Structure of 78208-73-8
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CAS No. : | 78208-73-8 |
Formula : | C8H12N2O2 |
M.W : | 168.19 |
SMILES Code : | CC(C)C1=NN(C)C(=C1)C(O)=O |
MDL No. : | MFCD07186363 |
InChI Key : | FJPHBZNCWOYBDN-UHFFFAOYSA-N |
Pubchem ID : | 3157470 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H317 |
Precautionary Statements: | P280 |
* 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 |
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(c) 5.9 g of the ester from (b) and 4.1 g of diemthyl sulfate are warmed at 90 C. for 2.5 hours; 18 ml of 6 N sodium hydroxide solution are then added dropwise, and the mixture is stirred at 80 C. for 2.5 hours and acidified, while warm, with concentrated hydrochloric acid; the precipitate is filtered off and stirred in ice-water to yield 4.1 g of 3-isopropyl-1-methylpyrazole-5-carboxylic acid, mp 159 to 160 C. (from dioxane/cyclohexane). |
Yield | Reaction Conditions | Operation in experiment |
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74% | In tetrahydrofuran; N,N-dimethyl acetamide; N,N-dimethyl-formamide; | Example 255 Production of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of <strong>[78208-73-8]3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid</strong> (144 mg, 0.86 mmol) in tetrahydrofuran (3.0 mL) were added N,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (75 μL, 0.86 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (216 mg, 74%) as a white powder. 1H-NMR (DMSO-d6, 300 MHz) δ 0.78-0.82 (4H, m), 1.21 (6H, d, J=6.6 Hz), 1.85-1.96 (1H, m), 2.83-2.96 (1H, m), 3.98 (3H, s), 6.91 (1H, s), 7.06 (1H, d, J=9.3 Hz), 7.17-7.22 (1H, m), 7.35-7.42 (1H, m), 7.50-7.54 (1H, m), 7.93 (1H, s), 8.03 (1H, d, J=9.3 Hz), 10.10 (1H, s), 11.06 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
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Example 210N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide Compound I-186A solution of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (41.8 mg, 0.110 mmol), <strong>[78208-73-8]3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid</strong> (20.2 mg, 0.12 mmol) and N,N-diisopropylethylamine (52.2 μL, 0.3 mmol) in DMF (1.0 mL, 13 mmol) was stirred at room temperature for 30 minutes. Methyl 4-(1-aminoethyl)benzoate hydrochloride (21.6 mg, 0.10 mmol) and N,N-diisopropylethylamine (17.4 μL, 0.10 mmol) in DMF (1 mL) was then added and the reaction solution was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCE (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was washed with additional DCE (2 mL) and the combined organic layers concentrated. The residue was dissolved in a mixture of MeOH (0.5 mL) and THF (2 mL); 1.0M aqueous NaOH (0.5 mL) was added and the solution heated to 40 C. overnight. Upon cooling to room temperature, the solution was neutralized by the addition of 1.0M aqueous HCl (0.5 mL) and evaporated to dryness. The residue obtained was taken up in DMF (2.0 mL) and to the solution was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (41.8 mg, 0.11 mmol), O-(tetrahydropyran-2-yl)hydroxylamine (14.0 mg, 0.120 mmol) and N,N-diisopropylethylamine (52 μL, 0.3 mmol). The reaction solution was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCE (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was washed with additional DCE (2 mL) and the combined organic layers concentrated. The material obtained was dissolved in MeOH (1 mL), 2.0 M HCl in dioxane (52.2 uL, 0.30 mmol) was added and the solution stirred at room temperature for 1 hour. The solvents were evaporated and the resulting material was dissolved in DMSO and purified on Agilent 1100 LC/MSD instrument to afford the title compound as a white solid (5.3 mg, 16%). LC-MS: (FA) ES+331. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In water; at 80℃; for 4h; | General procedure: 2a (0.05 mol) was added to a stirred mixture of NaOH (6.0 g, 0.15 mol) and water (100 mL). After 4 h under 80 C, the mixture was poured into ice water and the pH was adjusted to acidic. Then 10 % HCl was slowly added to the solutions until a large amount of solids precipitated. After filtration, the solids were dried; 4.6 g (92 % purity) white solid (3a) was obtained. Yield 60 %; GC-MS (EI, 70Ev) (m/z 140 (M+). 3b-p were synthesized in a similar procedure. | |
With water; sodium hydroxide; In ethanol; at 20℃; for 2h; | A mixture of ethyl 5-isopropyl-2-methyl-pyrazole-3-carboxylate (700 mg, 3.57 mmol) and NaOH (428.03 mg, 10.70 mmol) in ethanol (10 mL) and water (10 mL) was stirred at 20 C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the EtOH and then extracted with EtOAc (10 mL). The aqueous phase was acidified with HC1 (IN) to pH ~ 2 and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL), dried over Na2S04, filtered and concentrated to give the crude product (400 mg) as an oil. = 13.17 (br s, 1H), 6.62 (s, 1H), 3.99 (s, 3H), 2.91 - 2.80 (m, 1H), 1.17 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; In 1,2-dichloro-ethane; for 2h;Reflux; | General procedure: 3a (0.01 mol) and thionyl chloride (2.95 g, 0.025 mol) were successively added to 15 ml 1,2-dichloroethane. After 2 h under reflux, the solvent was removed under reduced pressure. 4a was obtained and without further purification and calculating the yield, next reaction was carried out immediately. The analogues 4b-p were prepared in a similar procedure. | |
With thionyl chloride; In 1,2-dichloro-ethane; N,N-dimethyl-formamide; for 3h;Reflux; | General procedure: Pyrazole acid 9a-k (3 mmol) and thionyl chloride (7.5 mmol)were successively added to 20 mL 1,2-dichloroethane, the mixturewere stirred under reflux for 3 h and then concentrated underreduced pressure, the crude products were added in drops into asolution of 5′a-f (5a-h) (3 mmol) and trimethylamine (6 mmol) inTHF (15 mL).The reaction mixturewas stirred under the 0 C for thenight. After reaction the mixture was poured in Na2CO3 solutionand aqueous phase was extracted with ethyl acetate (2 20 mL).The combined organic phase was washed with saturated salt water(2 20 mL), dried over anhydrous Na2SO4, and concentrated underreduced pressure and the residue was purified by silica gel columnchromatography |
Yield | Reaction Conditions | Operation in experiment |
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93% | With dmap; | General procedure: Pyrazole acid 9a-k (3 mmol) and thionyl chloride (7.5 mmol)were successively added to 20 mL 1,2-dichloroethane, the mixturewere stirred under reflux for 3 h and then concentrated underreduced pressure, the crude products were added in drops into asolution of 5′a-f (5a-h) (3 mmol) and trimethylamine (6 mmol) inTHF (15 mL).The reaction mixturewas stirred under the 0 C for thenight. After reaction the mixture was poured in Na2CO3 solutionand aqueous phase was extracted with ethyl acetate (2 20 mL).The combined organic phase was washed with saturated salt water(2 20 mL), dried over anhydrous Na2SO4, and concentrated underreduced pressure and the residue was purified by silica gel columnchromatography. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 2) N-(2 fluoro-3-(trifluoromethyl)benzyl)-3-isopropyl-1-methyl-1H pyrazole-5-carboxamide To a solution of amine (250 mg, 1.30 mmol, 1.0 eq) and acid (218 mg, 1.30 mmol, 1.0 eq) in DMF (15 mL) were added DIEA (835 mg, 6.48 mmol, 5 eq) and HBTU (589 mg, 1.55 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C16H18F4N3O2: 344.0 (M+H), Found 344.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 4) N-(2-chloro-3-(trifluoromethyl)benzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of amine (500 mg, 2.39 mmol, 1.0 eq) and acid (401 mg, 2.39 mmol, 1.0 eq) in DMF (15 mL) were added DIEA (1.54 g, 11.9 mmol, 5 eq) and HBTU (1.09 mg, 1.2.87 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C16H18ClF3N3O: 360.0 (M+H), Found 360.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 9) N-(2-fluoro-3-(trifluoromethoxy)benzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (1.0 g, 4.81 mmol, 1.0 eq) in toluene (20 mL) was added 2,4-dimethoxybenzyl amine (804 mg, 4.81 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (20 mL) and then NaBH4 (364 mg, 9.62 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (4.81 mmol, 1.0 eq) in DMF (15 mL) was added the acid (808 mg, 4.81 mmol, 1.0 eq), DIEA (3.10 g, 24.05 mmol, 5 eq) and HBTU (2.2 g, 5.77 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C16H18F4N3O2: 360.0 (M+H), Found 360.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 13) N-(3-chloro-4-propoxybenzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (500 mg, 2.53 mmol, 1.0 eq) in toluene (25 mL) was added 2,4-dimethoxybenzyl amine (464 mg, 2.78 mmol, 1.1 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (25 mL) and then NaBH4 (192 mg, 5.06 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (1.27 mmol, 1.0 eq) in DMF (10 mL) was added the acid (212 mg, 1.27 mmol, 1.0 eq), DIEA (0.816 mg, 1.13 mmol, 5 eq) and HBTU (575 mg, 1.52 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product (308 mg, >95% purity). Mass Spectrum (LCMS, ESI Pos.) Calcd. For C18H25ClN3O2: 350.0 (M+H), Found 350.0. |
Yield | Reaction Conditions | Operation in experiment |
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15) N-(3-chloro-4-(cyclopropylmethoxy)benzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (5.0 g, 32.05 mmol, 1.0 eq) in toluene (50 mL) was added 2,4-dimethoxybenzyl amine (5.36 g, 32.05 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (50 mL) and then NaBH4 (2.43 g, 64.1 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (1.79 mmol, 1.0 eq) in DMF (10 mL) was added the acid (300 mg, 1.79 mmol, 1.0 eq), DIEA (1.39 mg, 10.75 mmol, 5 eq) and HBTU (814 mg, 2.15 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was taken in 25 mL of methanol and NaOH (72 mg, 1.79 mmol, 1.0 eq) was added and stirred at room temperature for 24 h. Methanol was removed and the residue was neutralized with 10% aq HCl. The reaction mixture was then extracted with ethyl acetate (2*). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane) to give the amide. To a solution of the hydroxy amide (1.79 mmol, 1.0 eq) in DMF (15 mL) was added Cs2CO3 (1.34 g, 3.58 mmol, 2.0 eq) and stirred at room temperature for 20 min. Then bromide (967 mg, 7.16 mmol, 4 eq) was added and stirred at rt for 24 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and washed with water (4*). Organic layer was collected, dried (MgSO4) and evaporated to give a residue, which was then treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product (9 mg, >95% purity). Mass Spectrum (LCMS, ESI Pos.) Calcd. For C19H24ClN3O2: 362.0 (M+H), Found 362.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 17) N-(3-bromo-4-ethoxybenzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (1.0 g, 437 mmol, 1.0 eq) in toluene (25 mL) was added 2,4-dimethoxybenzyl amine (802 mg, 4.80 mmol, 1.1 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (25 mL) and then NaBH4 (330 mg, 8.74 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (1.46 mmol, 1.0 eq) in DMF (15 mL) was added the acid (244 mg, 1.46 mmol, 1.0 eq), DIEA (939 mg, 1.30 mmol, 5 eq) and HBTU (662 mg, 1.75 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C17H23BrN3O2: 380.0 (M+H), Found 380.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 25) 3-isopropyl-N-(2-methoxy-3-(trifluoromethyl)benzyl)-1-methyl-1H-pyrazole-5-carboxamide To a solution of amine (250 mg, 1.21 mmol, 1.0 eq) and acid (205 mg, 1.21 mmol, 1.0 eq) in DMF (15 mL) were added DIEA (780 mg, 6.0 mmol, 5 eq) and HBTU (550 mg, 1.45 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C16H16F4N3O2: 356.0 (M+H), Found 356.0. |
Yield | Reaction Conditions | Operation in experiment |
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at 20 - 25℃;Inert atmosphere; | 29) 3-isopropyl-N-(3-methoxy-2-methylbenzyl)-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (1.0 g, 6.66 mmol, 1.0 eq) in toluene (20 mL) was added 2,4-dimethoxybenzyl amine (1.23 g, 7.33 mmol, 1.1 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (25 mL) and then NaBH4 (506 mg, 13.32 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (2.22 mmol, 1.0 eq) in DMF (15 mL) was added the acid (372 mg, 2.22 mmol, 1.0 eq), DIEA (1.98 g, 11.11 mmol, 5 eq) and HBTU 1.01 g, 2.66 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aqHCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product (80 mg, >95% purity). Mass Spectrum (LCMS, ESI Pos.) Calcd. For C47H24N3O2: 302.0 (M+H), Found 302.0. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 40) N-(4-(difluoromethoxy)-3,5-dimethylbenzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of aldehyde (250 mg, 1.25 mmol, 1.0 eq) in toluene (20 mL) was added 2,4-dimethoxybenzyl amine (208 mg, 1.25 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (20 mL) and then NaBH4 (95 mg, 2.50 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (1.25 mmol, 1.0 eq) in DMF (15 mL) was added the acid (210 mg, 1.25 mmol, 1.0 eq), DIEA (806 mg, 6.25 mmol, 5 eq) and HBTU (569 mg, 1.50 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with 10% aq HCl (1*20 mL), sat NaHCO3 (1*20 mL) and water (4*20 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product (87 mg, >95% purity). Mass Spectrum (LCMS, ESI Pos.) Calcd. For C18H24F2N3O2: 352.0 (M+H), Found 352.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 42) N-(3-chloro-4-propoxy-5-methoxybenzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution aldehyde (1.0 g, 4.34 mmol, 1.0 eq) in toluene (20 mL) was added 2,4-dimethoxybenzyl amine (732 mg, 4.34 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 24 h. Toluene was removed to give a residue, which was taken in MeOH (25 mL) and then NaBH4 (328 mg, 8.68 mmol, 2.0 eq) was added slowly. The reaction mixture was stirred at room temperature for 6 h. Solvent was removed and the residue was extracted in Ethyl acetate and stirred with saturated aq NaHCO3 for 1 h. The organic layer was collected, dried and solvent was removed to give the crude amine, which was used in the next step without further purification. To a solution of the crude amine (42.17 mmol, 1.0 eq) in DMF (20 mL) was added the acid (365 mg, 2.17 mmol, 1.0 eq), DIEA (1.40 g, 10.85 mmol, 5 eq) and HBTU (987 mg, 2.86 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with 10% aqHCl (1*50 mL), sat NaHCO3 (1*50 mL) and water (4*50 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 25% to 75%)) to give the amide, which was directly used in the next step. The amide was treated with 95% TFA:H2O for 12 h. TFA was removed and azeotroped with toluene to give a residue, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C19H27ClN3O3: 380.0 (M+H), Found 380.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h;Inert atmosphere; | 32) N-(2,3-dimethoxybenzyl)-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide To a solution of the amine (365 mg, 2.17 mmol, 1.0 eq) in DMF (20 mL) were added the acid (365 mg, 2.17 mmol, 1.0 eq), DIEA (1.40 g, 10.85 mmol, 5 eq) and HBTU (987 mg, 2.86 mmol, 1.2 eq) and the reaction mixture was stirred at rt for 12 h. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with 10% aq HCl (1*50 mL), sat NaHCO3 (1*50 mL) and water (4*50 mL). Organic layer was collected, dried (MgSO4) and evaporated to give a crude product, which was purified by column chromatography (EtOAc/Hexane 10% to 50%) to give the desired product. Mass Spectrum (LCMS, ESI Pos.) Calcd. For C17H24N3O3: 318.0 (M+H), Found 318.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With pyridine; propylphosphonic anhydride; In ethyl acetate; acetonitrile; at 100℃; for 16h;Sealed tube; | To a suspension of 6-(2-amino-5-chlorothiazol-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.100 g, 0.41 mmol) and <strong>[78208-73-8]3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid</strong> (0.075 g, 0.45 mmol), and pyridine (0.16 mL, 1.96 mmol) in acetonitrile (2.5 mL) in a sealed tube was added propylphosphonic anhydride solution (50 wt % in ethyl acetate, 0.61 mL, 1.02 mmol). The sealed tube was heated to 100 C. for 16 h and the precipitation formed. After cooling, the precipitate was collected by filtration and washed with cold 1:1 acetonitrile/water to give 3-isopropyl-1-methyl-N-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)-1H-pyrazole-5-carboxamide (0.139 g, 86%). 1H NMR (400 MHz, DMSO-d): δ 12.60 (bs, 1H), 10.19 (s, 1H), 7.75 (m, 1H), 7.71 (dd, 1H, J=8.4, 2.0 Hz), 7.53 (s, 1H), 7.27 (s, 1H), 6.91 (d, 1H, J=8.0 Hz), 4.07 (s, 3H), 2.93 (t, 2H, J=7.2 Hz), 2.48 (partial masked under d-DMSO, m, 2H), 1.23 (s, 6H). MS (ESI): Calcd. for C20H21N5O2S: 395, found 396 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 5′-O-sulfamoylated intermediate (1 eq) in anhydrousCH2Cl2 was added the corresponding acid (1.5 eq) and DMAP(0.05 eq) at room temperature. 1M DCC in CH2Cl2 (1.5 eq) was addeddropwise and the reaction mixture was stirred for 12 h at room temperature.The reaction mixture was filtered through celite pad, washedwith EtOAc and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel(EtOAc:MeOH=10:1) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 5′-O-sulfamoylated intermediate (1 eq) in anhydrousCH2Cl2 was added the corresponding acid (1.5 eq) and DMAP(0.05 eq) at room temperature. 1M DCC in CH2Cl2 (1.5 eq) was addeddropwise and the reaction mixture was stirred for 12 h at room temperature.The reaction mixture was filtered through celite pad, washedwith EtOAc and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel(EtOAc:MeOH=10:1) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
180 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | A mixture of 5-isopropyl -2-methyl -pyrazole-3 -carboxylic acid (120 mg, 0.71 mmol), DIPEA (0.62 mL, 3.57 mmol), HOBt (192.82 mg, 1.43 mmol) EDCI (205.16 mg, 1.07 mmol) and l-[3-(3-fluorophenyl)-l,2,4-oxadiazol-5-yl]ethanamine hydrochloride (173.85 mg, 0.71 mmol) in DCM (15 mL) was stirred at 20 C for 16 hours. The mixture was diluted with NH4CI (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL), dried over NaiSCh, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Waters XBridge (150 mm x 25 mm, 5 pm), A = H20 (10 mM NH4HCO3) and B = CH3CN; 24-54% B over 8 min) to give the product (180 mg, 0.50 mmol, 70% yield) as an oil. LCMS Rt = 0.88 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C18H21FN5O2 [M+H]+ 358.2, found 358.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 16h;Inert atmosphere; | To a mixture of l-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol) in DCM (10 mL) was added HOBt (160.69 mg, 1.19 mmol), EDCI (227.96 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol) and (lR)-l-[3-(m-tolyl)-l,2,4-oxadiazol-5- yljethanamine (120.84 mg, 0.59 mmol) and the reaction mixture was stirred at 25 C for 16 hours. The reaction was quenched with FbO (10 mL), then extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over NaiSCL, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = FhO (0.05 % NH4OH) and B = CFECN; 17-47 % B over 8 min) to give the product as an oil. Analytical SFC (Daicel CHIRALPAK AS-3 (150 mm x 4.6 mm, 3 pm), mobile phase: A: CO2 B:ethanol (0.05% DEA), gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, flow rate: 2.5 mL/min, column temp: 35 C, ABPR: 1500 psi) showed 2.39 min (main peak, 91.6%) and 2.55 min (8.4%). Note: the condensation reaction leads to some racemization. Then the product was purified by SFC (Dai cel CHIRALPAK AS-H (250 mm x 30 mm, 5 pm); A = C02 and B = EtOH (0.1% NH H20); 38 C; 65 mL/min; 20% B; 8.60 min run; 50 injections, Rt of peak 1 = 5.57 min, Rt of peak 2 = 6.60 min) to give the product (66.75 mg, 0.19 mmol, 32% yield) as an oil. NMR (400MHz, CD CN) d = 8.00 (s, 1H), 7.89 (s, 1H), 7.86 (d, 1H), 7.48 - 7.38 (m, 2H), 7.06 (br d, 1H), 5.50 - 5.40 (m, 1H), 4.46 (quin, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 1.69 (d, 3H), 1.48 (d, 6H). LCMS Rt = 1.13 min in in 2.0 min chromatography, 10-80AB, MS ESI calcd. for Ci9H24N502 [M+H]+ 354.2, found 354.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | A mixture of 5-isopropyl-2-methyl-pyrazole-3-carboxylic acid (54.41 mg, 0.32 mmol), HOBt (92.03 mg, 0.68 mmol), Et N (0.24 mL, 1.7 mmol), EDCI (97.92 mg, 0.51mmol) and l-[3-[3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.34 mmol) in DCM (20 mL) was stirred at 20 C for 16 hours under N2. The reaction mixture was quenched with sat. NFLCl (20 mL), and the mixture was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Boston Prime (150 mm x 30 mm, 5 pm), A = FLO (0.05% NH4OH) and B = CFLCN; 20-80% B over 8 min) to give the product (85 mg, 0.21 mmol, 61% yield) as a an oil. LCMS Rt = 0.93 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C19H21F3N5O2 [M +H]+ 408.2, found 408.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.51 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h; | A mixture of l-[3-(m-tolyl)-l,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol), 5-isopropyl-2-methyl-pyrazole-3-carboxylic acid (70.17 mg, 0.42 mmol), HOBt (112.75 mg, 0.83 mmol), EDCI (119.96 mg, 0.63 mmol) and TEA (0.29 mL, 2.09 mmol) in DCM (20 mL) was stirred at 20 C for 16 hours. The mixture was concentrated, diluted with H2O (10 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Kromasil (150 mm x 30 mm, 5 pm), A = H20 (0.05% NH4OH) and B = CH3CN; 55-85% B over 8 min) to give the product (44.51 mg, 0.13 mmol, 30% yield) as a solid. *H NMR (400MHz, CDCh) dH = 7.92 - 7.84 (m, 2H), 7.42 - 7.30 (m, 2H), 6.63 (d, 1H), 6.46 (s, 1H), 5.66 - 5.56 (m, 1H), 4.12 (s, 3H), 3.05 - 2.94 (m, 1H), 2.43 (s, 3H), 1.75 (d, 3H), 1.28 (d, 6H). LCMS Rt = 1.30 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C19H24N5O2 [M+H]+ 354.19, found 354.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.2 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 15h; | Note the stereochemistry is randomly assigned. To a stirred solution of A-17 (0.300 g, 1.166 mmol) and 3-isopropyl-1-methyl-1H-pyrazole- 5-carboxylic acid (0.226 g, 1.341 mmol) in DMF (5 mL) was added HATU (0.886 g, 2.332 mmol) followed by DIPEA (1.01 mL, 5.830 mmol) at room temperature and stirred for 15 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure resulting in the residue A-51 (198 mg) as a liquid. The residue was purified by Combiflash column chromatography eluting with 0-40% ethyl acetate in n-hexane to afford A-51 (0.200 g) as a solid. Chiral separation of A-51 was done by preparative chiral HPLC to afford 24 (0.060 g, 0.147 mmol, 13% yield) and 25 (0.086 g, 0.211 mmol, 18% yield) as solids. 24: LCMS : 407.95 (M+H), Rt = 2.722 min, Column: Kinetex EVO C18 (50*3) mm 2.6 µ; Mobile Phase: A: 2.5mM Ammonium Bicarbonate in water, B: Acetonitrile; HPLC: Rt = 4.959 min, 98.71% Column; X SELECT CSH C18 (150 X 4.6mm, 3.5um); Mobile Phase A 5mM AMMONIUM BICARBONATE; Mobile Phase B : ACETONITRILE; CHIRAL HPLC: Rt = 7.233 min, 95.77%; Column: Chiralpak IG (250 X4.6mm, 5 μm); Mobile Phase: A-0.1% DEA in n- Hexane; Mobile Phase B: EtOH; A:B: 80:20; Flow Rate : 1.0 mL/min.1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, 1H), 8.93 (d, 1H), 8.34 (s, 1H), 8.20-8.23 (m, 1H), 7.34 (d, 1H), 6.82 (s, 1H), 5.35-5.42 (m, 1H), 3.99 (s, 3H), 2.84-2.91 (m, 1H), 1.59 (d, 3H), 1.20 (d, 6H). 25: LCMS : 408.20 (M+H), Rt = 2.232 min, Column: X-Bridge BEH C-18 (3.0*50 mm, 2.5 µm); Mobile Phase: A: 0.02.5% Formic acid in water, B: Acetonitrile; HPLC: Rt = 7.240 min, 94.88% Column; X SELECT CSH C18 (150 X 4.6mm, 3.5um); Mobile Phase A 5mM AMMONIUM BICARBONATE; Mobile Phase B: ACETONITRILE; CHIRAL HPLC: Rt = 6.330 min, 99.04%; Column: Chiralpak IG (250 X4.6mm, 5 μm); Mobile Phase: A-0.1% DEA in n- Hexane; Mobile Phase B: EtOH; A:B: 80:20; Flow Rate : 1.0 mL/min.1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, 1H), 8.93 (d, 1H), 8.34 (s, 1H), 8.21 (d, 1H), 7.34 (d, 1H), 6.82 (s, 1H), 5.35-5.42 (m, 1H), 3.99 (s, 3H), 2.84-2.91 (m, 1H), 1.59 (d,, 3H), 1.20 (d, 6H). |
Tags: 78208-73-8 synthesis path| 78208-73-8 SDS| 78208-73-8 COA| 78208-73-8 purity| 78208-73-8 application| 78208-73-8 NMR| 78208-73-8 COA| 78208-73-8 structure
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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 |
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