Structure of 16034-49-4
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CAS No. : | 16034-49-4 |
Formula : | C7H10N2O2 |
M.W : | 154.17 |
SMILES Code : | O=C(O)CN1N=C(C)C=C1C |
MDL No. : | MFCD00297249 |
InChI Key : | JYSWEDYPQJOEPO-UHFFFAOYSA-N |
Pubchem ID : | 572875 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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 |
---|---|---|
86% | To a vial containing the 2-piperazin-l-yl-benzoic acid methyl ester (0.667 g, 3.03 mmol) is added a pre-mixed solution containing (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.428 g, 2.78 mmol) and carbonyl dimidazole (0.567 g, 3.50 mmol). The mixture is stirred overnight and then diluted with 200 mL of EtOAc followed by 200 mL of saturated NH4Cl. The organic phase is washed with 2x200 mL of H2O and 1x200 mL of brine, dried (MgSO4), filtered and concentrated to give 0.849 g of 2-{4-[2-(3,5-dimethyl- pyrazol-l-yl)-acetyl]-piperazin-l-yl} -benzoic acid methyl ester in 86% yield. | |
With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 20℃; | To a vial containing the 2-piperazin-l-yl-benzoic acid methyl ester (0.667 g, 3.03 mmol) is added a pre-mixed solution containing (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.428 g, 2.78 mmol) and carbonyl diimidazole (0.567 g, 3.50 mmol). The mixture is stirred overnight and then diluted with 200 mL of EtOAc followed by 200 mL of sat. NH4Cl. The organic phase is washed with 2 x 200 mL of H2O and 1 x 200 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated to give 0.849 g of 2-{4-[2- (3,5-dimethyl-pyrazol-l-yl)-acetyl]-piperazin-l-yl} -benzoic acid methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at -5 - 20℃; | (3,5-Dimethyl-lH-pyrazol-l-yl)acetic acid (21 mg, 0.125 mmol) is dissolved in dichloromethane (1 mL) and cooled to -5 0C. To this is added oxalyl chloride solution (2 M in dichloromethane, 0.063 mL, 0.125 mmol), followed by 0.02 mL DMF. The mixture is stirred for 2 h warming to room temperature. To the acid chloride solution is then added a solution of the above piperazine intermediate (30 mg, 0.119 mmol) and Hunig's base (0.104 mL, 0.595 mmol) in dichloromethane (1 mL) and the reaction is stirred at ambient temp for 20 h. The reaction is concentrated in vacuo at 40 0C to a residue. The residue is diluted with DMF (2 mL), water (1 mL) and TFA (0.2 mL) and purified by reverse-phase preparative HPLC (10-100% CH3CN/H2O) to give 21 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 20℃; | The above tert-butyl ester (0.045 g, 0.097 mmol) in a vial is dissolved in 1 rnL of CH2Cl2 and 1 rnL of TFA. The mixture is stirred for Ih. and then concentrated to dryness to give crude iV-(2-amino-4-trifluoromethyl-phenyl)-2-piperazin- 1 -yl-benzamide trifluoroacetamide. To a vial containing the amine salt is added 1.0 mL of a premixed (1 hr) solution containing (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.016 g, 0.104 mmol) and carbonyl diimidazole (0.017 g, 0.104 mmol). The mixture is stirred overnight and then 20 mL of sat. NH4Cl is added followed by 50 mL of CH2Cl2. The mixture is washed with 2 x 20 mL of H2O and 1 x 20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated to give 52 mg of N-(2-amino-4-trifluoromethyl-phenyl)-2-{4- [2-(3,5-dimethyl-pyrazol-l-yl)-acetyl]-piperazin-l-yl}-benzamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Example 5: N-(2-{4-[2-(3,5-Dimethyl-pyrazol-l-yl)-acetyl]-piperazin-l-yl}-phenyl)- benzamide. To (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.140 g, 0.908 mmol) in DMF is added carbonyl diimidazole (0.140 g, 0.863 mmol) in one portion. The mixture is stirred for 1 h. To this is added l-(2-nitro-phenyl)-piperazine (0.197 g, 0.950 mmol). The mixture is stirred for 14 h and then diluted with 100 mL EtOAc. The reaction is quenched with 20 mL of saturated NH4Cl, washed with 2x20 mL of H2O and 1x20 mL of brine. The organic phase is dried (MgSO4), filtered and concentrated to give 2-(3,5-dimethyl- pyrazol-l-yl)-l-[4-(2-nitro-phenyl)-piperazin-l-yl]-ethanone in 64% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-(2-Phenylcarbamoyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (0.065 g, 0.171 mmol) in a vial is dissolved into 1 mL of CH2Cl2 and 1 mL of TFA. The mixture is stirred for Ih. The mixture is concentrated to dryness to give crude iV-phenyl-2- piperazin-1-yl-benzamide trifluoroacetamide. To a vial containing the amine salt is added 1.0 mL of a premixed solution, containing (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.023 g, 0.150 mmol) and carbonyl diimidazole (0.028 g, 0.170 mmol) (premixed for Ih). The mixture is stirred overnight. The mixture is partially purified mixture via preparative HPLC (20%- 100% CH3CN/H2O) and then purified via the preparative HPLC system (30%-70% CH3CN/H2O) to give the title compound (0.043 g, 69% yield). MS MH+=418.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Example 7: Synthesis of 3-Chloro-N-(5-chloro-2-{4-[2-(3,5-dimethyl-pyrazol-l-yl)- acetyl]-piperazin-l-yl}-pyridin-3-yl)-benzamide RT, 5hTo a solution of (3,5-dimethyl-pyrazol-l-yl)-acetic acid (0.800 g, 5.19 mmol) in dimethylformamide (20 niL) is added 2.1 g (5.5 mmol) of tetramethyluroniumhydroxybenzotriazole hexafluorophosphate followed by of N,N- diisopropylethylamine (2.70 mL, 15 mmol). The mixture is stirred at room temperature for 1 h then l-(5-chloro-3-nitro-pyridin-2-yl)-piperazine hydrochloride (1.60 g, 5.70 mmol) is added and the mixture is stirred at room temperature for 1 h. The mixture is diluted with water which causes a solid to precipitate from solution. The orange solid is collected by filtration, washed with water, and dried on the filter pad. The collected material is purified by flash silica gel chromatography to provide, after removal of the eluent under reduced pressure, 1.1 g of l-[4-(5-chloro-3-nitro-pyridin-2-yl)-piperazin-l- yl]-2-(3,5-dimethyl-pyrazol-l-yl)-ethanone as a dark brown oil in 56% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | To solution of (3,5-dimethyl-pyrazol-l-yl)-acetic acid (O.OlOg, 0.068 mmol) in N,N- dimethylformamide (2mL) is added 0.006 mL (0.071 mmol) of pyridine followed by) tetramethyluroniumhydroxybenzotriazolehexaflourophosphate (0.123 g, 0.324 mmol). The mixture stirred for 1 hour. To this is added 3-chloro-N-(5-chloro-2-[l,4]diazepan-l- yl-phenyl)-benzamide (0.025 g, 0.068 mmol). The mixture is allowed to stir overnight. The mixture is concentrated under reduced pressure and is purified by reverse phase HPLC to provide 0.010 g of 3-chloro-N-(5-chloro-2-{4-[2-(3,5-dimethyl-pyrazol-l-yl)- acetyl]-[l,4]diazepan-l-yl}-pyridin-3-yl)-benzamide in 29% yield. MS MH+ = 501.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 2.5h;Cooling with ice; | Example 1115-{1 -[(3,5-dimethyl-1 H^yrazol-1 -yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amineTo a mixture of 5-(2,3-dihydro-1 H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (175 mg, 0.517 mmol) and (3,5-dimethyl-1 H-pyrazol-1 -yl)acetic acid (80 mg, 0.517 mmol) in Ν,Ν-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.271 mL, 1.552 mmol) dropwise. The mixture was cooled in an ice bath, and T3P (1- propanephosphonic acid cyclic anhydride), 50% in ethylacetate (-1.68M) (0.370 mL, 0.621 mmol) was then added dropwise. After stirring 30 minutes, the ice bath was removed and the mixture was allowed to warm to room temperature and stir 2hours. The mixture was diluted with water (~5 mL) and basified to pH 7-8 with 0.5M NaOH. Methanol was added to give a clear solution. This solution was loaded onto a reversed phase C18 SF25-55g Analogix cartidge and the product purified by eluting with a gradient of 30-95% methanol-water. The combined pure fractions containing the product was evaporated and azeotroped with acetonitrile and then benzene to give a solid that was triturated with acetonitrile (~4 mL), filtered and washed with acetonitrile to afford 5-{1-[(3,5-dimethyl-1 H- pyrazol-1-yl)acetyl]-2,3-dihydro-1 H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (90 mg, 41 .2 % yield) as a white solid after drying under vacuum. LCMS (ES) m/z = 402.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1 H) 8.07 (d, J=8.1 Hz, 1 H) 7.34 (s, 1 H) 7.20 - 7.29 (m, 2 H) 6.08 (br. s, 2 H) 5.86 (s, 1 H) 5.09 (s, 2 H) 4.26 (t, J=8.3 Hz, 2 H) 3.74 (s, 3 H) 3.27 (t, J=8.3 Hz, 2 H) 2.17 (s, 3 H) 2.10 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Cooling with ice; | Example 1473-{1 -[(3,5-dimethyl-1 H-pyrazol-1 -yl)acetyl]-2,3-dihydro-1 H-indol-5-yl}-1 -methyl-1 H- pyrazolo[3,4-d]pyrimidin-4-amineDIPEA (1 .158 ml_, 6.63 mmol) was added dropwise to a stirring mixture of 3-(2,3-dihydro- 1 H-indol-5-yl)-1 -methyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCI (500 mg, 1 .474 mmol) and (3, 5-dimethyl-1 H-pyrazol-1 -yl)acetic acid (239 mg, 1 .474 mmol) in N,N- Dimethylformamide (DMF) (10 ml.) under nitrogen. The solution was then cooled in an ice bath, and T3P (50 wt% in ethyl acetate) (1 .053 ml_, 1.769 mmol) was added dropwise slowly over 5 minutes. The mixture was left in the ice bath, and allowed to slowly warm to room temperature and stir overnight. HPLC indicated some starting material remaining, so an additional 0.2 eq (0.175 ml.) of T3P solution was added. After stirring 1 hour, HPLC showed no change, so additional DIPEA (1 eq., 0.26 ml) was added, and stirring continued 1 hour, at which time there was no change in conversion. An additional 24mg of (3, 5-dimethyl-1 H-pyrazol-1 -yl)acetic acid was added and the mixture stirred 1 hour - no change. The Mixture was diluted with water (30 ml.) and extracted with 10:1 chloroform:isopropanol (5 x 25 ml_). The combined organics was dried over Na2S04 overnight, then filtered and evaporated. Purification by silicagel chromatography (Analogix SF25-60g cartridge) eluting with 0-5% methanol-chloroform afforded the pure product as an off-white powder. Impure fractions were combined and purified by silicagel chromatography (Analogix SF15-24g cartridge) eluting with 0-5% methanol-chloroform to give additional pure product. The combined product was dried under high vacuum to give 3-{1-[(3,5-dimethyl-1 H-pyrazol-1 -yl)acetyl]-2,3-dihydro-1 H-indol-5-yl}-1 -methyl-1 H- pyrazolo[3,4-d]pyrimidin-4-amine (376 mg) as an off-white powder. LC-MS (ESI) 403.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (s, 1 H) 8.12 (d, J=8.3 Hz, 1 H) 7.54 (s, 1 H) 7.46 (d, J=8.3 Hz, 1 H) 5.86 (s, 1 H) 5.1 1 (s, 2 H) 4.29 (t, J=8.5 Hz, 2 H) 3.94 (s, 3 H) 3.30 (d, J=8.5 Hz, 2 H) 2.17 (s, 3 H) 2.10 (s, 3 H) (NH2 protons not observed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
460 mg | With dmap; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃; | Step 214.1 : A mixture of <strong>[16034-49-4](3,5-dimethyl-1H-pyrazol-1-yl)acetic acid</strong> (600mg), benzyl alcohol (0.402ml), DMAP (194mg) and DCC (802mg) in MeCN (40ml) was stirred at RT overnight. The suspension was filtered off and the resulting solution was evaporated to dryness. The residue was purified by CC (Hept/EA 7/3) to afford benzyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetate (460mg, white solid). LC-MS (B): tR = 0.80min; [M+H]+: 245.18. |
460 mg | With dmap; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃; | Step 214.1: A mixture of <strong>[16034-49-4](3,5-dimethyl-1H-pyrazol-1-yl)acetic acid</strong> (600 mg), benzyl alcohol (0.402 mL), DMAP (194 mg) and DCC (802 mg) in MeCN (40 mL) was stirred at RT overnight. The suspension was filtered off and the resulting solution was evaporated to dryness. The residue was purified by CC (Hept/EA 7/3) to afford benzyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetate (460 mg, white solid). LC-MS (B): tR=0.80 min; [M+H]+: 245.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 85-Amino-3-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazole-4-carboxamideA solution of 5-amino-3-(4-fluoro-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-pyrazole-4- carboxamide (100 mg, 0.321 mmol), (3,5-dimethyl-1 H-pyrazol-1-yl)acetic acid (64.3 mg,0.417 mmol) and HATU (134 mg, 0.353 mmol) in N,N-dimethylformamide (DMF) (2 mL) was cooled in an ice bath then DIEA (0.279 mL, 1.604 mmol) was added slowly. After addition, the reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was then loaded directly on to a Analogix 24 g column conditioned with hexane and purified by flash silica chromatography (3 min at 100% hexane then a gradient of 0 to 10% MeOH in DCM over 25 min). The fractions with the desired product were combined then concentrated. The solid was triturated with EtOAc and hexane then filtered to afford 5-amino-3-{1-[(3,5-dimethyl-1 H-pyrazol-1-yl)acetyl]-4-fluoro-2,3-dihydro- 1 H-indol-5-yl}-1-methyl-1 H-pyrazole-4-carboxamide (60 mg, 0.146 mmol, 45.5 % yield) as a pink colored solid. LC-MS(ES) m/z = 412 [M+H]+. H NMR (400 MHz, DMSO-cfe) δ 2.09 (s, 3 H), 2.15 (s, 3 H), 3.25 (t, J = 8.46 Hz, 2 H), 3.56 (s, 3 H), 4.33 (t, J = 8.46 Hz, 2 H), 5.09 (s, 2 H), 5.85 (s, 1 H), 6.27 (s, 2 H), 7.22 (t, J = 7.83 Hz, 1 H), 7.85 (d, J = 8.08 Hz, 1 H). Two protons were not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 125-Amino-3-(1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl)indolin-5-yl)-1-methyl-1H-pyrazole-4-carboxamideTo 5-amino-3-(indolin-5-yl)-1 -methyl-1 H-pyrazole-4-carboxamide, hydrochloride (100 mg,0.340 mmol), 2-(3,5-dimethyl-1 H-pyrazol-1-yl)acetic acid (68.2 mg, 0.443 mmol) and HATU (142 mg, 0.374 mmol) in a 40 ml_ vial was added Ν,Ν-dimethylformamide (DMF) (1.5 ml_). The reaction was cooled in an ice bath, and then DIEA (0.296 ml_, 1.702 mmol) was added dropwise. After addition, the reaction was removed from ice bath and stirred at room temperature for 1 hour. The reaction solution was then loaded directly onto a double stacked (2X) 10 g Biotage SNAP column first conditioned with hexane and purified by flash silica chromatography (4 min 100% hexane, then 3 min 100% DCM, then 0 to 10% MeOH in DCM for 20 min). The product fractions were combined and concentrated and the residue was purified by flash silica chromatography on a 10 g Biotage column conditioned with hexanes (3 min 100% hexane, then 0 to 100% EtOAC for 10 min then 0 to 10% MeOH in EtOAc). The product fractions were combined, concentrated, and then transferred to a 40 ml_ vial and MeCN and water was added. The sample was freeze- dried to afford 5-amino-3-(1-(2-(3,5-dimethyl-1 H-pyrazol-1-yl)acetyl)indolin-5-yl)-1-methyl- 1 H-pyrazole-4-carboxamide (79 mg) as a white powder. LC-MS(ES) m/z = 394 [M+H]+. H NMR (400 MHz, DMSO-d6) δ 2.09 (s, 3 H), 2.16 (s, 3 H), 3.19 - 3.28 (m, 2 H), 3.55 (s, 3 H), 4.25 (t, J = 8.08 Hz, 2 H), 5.08 (s, 2 H), 5.84 (s, 1 H), 6.27 (s, 2 H), 7.26 (d, J = 8.08 Hz, 1 H), 7.36 (s, 1 H), 8.02 (d, J = 8.08 Hz, 1 H). Two protons were not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 23℃; for 16h; | General procedure: The fragment carboxylic acid (0.35 mmol) was dissolved in dimethylformamide (0.2 M, 1.75 mL), then 14 (42.6 mg, 0.35 mmol), HBTU (128 mg, 0.34 mmol), and HOBT (51.8 mg, 0.38 mmol) were added, followed by diisopropylethylamine (175 µL, 1.047 mmol). The reaction was stirred at 23 C for 16 h. TLC at 16 h showed conversion to product. The reaction was quenched with H2O (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and saturated aqueous NaCl (10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. Purification with flash column chromatography with CH3OH/CH2Cl2 ( CH3OH gradient 0 → 5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | 1.6. 1-(8-{(R)-4-[2-(3, 5-Dimethyl-pyrazol-1-yl)-acetyl]-3-methyl-piperazin-1-yl)-5-trifluoromethyl-3, 4-dihydro- 1H-isoquinolin-2-yl)-2, 2, 2-trifluoro-ethanone:A mixture of intermediate 1.5 (3.21g), <strong>[16034-49-4](3,5-dimethyl-1H-pyrazol-1-yl)acetic acid</strong> (1.26g) and HATU (3.12g) in DIPEA (3.9SmL) and DCM (SgmL) was stirred at RT overnight. NaHCO3 and DCM were added, the phases were separated and the org. layer was evaporatedvacuo. The crude was purified by CC (Biotage, SNAP bOg cartridge, solvent A: Hept;solvent B: EA; gradient in %B: 25 for 2CV, 25 to 100 over SCV, 100 for 6CV) to afford 3.9g of yellow solid. LC-MS (B): tR = 0.92 mm; [M+H]: 532.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 1h; | [00576] Intermediate 59: 2-(3,5-dimethylpyrazol-1 -yI)acetic acid[00577] Benzyl 2-(3,5-dimethylpyrazol-1-yl)acetate (228mg, 0.g3mmol) was diluted in EtOAc (1 8mL) and hydrogenated by circulating through an H-cube reactor using a 10% Pd/C CatCart for 1 hour. The reaction mixture was then reduced in vacuo to give 2-(3,5-dimethylpyrazol-1-yl)aceticacid (1 20mg, 0.78mmol, 83% yield) as a pale yellow solid which was used in the next step without further purification.MS Method 2: RT: 0.79 mi m/z 155.0 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2.5h; | The ester from step 1 (226.3 mg, 1.3 mmol) was dissolved in THF (4 mL) and cooled to 0 C, then 1 N aqueouslithium hydroxide (1.48 mL, 1.5 mmol) was added and the reaction was allowed to warm to room temperature. After 2.5h, 1 M HCl was used to quench the reaction and the solution was concentrated to afford the title compound in quantitativeyield. |
Yield | Reaction Conditions | Operation in experiment |
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43% | To a solution of 2-(2-methyl-1 H-indol-1-yl)acetic acid (54.7 mg, 289 µmol) in anhydrous 33 CH2Cl2 (4 mL) was added 43 DCC (59.9 mg, 290 µmol), 44 DMAP (8 mg, 65 µmol) and 37 N-(3,5-dimethyl-1-phenyl-1 H-pyrazol-4-yl)-2-hydroxyacetamide (71.0 mg, 290 µmol) at 0 C under argon. The mixture was allowed to warm to room temperature and for 18 h. The reaction mixture was filtered over cotton, washed with NH4Cl (2 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by column chromatography (75% 24 EtOAc in 25 petroleum ether) gave 98 mg (81%) of the title compound.TLC: Rf (5% MeOH in CH2Cl2): 0.15.1H NMR (400 MHz, DMSO-d6) δ: 9.37 (bs, 1H), 7.48 - 7.54 (m, 4H), 7.36-7.45 (m, 3H), 7.04 (ddd, 1 H, J = 8.3, 7.1, 1.3 Hz), 6.98 (ddd, 1 H, J = 7.8, 7.2, 1.2 Hz), 6.24 (dq, J = 2.0, 0.9 Hz, 1 H), 5.21 (s, 2H), 4.79 (s, 2H), 2.37 (d, J= 0.8 Hz, 3H), 2.13 (s, 3H), 2.05 (s, 3H) ppm.13C NMR (100 MHz, DMSO-d6) δ: 168.9, 165.9, 144.7, 139.6, 137.1, 137.1, 134.4, 129.2, 127.7, 127.0, 123.8, 120.3, 119.3, 119.1, 116.6, 109.2, 100.1, 63.0, 44.0, 12.1, 11.3, 10.6 ppm HRMS (ESI) m/z: (M+H)+ calcd for C24H25N4O3: 417.1921; found: 417.1926The acid from step 2 (31.8 mg, 0.2 mmol) was dissolved in DCM (2 mL) at 0 C under Argon atmosphere. Oxalylchloride (25 μL, 0.3 mmol) and 2 drops of dry DMF was added and the mixture was stirred for 1.5 h at room temperature. The solution was evaporated in vacuo and redissolved in THF (2 mL). N-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-hydroxyacetamide (30 mg, 122 μmol), ), synthesized as reported in Example 1, DMAP (0.1 eq) and Et3N (30 μL, 220 μmol, 1.8 eq) were added and the mixture was stirred overnight. The solution was quenched with NH4Cl solution (semi-saturated) and diluted with EtOAc. The organic phase was dried with MgSO4 and the solvent was evaporated. Purification by column chromatography (3% → 5% MeOH in DCM) yielded 20 mg (43%) of the title compound. TLC: Rf (5% MeOH in DCM): 0.30 1H NMR (400 MHz, CDCl3) δ: 8.27 (bs, 1 H), 7.40-7.50 (m, 4H), 7.32-7.39 (m, 1 H), 5.33 (bs, 1 H), 4.87 (s, 4H), 2.29 (d, J= 0.6 Hz, 3H), 2.19 (s, 3H), 2.19 (s,3H), 2.02 (s, 3H) ppm 13C NMR (101 MHz, CDCl3) δ: 166.4, 166.2, 149.4, 145.5, 140.6, 139.8, 135.5, 129.2, 127.4, 123.7, 115.3, 106.0, 63.4, 50.1, 13.1, 11.3, 10.9, 10.8 ppm HRMS (ESI) m/z: (M+H)+ calcd for C22H26N2O4: 382.1887; found: 382.1873 |
Tags: 16034-49-4 synthesis path| 16034-49-4 SDS| 16034-49-4 COA| 16034-49-4 purity| 16034-49-4 application| 16034-49-4 NMR| 16034-49-4 COA| 16034-49-4 structure
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