Structure of 1152582-56-3
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CAS No. : | 1152582-56-3 |
Formula : | C6H8N2O2 |
M.W : | 140.14 |
SMILES Code : | O=C(O)CC1=CN(C)N=C1 |
MDL No. : | MFCD09925217 |
InChI Key : | CVVXBWFAPQPDCQ-UHFFFAOYSA-N |
Pubchem ID : | 28950344 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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 |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 100℃; for 0.166667h; | Example 22 N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide [0706] A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 muL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 muL, 0.046 mmol), and <strong>[1152582-56-3]2-<strong>[1152582-56-3](1-methyl-1H-pyrazol-4-yl)acetic acid</strong></strong> (0.40 M in N,N-dimethylacetamide, 113 muL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100 C., and passed through the reactor at 180 muL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) give 0.0067 g (38%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) delta 8.49 (d, J=2.44 Hz, 1H), 8.45 (d, J=2.75 Hz, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.60 (m, 2H), 4.07 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H). MS (APCI+) m/z 484.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Example 28 N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide [0718] A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 [0719] M in N,N-dimethylacetamide, respectively, 275 muL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 muL, 0.063 mmol), and <strong>[1152582-56-3]2-<strong>[1152582-56-3](1-methyl-1H-pyrazol-4-yl)acetic acid</strong></strong> (0.40 M in N,N-dimethylacetamide, 125 muL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100 C., and passed through the reactor at 180 muL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0168 g (68%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) delta 8.03 (d, J=2.14 Hz, 1H), 7.57 (s, 2H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H). MS (APCI+) m/z 483.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0367] AsolutionofExample 1GandDIPEA(0.182 Mand0.52 Min DMA, respectively, 221 f.LL, 0.40 mmol Example1 G (1.0 equivalent) and 1.21 mmol DIPEA (3.0 equivalents)),HATU (0.182 Min DMA, 221 f.LL, 0.40 mmol, 1 equivalent)and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 Min DMA,151 f.LL, 0.60 mmol, 1.5 equivalents) were mixed through aperfluoroalkoxy mixing tube (0.2 mm inner diameter), andloaded into an injection loop. The reaction segment wasinjected into the flow reactor (Hastelloy coil, 0.75 mm innerdiameter, 1.8 mL internal volume) set at 100 C., and passedthrough the reactor at 180 flL min-1 (10 minute residencetime). Upon exiting the reactor, the solution was loadeddirectly into an injection loop and purified by preparativeHPLC on a Phenomenex Lnna C8(2) 5 flill 100 A AXIAcolunm (50 mmx21.2 mm), eluting with a gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) at a flowrate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min lineargradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min lineargradient 100-5% A, 9.0-10 min 5% A) to provide the titlecompound. 1H NMR (400 MHz, DMSO-d6D20) o10.37 (s,lH), 7.59-7.46 (m, 4H), 7.37-7.27 (m, 2H), 7.18 (td, 1=8.5,3.1 Hz, lH), 7.14-6.93 (m, 2H), 6.90 (d, 1=8.7 Hz, lH), 5.82(s, lH), 3.92 (q, 1=7.0 Hz, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 1.14(t, 1=7.0 Hz, 3H). MS (APCI+) m/z 543.0 (M+Ht. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 10 - 35℃; for 10.0h; | Example 20 2-(4-methoxyphenyl)-2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide A solution of 2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100 mg, 0.30 mmol), <strong>[1152582-56-3]2-<strong>[1152582-56-3](1-methyl-1H-pyrazol-4-yl)acetic acid</strong></strong> (51.2 mg, 0.37 mmol), HATU (150 mg, 0.40 mmol) and DIEA (0.106 mL, 0.61 mmol) in DMF (3 mL) was stirred at room temperature for 10 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 75?99% ethyl acetate/hexane) to give the title compound (83 mg, 0.183 mmol, 60.2%) as white crystals. MS (API): Calculated 450.6, Found 451.1(M+H) 1H NMR(300 MHz,DMSO-d6):delta0.20(9H,s),3.36(2H,s),3.72(3H,s),3.76(3H,s),5.55(1H,d,J=7. 9 Hz),6.92(2H,d,J=8.7Hz),7.25(1H,s),7.34-7.60(7H,m),8.63(1H,d,J=7.6 Hz),10.28(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.9% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 10 - 35℃; for 10.0h; | (Step 4) A solution of 2-amino-2-(4-(methoxymethyl)phenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (104 mg, 0.30 mmol), <strong>[1152582-56-3]2-<strong>[1152582-56-3](1-methyl-1H-pyrazol-4-yl)acetic acid</strong></strong> (51.1 mg, 0.36 mmol), HATU (150 mg, 0.39 mmol) and DIEA (0.106 mL, 0.61 mmol) in DMF (1.5 mL) was stirred at room temperature for 10 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 40?80% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (45.0 mg, 0.097 mmol, 31.9%) as white crystals. MS(API): Calculated 464.6, Found 465.1(M+H) 1H NMR(300 MHz,DMSO-d6):delta0.17-0.22(9H,m),3.31(3H,s),3.38(2H,s),3.76(3H,s),4.37(2H,s),5.63(1H ,d,J=7.9 Hz),7.24-7.34(3H,m),7.39-7.60(7H,m),8.71(1H,d,J=7. 9 Hz),10.35(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; | Into a 100-mL round-bottom flask, was placed tert-butyl 5-[[5-(2-aminopyridin-4- yl)-1,3,4-thiadiazol-2-yl][(tert-butoxy)carbonyl]amino]-4-chloro-1H-indazole-1-carboxylate (120 mg, 0.22 mmol, 1.00 equiv), dichloromethane (10 mL), 2-(1-methyl-1H-pyrazol-4- yl)acetic acid (34 mg, 0.24 mmol, 1.10 equiv), HATU (109 mg, 0.29 mmol, 1.30 equiv), and DIEA (114 mg, 0.88 mmol, 4.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 20 mL of H2O then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) and chromatographed to give 60 mg (41%) of tert-butyl 5-[[(tert-butoxy)carbonyl](5-[2- [2-(1-methyl-1H-pyrazol-4-yl)acetamido]pyridin-4-yl]-1,3,4-thiadiazol-2-yl)amino]-4-chloro- 1H-indazole-1-carboxylate as a solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With thionyl chloride; at 0 - 20℃; | General procedure: Thionyl chloride (20.2g, 12.3mL, 0.170mol) was added dropwise to a solution of acid 26 (20.0g, 0.113mol) in dry methanol (200mL) at 0C over 1h. The reaction mixture was stirred overnight at rt. The methanol was evaporated, the solid residue was dissolved in water (300mL) and washed with CH2Cl2 (150mL). The layers were separated, and NaOH was added to the aqueous layer to pH=12-14, with further extraction with CH2Cl2 (3×200mL). The organic layers were mixed, dried over Na2SO4 and CH2Cl2 was evaporated to give ester 27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; at 100℃; for 10.0h; | General procedure: Nitrile 25 (21,5g, 0.1775mol) was added to a solution of NaOH (71.0g, 1.775mol) in distilled water (640mL). The reaction mixture was stirred overnight at reflux. The mixture was allowed to cool to rt, washed with CH2Cl2 (300mL), and aq HCl was added to acidify to pH=1. The water from the solution was evaporated and triturated with i-PrOH (300mL). The solid was filtered off, and the filtrate was evaporated in vacuo to give acid 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.9% | With dmap; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 1.5h; | To a suspension of 6-(3-methylimidazol-4-yl)isoquinolin-3-amine (XLVIII) (100 mg, 0.45 mmol), <strong>[1152582-56-3]2-(1-methylpyrazol-4-yl)acetic acid</strong> (XLIX (purchased from Enamine) (75 mg, 0.54 mmol), DMAP (27.2 mg, 0.22 mmol) and HATU (203.5 mg, 0.54 mmol) in DMF (5 mL) was added DIPEA (0.19 mL, 1.1 mmol). The resulting mixture was stirred at 80 C. for 1.5 h. The reaction mixture was cooled to room temperature and poured into water. The resulting solid was filtered and purified by silica gel chromatography (0?10% MeOH/CHCl3). The fractions containing the product were concentrated. The product was further purified by HPLC (0?35% MeCN/water) and the fractions containing the product concentrated, re-dissolved in MeOH and filtered through bicarbonate resin. The filtrate was concentrated and triturated in ether, filtered and dried under high vacuo to afford N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide 47 as a white solid (20.0 mg, 0.058 mmol, 12.9% yield). 1H NMR (499 MHz, DMSO-d6) delta ppm 3.59 (2H, s), 3.79 (3H, s), 3.82 (3H, s), 7.30 (1H, d, J=0.82 Hz), 7.36 (1H, s), 7.61 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 7.99 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.50 (1H, s), 9.13 (1H, s), 10.66 (1H, s); ESIMS found for C19H18N6O m/z 347.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 1.0h;Inert atmosphere; | To a solution of 5-((3R,5S)-3-Amino-5-methyl-piperidin-l -yl)-7-fluoro-quinoline-8- carbonitrile (40. mg; 0.14 mmol; 1.0 eq.), (1 -Methyl- lH-pyrazol-4-yl)-acetic acid (29 mg; 0.21 mmol; 1.50 eq.) and DIEPA (0.05 ml; 0.28 mmol; 2.0 eq.) in DMSO (2 ml) was added benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (93 mg; 0.21 mmol; 1.50 eq.). The resulting mixture was stirred at RT for lhr, until the reaction was completed. The crude was purified by prep HPLC, eluting with 20-60 %ACN/water (contained 0.1% ammonia), to yield the title compound. LC-MS (M+l) = 407.1H NMR (400 MHz, Methanol-i/4) d 9.04 - 8.91 (m, 1H), 8.59 (dd, J = 8.6, 1.6 Hz, 1H), 7.61 (dd, J = 8.6, 4.3 Hz, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 7.10 (d, J = 1 1.8 Hz, 1H), 4.19 (t, J = 11.3 Hz, 1H), 3.85 (s, 3H), 3.79 (d, J = 1 1.8 Hz, 1H), 3.52 (d, j = 12.1 Hz, 1H), 3.38 (s, 2H), 2.58 (q, j = 11.0 Hz, 2H), 2.13 (d, j = 11.6 Hz, 1H), 1.22 (q, J = 12.5 Hz, 2H), 1.05 (d, J = 6.3 Hz, 3H). |