Structure of 2093329-79-2
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| CAS No. : | 2093329-79-2 |
| Formula : | C10H11BrN4 |
| M.W : | 267.13 |
| SMILES Code : | CC(C)N1C(C2=CC=CC(Br)=N2)=NN=C1 |
| English Name : | 2-Bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine |
| MDL No. : | MFCD31555826 |
| InChI Key : | JGZSLGXLSHEGFA-UHFFFAOYSA-N |
| Pubchem ID : | 131801140 |
* 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 |
|---|---|---|
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 20 °C 2: 80 °C 3: acetic acid / acetonitrile / 95 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 1 h / 20 °C 2: dichloromethane / 6 h / Reflux 3: acetic acid; N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 90 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 1 h / 20 °C 2: dichloromethane / 6 h / Reflux 3: acetic acid; N-ethyl-N,N-diisopropylamine / acetonitrile / 90 °C |
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 2 h 2: 16 h / 80 °C 3: acetic acid / acetonitrile / 16 h / 95 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 2 h / 20 °C 2: 6 h / 55 °C 3: acetic acid / 6 h / 90 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 1 h / 20 °C 2: dichloromethane / 6 h / Reflux 3: N-ethyl-N,N-diisopropylamine; acetic acid / acetonitrile / 90 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / ethanol / 12 h / 90 °C 2: N,N-dimethyl-formamide / 12 h / 100 °C 3: acetic acid / acetonitrile / 12 h / 80 °C | ||
| Multi-step reaction with 3 steps 1: hydrazine hydrate / methanol / 16 h / 20 °C 2: 16 h / 80 °C 3: acetic acid / acetonitrile / 16 h / 95 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 80 °C 2: acetic acid / acetonitrile / 95 °C | ||
| Multi-step reaction with 2 steps 1: dichloromethane / 6 h / Reflux 2: acetic acid; N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: dichloromethane / 6 h / Reflux 2: acetic acid; N-ethyl-N,N-diisopropylamine / acetonitrile / 90 °C |
| Multi-step reaction with 2 steps 1: 16 h / 80 °C 2: acetic acid / acetonitrile / 16 h / 95 °C | ||
| Multi-step reaction with 2 steps 1: 6 h / 55 °C 2: acetic acid / 6 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: dichloromethane / 6 h / Reflux 2: N-ethyl-N,N-diisopropylamine; acetic acid / acetonitrile / 90 °C | ||
| Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 12 h / 100 °C 2: acetic acid / acetonitrile / 12 h / 80 °C | ||
| Multi-step reaction with 2 steps 1: 16 h / 80 °C 2: acetic acid / acetonitrile / 16 h / 95 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | With acetic acid In acetonitrile at 95℃; | |
| 82% | With acetic acid In acetonitrile at 95℃; for 16h; | 3 Step 3: 2-bromo-6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridine (Intermediate 1) N-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (1b) (16.0 g, 59.0 mmol) and iso-propylamine (12.0 g, 200 mmol) were dissolved in acetic acid (33 ml_) and acetonitrile (130 ml_). After observed smoke evolution subsided, the resultant solution was stirred at 95 °C for 16 hours. The reaction mixture was combined with another batch of this reaction (5 g scale) and concentrated in vacuo. The resulting material was diluted with water (130 ml_) and adjusted to pH = 7 with 1 N aqueous sodium hydroxide (120 ml_). The resulting mixture was then extracted with ethyl acetate (2 x 150 ml_) and the combined organic layer was washed with water (2 x 130 ml_) and concentrated in vacuo. The crude product was purified using column chromatography (0-100% ethyl acetate in petroleum ether) to provide the title compound as a yellow solid (16.9 g, average yield 82%). 1H NMR (400 MHz, CDCb) d 8.42 - 8.34 (m, 1H), 8.28 (d, J= 7.8 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 7.52 (d, J= 7.8 Hz, 1H), 5.57 (spt, J= 6.7 Hz, 1H), 1.56 (d, J=6.5 Hz, 6H). m/z (ESI) for (Ci0HnBrN4) 268.8 (M+H)+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 35% | With copper(I) thiophene-2-carboxylate; potassium carbonate In dimethyl sulfoxide at 140℃; for 1h; Microwave irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; Inert atmosphere; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; Inert atmosphere; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 42% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 20h; Inert atmosphere; | 161.4 Step 4: Example 161 [0655] To a solution of Example 161e (72 mg, 0.373 mmol), Example 161f (100 mg, 0.373 mmol), Pd2(dba)3 (34 mg, 0.373 mmol) and Cs2C03 (243 mg, 0.746 mmol) in 1,4-dioxane (10 mL) was added Xantphos (43 mg, 0.0746 mmol). The mixture was degassed with N2 three times, then heated to 100°C and stirred overnight for 20 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL), and extracted with DCM (50 mL*2). Combined organic layer was concentrated under reduced pressure to give crude product as a brown solid, which was then purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product (59 mg, yield 42%) as a white solid. LCMS [M+l]+ =380.0 1H NMR (400 MHz, DMSO-d6) 5 8.90 (s, 1H), 8.58 (d, J= 8.4 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.85 (d, J= 7.5 Hz, 1H), 7.28 (d, J= 21.8 Hz, 2H), 5.48-5.54(m, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium phosphate; copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane In N,N-dimethyl-formamide at 120℃; for 1h; Microwave irradiation; Inert atmosphere; Sealed tube; | 78.1 Step 1: Example 78d [0472] Into a 20-mL microwave tube was added Example 78a (1.0 g, 4.46 mmol), Example 78b (171 mg, 6.43 mmol), Cul (511 mg, 2.68 mmol), K3P04 (2.3 g, 10.71 mmol) and Example 78c (380 mg, 2.68 mmol) successively. DMF (10 mL) was added by syringe. The mixture was degassed by nitrogen for three times and sealed. The reaction was heated up to 120°C by microwave for 60 min. LCMS showed reaction completed. The mixture was added into 100 mL of H20 and extracted with ether acetate. The combined organic layers were washed by brine, dried over Na2S04 and concentrated. The residue was purified by flash chromatography to afford Example 78d (950 mg, crude, yield: 51.9%) as a brown solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 44.6% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 5h; Inert atmosphere; | 3 3-(4-Cyclopropylimidazol- 1 -yl)-6-[6-(4-isopropyl- 1 ,2,4-triazol-3-yl)-2-pyridyl]-7,8-dihydro-1 ,6-naphthyridin-5 -one; hydrochloride A solution of 2-bromo-6-(4-isopropyl- 1 ,2,4-triazol-3 -yl)pyridine (0.0819 g, 0.276mmol), 3 -(4-cyclopropylimidazol -1 -yl)-’7, 8-dihydro-6H- 1 ,6-naphthyridin-5 -one (0.060 g, 0.212 mmol) and Cs2CO3 (0.208 g, 0.637 mmol) in 1,4-dioxane (4.00 mL) is stirred for 1 minute under N2. XantPhos (0.0368 g, 0.0637 mmol) and Pd2(dba)3 (0.0200 g, 0.0212 mmol) are added sequentially and the resulting mixture is stirred at 110 °C for 5 hours underN2. The mixture is diluted with DCM (2x75mL) and washed with saturated brine (25 mL).The organic layer is dried over Na2SO4, filtered, and evaporated to dryness. The crudeproduct is purified by silica gel flash chromatography, eluting with a gradient of 0% to 5%MeOH in DCM to give a residue. The material is further purified by Pre-HPLC: LC column:YIVIC-Actus Triart C18 150x30 5 tm; A: H20 (0.05% HC1); B: ACN, gradient: 0-70% B inA; column temperature: room temperature; flow rate: 25 mL/min. The material is dissolvedin water and lyophilized to give the title compound (0.0468 g, 44.6%) as a white solid. ES/MS (m/z): 441.0 (M+H), LCMS: t(R) = 1.303 mm in 10-80% A to B, 4 mm chromatography (Xtimate C18 2.1x30 mm), ‘H NMR (400 IVIFIz, CD3OD) 9.84 (s, 1H), 9.52 (d, J1.6 Hz, 1H), 9.09 (d, J=2.4 Hz, 1H), 8.78 (d, J=3.2 Hz, 1H), 8.25 - 8.21 (m, 1H),8.17 (t, J=7.6 Hz, 1H), 8.11 -8.07 (m, 1H), 7.97 (s, 1H), 5.70 (td, J=6.4, 13.2 Hz, 1H), 4.51 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.16 - 2.01 (m, 1H), 1.71 (d, J=6.4 Hz, 6H), 1.22 - 1.15 (m, 2H), 0.99-0.93 (m, 2H) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85.6% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 3h; Inert atmosphere; | 4 3-(1 -Isopropylpyrazol-4-yl)-6-[6-(4-isopropyl- 1 ,2,4-triazol-3-yl)-2-pyridyl]-7,8-dihydro- 1,6-naphthyri din-S -one To a solution of 3 -(1-i sopropylpyrazol -4-yl)-7, 8-dihydro-6H- 1 ,6-naphthyridin-S -one (0.0800 g, 0.297 mmol) and 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (0.114 g,0.3 86 mmol) in 1,4-dioxane (6.00 mL) is added Cs2CO3 (0.242 g, 0.74 1 mmol). The mixture is degassed with a stream of N2 for 5 minutes. XantPhos (0.0343 g, 0.0593 mmol) and Pd2(dba)3 (0.0280 g, 0.0297 mmol) are added sequentially and the resulting mixture is stirred at 110 °C for 3 hours under N2. The mixture is extracted with DCM (2x75mL) and washed with saturated brine (25 mL). The organic extracts are dried over Na2SO4, filtered, andevaporated to dryness. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0% to 5% MeOH in DCM. The residue is re-crystallized from water and CH3CN and dried by lyophilization to give the title compound (0.1165 g, 85.6%) as a light yellow solid. ES/MS (m/z): 443.1 (M+H), LCMS: t(R) = 1.918 mm in 10-80% A to B A: H20 (0.05% HC1); B: ACN, 4mm chromatography (Xtimate C18 2.1*30 mm), ‘HNMR (400 IVIHz, CDC13) 8.83 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.38 (s, 1H), 8.14(d, J=7.2 Hz, 1H), 8.06 - 7.99 (m, 1H), 7.96 - 7.91 (m, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 5.52(quin, J=6.8 Hz, 1H), 4.62 - 4.52 (m, 1H), 4.36 (t, J=6.8 Hz, 2H), 3.35 (t, J=6.4 Hz, 2H), 1.58(d, J 1.6 Hz, 6H), 1.57 (d, J= 1.6 Hz, 6H) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | Stage #1: 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine With hydrogen bromide; sodium nitrite In water at 0℃; for 0.5h; Stage #2: With bromine In water at 20℃; for 2h; | 1.4 Fourth step: Preparation of 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine The compound obtained in the third step (3.0 g, 14.8 mmol)The aqueous solution (30 mL) was dissolved in hydrobromic acid, and after cooling to 0 ° C, an aqueous solution of sodium nitrite (1.0 g, 14.8 mmol) was added dropwise.Stirring was continued at this temperature for 0.5 hours.Then bromine (2.37 g, 14.8 mmol) was added dropwise.Stir at room temperature for 2 hours.The reaction solution was made weakly alkaline with a 2N aqueous solution of sodium hydroxide.The ethyl acetate layer was extracted, and the ethyl acetate layer was washed with an aqueous sodium thiosulfate solution.Dry, filter, concentrate,The residue was purified by silica gel column chromatography.The title compound (2.8 g, yield: 72%) was obtained. |
| 37.7% | With tert.-butylnitrite; benzyltriethylammonium bromide at 25℃; for 6h; | 5 2-Bromo-6-(4-isopropyl- 1 ,2,4-triazol-3 -yl)pyridine To a solution of 6-(4-isopropyl- 1 ,2,4-triazol-3 -yl)pyridin-2-amine (10.0 g, 48.2 mmol) in dibromomethane (150 mL) is added benzyltriethylammonium bromide (45.3 g, 193 mmol) and tert-butyl nitrite (49.7 g, 482 mmol) at 25 °C. The mixture is stirred at 25 °C for 6 hours. The reaction is quenched by the addition of aq. NaHCO3 (30 mL) solution and theproduct is extracted with DCM (150 mL). The organic extracts are washed with brine (15 mL), dried over Na2504, and concentrated in vacuo. The residue is purified by silica gel flash chromatography, eluting with a gradient of 2.5% to 3.3% MeOH in DCM to give the title compound (5.4 g, 37.7%) as a yellow solid. ‘H NMR (400 IVIFIz, CDC13) 8.30 (s, 1H), 8.26- 8.18 (m, 1H), 7.67 -7.61 (m, 1H), 7.47 (d, J=8.0 Hz, 1H), 5.63 - 5.41 (m, 1H), 1.50 (d,J=7.2Hz,6H) |
| 27% | With hydrogen bromide; bromine; sodium nitrite In water at 0 - 20℃; | 2 Dissolve intermediate 1 (3 g, 14.8 mmol) in hydrobromic acid solution (30 mL), cool to 0 °C, add NaNO2(1 g, 14.8 mmol) aqueous solution (10 mL) dropwise until the solution turns starch potassium iodide paper blue, then add Br2(1 g, 14.8 mmol) dropwise, stir overnight at room temperature. Adjust to weak alkalinity with 1N NaOH aqueous solution, extract with ethyl acetate, wash the organic phase with sodium thiosulfate aqueous solution, dry column chromatography (DCM/MeOH = 80/1 - 30/1) to obtain intermediate 2.1.17 g of brown solid was obtained by this method with a yield of 27%. |
| With hydrogen bromide; bromine; sodium nitrite In water at 0 - 25℃; for 16h; | 1 Step 1: Synthesis of Compound WXBB-9 Compound WXBB-8 (10.00 g, 48.71 mmol, 98.99% purity, 1.00 eq) was dissolved in hydrogen bromide (92.90 g, 539.71 mmol, 62.35 mL, 47% purity, 11.08 eq), and then liquid bromine (46.62 g, 291.77 mmol, 15.04 mL, 5.99 eq) was added dropwise slowly at 0° C. Then sodium nitrite (18.72 g, 271.31 mmol, 14.74 mL, 5.57 eq) was dissolved in water (12.60 mL), and then added to the mixture. The system was gradually warmed to 25° C. and stirred for 16 hours. After the reaction was completed, the reaction solution was poured into water (300 mL), adjusted to pH 7-8 with sodium hydroxide and extracted with dichloromethane (300 mL*2). The organic phases were combined, washed successively with water (300 mL) and saturated brine (300 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was dried on a rotary evaporator under reduced pressure to obtain a crude product. The crude product was purified by a column. Compound WXBB-9 (6.00 g, 20.40 mmol, 41.88% yield, 90.81% purity) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.370 (s, 1H), 8.306-8.287 (d, 1H), 7.718-7.679 (m, 1H), 7.545-7.509 (t, 1H), 5.634-5.550 (m, 1H), 1.577-1.561 (d, 6H). MS m/z: 268.8 [M+H]+. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With acetic acid; N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 16h; | 34 A mixture of 1C (2.1 g, 7.75 mmol), propan-2-amine hydrochloride (3.71 g, 38.8 mmol) and 236 DIPEA (5.0 g, 38.8 mmol) in 237 acetonitrile (32 mL) and 4 acetic acid (8 mL) was heated to 90° C. overnight. After cooling, the reaction mixture was concentrated under vacuum and purified by column chromatography on silica gel (1%-50% 32 EtOAc in 60 pet. ether) to give 211 triazole 85A (1.7 g, 82% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1), 8.15 (d, J=8 Hz, 1H), 7.96-7.92 (m, 1H), 7.77 (d, J=8 Hz, 1H), 5.34-5.24 (m, 1H), 1.48 (d, J=6.8 Hz, 6H) ; ESI m/z 266.9, 268.9 [M+H]+ . |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 55% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; | 34 A mixture of 85B (210 mg, 1.0 mmol), 211 85A (267 mg, 1.0 mmol), 51 Pd2(dba)3 (28 mg, 0.03 mmol), Xantphos (29 mg, 0.05 mmol) and 50 Cs2CO3 (391 mg, 1.2 mmol) in 52 dioxane (45 mL) was heated to 100° C. overnight. After cooling to room temperature, the reaction was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (1%-5% 23 MeOH in 32 EtOAc) to provide 240 compound 85 (220 mg, 55% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 9.0 (s, 1H), 8.93 (s, 1H), 8.66-8.61 (m, 2H), 8.19 (d, J=8 Hz, 1H), 8.13 (s, 1H), 8.10-8.06 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.54-7.51 (m, 1H), 5.57-5.51 (m, 1H), 5.21 (s, 2H), 1.59 (d, J=6.8 Hz, 6H); ESI m/z 397.0 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 4% | With tris(dibenzylideneacetone)dipalladium (0) chloroform adduct; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 2h; Inert atmosphere; | 18 3-(2-Fluoro-4-methylphenyl)-l-(6-(4-isopropyl-4//-l,2,4-tnazol-3-yl)pyndin-2- yl)-l//-imidazol-2(3i/)-one (Compound III-01): To a solution of Compound l7c (80 mg, 0.33 mmol) and 2-bromo-6-[4-(propan-2-yl)-4i/-l, 2, 4-triazol-3-yl] pyridine (88 mg, 0.33 mmol) in dioxane (2 mL) was added Pd2(dba)3.CHCL (34 mg, 0.03 mmol), Xantphos (35 mg, 0.06 mmol) and CS2CO3 (215 mg, 0.66 mmol). The mixture solution was stirred for 2 h at 80°C under N2 atmosphere. The mixture was diluted with ethyl acetate. The resulted mixture was washed with water and brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with MeOH/DCM (7:93). The resulted crude was purified by a Cl 8 column with ACN/H2O (42:58). This resulted in 6.0 mg (4%) of the title compound as a white solid. LCMS (ESI, m/z): [M+H]+ = 379.3. TlNMR (300 MHz, DMSO-rie, ppm): d 8.93 (s, 1H), 8.42-8.39 (m, 1H), 8.15-8.13 (m, 1H), 8.00-7.98 (m, 1H), 7.51-7.06 (m, 5H), 5.43-5.34 (m, 1H), 2.37 (s, 3H), 1.54-1.45 (m, 6H). |