 3: Preparation of N-[1-[(2-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.090 g, 0.50 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.229 g, 0.60 mmol), 1-[(2-fluorophenyl)methyl]pyrazol-4-amine (0.106 g, 0.56 mmol) and diisopropylethylamine (0.263 mL, 1.51 mmol) at 15 C. The mixture was stirred at 15 C. for 2 h. The mixture was purified by prep-HPLC (Waters X bridge 150*25 5 mum column; 35-65% acetonitrile in a 10 mM ammonium acetate solution in water, 10 min gradient) to give N-[1-[(2-fluorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.075 g, 0.21 mmol, 43%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 8.51 (s, 1H), 8.08 (s, 1H), 7.64-7.58 (m, 2H), 7.36-7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.15-7.07 (m, 2H), 6.99 (d, J=3.5 Hz, 1H), 6.92 (s, 1H), 6.58 (dd, J=1.8, 3.3 Hz, 1H), 5.37 (s, 2H); LCMS (ESI) m/z: 353.1 M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.045 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step 3: Preparation of N-[1-[(3-chlorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 1-[(3-chlorophenyl)methyl]pyrazol-4-amine (0.115 g, 0.554 mmol) in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (0.276 mL, 1.58 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.200 g, 0.527 mmol) and 5-(2-furyl)isoxazole-3-carboxylic acid (0.094 g, 0.527 mmol). The mixture was stirred at 20 C. for 16 h. The reaction mixture was filtered and purified by prep-HPLC (column: Agela Durashell C18 150*25 5 mum; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B %: 40%-75%, 12 min gradient) to afford N-[1-[(3-chlorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.0450 g, 0.122 mmol, 23%) as a white solid. 1H NMR (400 MHz, Chloroform-d) delta 8.55 (s, 1H), 8.06 (s, 1H), 7.65-7.55 (m, 2H), 7.31-7.26 (m, 2H), 7.22 (s, 1H), 7.16-7.08 (m, 1H), 6.98 (d, J=3.5 Hz, 1H), 6.91 (s, 1H), 6.57 (m, 1H), 5.27 (s, 2H); LCMS (ESI) m/z: 369.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.066 mg | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step 3: Preparation of -[1-[(2-chlorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a solution of 1-[(2-chlorophenyl)methyl]pyrazol-4-amine (0.150 g, 0.722 mmol) in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (359 mL, 2.06 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.261 g, 0.688 mmol) and 5-(2-furyl)isoxazole-3-carboxylic acid (0.123 g, 0.688 mmol). The mixture was stirred at 20 C. for 16 h. The reaction mixture was filtered. The crude residue was purified by prep-HPLC (Agela Durashell 150*25 5 mum column; 40-70% acetonitrile in a 10 mM ammonium bicarbonate solution in water, 12 min gradient) to afford N-[1-[(2-chlorophenyl)methyl]pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.066 mg, 0.180 mmol, 26%) as a white solid. 1H NMR (400 MHz, Chloroform-d) (8.53 (s, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=1.1 Hz, 1H), 7.40 (dd, J=1.7, 7.6 Hz, 1H), 7.28-7.22 (m, 2H), 7.06 (dd, J=1.8, 7.3 Hz, 1H), 6.98 (d, J=3.5 Hz, 1H), 6.91 (s, 1H), 6.58 (m, 1H), 5.43 (s, 2H); LCMS (ESI) m/z: 369.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 3h; | Step 3: Preparation of 5-(2-furyl)-N-[1-(4,4,4-trifluorobutyl)pyrazol-4-yl]isoxazole-3-carboxamide To a stirred solution of 1-(4,4,4-trifluorobutyl)pyrazol-4-amine (0.090 g, 0.466 mmol) and 5-(2-furyl)isoxazole-3-carboxylic acid (0.092 g, 0.513 mmol) in N,N-dimethylformamide (1 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.194 g, 0.513 mmol) and diisopropylethylamine (0.162 mL, 0.932 mmol) at 15 C. The reaction mixture was stirred at 15 C. for 3 h then purified by prep-HPLC (Agela Durashell C18 150*25 5 mum column; 20%-70% acetonitrile in an a 0.04% ammonium hydroxide, 12 min gradient). Then purified by prep-HPLC (YMC-Actus ODS-AQ 100*30 5 um column; 38%-68% acetonitrile in a 0.225% formic acid solution in water, 12 min gradient) to give 5-(2-furyl)-N-[1-(4,4,4-trifluorobutyl)pyrazol-4-yl]isoxazole-3-carboxamide (0.035 g, 0.099 mmol, 21%) as a white solid. 1H NMR (400 MHz, Chloroform-d) delta 8.55 (s, 1H), 8.06 (s, 1H), 7.62-7.56 (m, 2H), 6.99 (d, J=3.4 Hz, 1H), 6.93 (s, 1H), 6.58 (dd, J=1.8, 3.5 Hz, 1H), 4.20 (t, J=6.4 Hz, 2H), 2.22-2.03 (m, 4H); LCMS (ESI) m/z: 355.1[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 3h; | Step 3: Preparation of N-[1-(cyclohexylmethyl)pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide To a stirred solution of 1-(cyclohexylmethyl)pyrazol-4-amine (0.090 g, 0.502 mmol) and 5-(2-furyl)isoxazole-3-carboxylic acid (0.090 g, 0.502 mmol) in N,N-dimethylformamide (1 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.190 g, 0.502 mmol) and diisopropylethylamine (0.175 mL, 1.00 mmol) at 15 C., and then stirred at 15 C. for 3 h. The reaction mixture was purified directly by prep-HPLC (Agela Durashell C18 150*25 5 mum column; 40%-90% acetonitrile in an a 0.04% ammonium hydroxide, 12 min gradient) to give N-[1-(cyclohexylmethyl)pyrazol-4-yl]-5-(2-furyl)isoxazole-3-carboxamide (0.055 g, 0.160 mmol, 32%) as a white solid. 1H NMR (400 MHz, Chloroform-d) delta 8.50 (br. s, 1H), 7.99 (s, 1H), 7.62-7.53 (m, 2H), 6.99 (d, J=3.4 Hz, 1H), 6.92 (s, 1H), 6.57 (dd, J=1.7, 3.4 Hz, 1H), 3.93 (d, J=7.2 Hz, 2H), 1.89 (ttd, J=3.8, 7.4, 14.8 Hz, 1H), 1.76-1.61 (m, 5H), 1.30-1.10 (m, 3H), 1.05-0.91 (m, 2H); LCMS (ESI) m/z: 341.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 15℃; for 12h; | Step 1: Preparation of N-(1-(3,4-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide The mixture of <strong>[98434-06-1]5-(furan-2-yl)isoxazole-3-carboxylic acid</strong> (0.120 g, 0.669 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.254 g, 0.670 mmol) and diisopropylethylamine (0.234 g, 1.34 mmol) in N,N-dimethylformamide (1 mL) at 0 C. was added 1-(3,4-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (0.199 g, 0.737 mmol). The reaction mixture was stirred at 15 C. for 12 h. The residue was purified by prep-HPLC (column: Luna C8 100*30 5p; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; B %: 40%-65%, 12 min gradient) to give N-(1-(3,4-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (0.0963 g, 0.222 mmol, 33%) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 7.90 (s, 1H), 7.61 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J=3.5 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 6.59 (dd, J=1.8, 3.5 Hz, 1H), 5.18 (s, 2H), 2.24 (s, 3H), 2.15 (s, 3H); LCMS (ESI) m/z: 431.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 2h; | Example 98. Preparation of [5-(2-furyl)isoxazol-3-yl]-(3-phenylazetidin-1-yl)methanone (207) To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (140 mg, 0.78 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (356 mg, 0.94 mmol) in N,N'-dimethylformamide (3 mL) was added diisopropylethylamine (303 mg, 2.34 mmol) and 3-phenylazetidine hydrochloride (146 mg, 0.86 mmol). The mixture was stirred at 15 C. for 2 h. The mixture was purified by prep-HPLC (Waters X bridge 150*25 5 muM column; 35-70% acetonitrile in a 10 mM ammonium acetate solution in water, 10 min gradient) to afford [5-(2-furyl)isoxazol-3-yl]-(3-phenylazetidin-1-yl)methanone (0.086 g, 0.29 mmol, 37%) as a brown solid. 1H NMR (400 MHz, Chloroform-d) delta 7.59 (s, 1H), 7.41-7.35 (m, 4H), 7.31 (br. d, J=7.0 Hz, 1H), 6.95 (d, J=3.5 Hz, 1H), 6.89 (s, 1H), 6.56 (dd, J=1.8, 3.5 Hz, 1H), 5.02 (t, J=9.6 Hz, 1H), 4.68-4.61 (m, 2H), 4.32-4.26 (m, 1H), 4.01-3.92 (m, 1H); LCMS (ESI) m/z: 295.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15℃; for 1h; | Example 103. Preparation of (3-benzylazetidin-1-yl)-[5-(2-furyl)isoxazol-3-yl]methanone (205) To a solution of 5-(2-furyl)isoxazole-3-carboxylic acid (0.100 g, 0.56 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.254 g, 0.67 mmol) in N,N'-dimethylformamide (3 mL) was added diisopropylethylamine (0.216 g, 1.67 mmol) and 3-benzylazetidine hydrochloride (0.113 g, 0.61 mmol). The mixture was stirred at 15 C. for 1 h and then directly purified by prep-HPLC (Waters X bridge 150*25 5 muM column; 35-75% acetonitrile in a 10 mM ammonium acetate solution in water, 10 min gradient) to give (3-benzylazetidin-1-yl)-[5-(2-furyl)isoxazol-3-yl]methanone (0.062 g, 0.20 mmol, 36%) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 7.57 (s, 1H), 7.31 (d, J=7.6 Hz, 2H), 7.26-7.22 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 6.94 (d, J=3.4 Hz, 1H), 6.85 (s, 1H), 6.56 (dd, J=1.7, 3.3 Hz, 1H), 4.68-4.62 (m, 1H), 4.33-4.26 (m, 2H), 3.95 (dd, J=4.7, 10.8 Hz, 1H), 3.05-2.97 (m, 3H); LCMS (ESI) m/z: 309.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 mg | Stage #1: 5-(furan-2-yl)-1,2-oxazole-3-carboxylic acid With 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 20℃; for 0.25h; Stage #2: 1-cyclopentyl-1H-pyrazol-4-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; | S3-1.3 [248] Step 3: Synthesis of N-(l-cyclopentyl-lH-pyrazol-4-yl)-5-(furan-2-yl) isoxazole-3-carboxamide. To a stirred solution of 5-(furan-2-yl) isoxazole-3-carboxylic acid (118.54 mg, 0.662 mmol, and 1 equiv.) in DMF (4 mL), HATU (251.56 mg, 0.662 mmol, 1 equiv.) was added and allowed to stir at RT for 15 min. Then, stirred solution of 1- cy cl opentyl-lH-pyrazol -4-amine (100 mg, 0.662 mmol, 1 equiv.) and DIPEA (256.19 mg, 1.986 mmol, 3 equiv.) was added. Reaction mixture was allowed to stir at RT for 18 hr. After reaction completion, reaction mixture was extracted with ethyl acetate and water 2 times. Organic layer was collected and evaporated to give crude product. Crude product was purified by using combiflash chromatography and further triturated using diethyl ether and pentane to yield N-(l -cyclopentyl- lH-pyrazol-4-yl)-5-(furan-2-yl) isoxazole-3-carboxamide. (70 mg white solid), LCMS 313 [M+H]+, NMR (400 MHz, DMSO-rf6) d ppm 10.96 (s, 1H) 7.98 - 8.07 (m, 2 H) 7.63 (s, 1H) 7.29 (d, 7=3.51Hz, 1H) 7.15 (s, 1H) 6.77 (br. s., 1H) 4.66 - 4.74 (m, 1H) 2.05 (br. s., 2 H) 1.89 (d, 7=5.26 Hz, 2 H) 1.77 (br. s., 2 H) 1.63 (br. s., 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | Stage #1: 5-(furan-2-yl)-1,2-oxazole-3-carboxylic acid With 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 20℃; for 0.25h; Stage #2: tert-butyl 3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; | S3-3.4 [256] Step 4: Synthesis of tert-butyl 3-(4-(5-(furan-2-yl)isoxazole-3-carboxamido)- lH-pyrazol-l-yl)azetidine-l-carboxylate. To the stirred solution of 5-(furan-2-yl)isoxazole- 3-carboxylic acid, 1 eq.) in DMF (4 mL), HATU (210.4 mg, 0.552 mmol, 1 eq.) was added and allowed to stir at RT for 15 min. Then, stirred solution of tert-butyl 3 -(4-amino- 1H- pyrazol-l-yl)azetidine-l-carboxylate (131 mg, 0.552 mmol, 1 eq.) and DIPEA (0.286 ml, 1.656 mmol, 3 eq.) was added. Reaction mixture was allowed to stir at RT for 18 hr. After the reaction completion, reaction mixture was poured into ice cold water, precipitate obtained was filtered off to obatain crude product. Crude product was purified by using combiflash chromatography to yield tert-butyl 3-(4-(5-(furan-2-yl)isoxazole-3-carboxamido)-lH- pyrazol-l-yl)azetidine-l-carboxylate. (120 mg, white solid), LCMS: 400 [M+H]+. |
Tags: 98434-06-1 synthesis path| 98434-06-1 SDS| 98434-06-1 COA| 98434-06-1 purity| 98434-06-1 application| 98434-06-1 NMR| 98434-06-1 COA| 98434-06-1 structure
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P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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