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CAS No. : | 356560-80-0 | MDL No. : | MFCD08689534 |
Formula : | C6H4BrN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CXRXKDSDRWLKTK-UHFFFAOYSA-N |
M.W : | 198.02 | Pubchem ID : | 11513934 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.69 |
TPSA : | 30.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.49 cm/s |
Log Po/w (iLOGP) : | 1.86 |
Log Po/w (XLOGP3) : | 1.44 |
Log Po/w (WLOGP) : | 1.49 |
Log Po/w (MLOGP) : | 1.76 |
Log Po/w (SILICOS-IT) : | 1.2 |
Consensus Log Po/w : | 1.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.64 |
Solubility : | 0.453 mg/ml ; 0.00229 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.68 |
Solubility : | 4.14 mg/ml ; 0.0209 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.57 |
Solubility : | 0.533 mg/ml ; 0.00269 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.61 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With pyridine; hydroxylamine-O-sulfonic acid In methanol at 0 - 20℃; for 12 h; Inert atmosphere | To a solution of N'-(5-bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 1 7.54 mmol, 1 .00 equiv) in methanol (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2,00 equiv) and (aminooxy)sulfonic acid (3 , 6 g, 31 .83 mmol, 1 .30 equiv). The resulting solution was stirred for 1 2 h at rt. After the reaction completed, the mixture was concentrated under vacuum The residue was diluted with 1 50 mL of ethyl acetate then washed with 1 x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a sil ica gel column eluted with ethyl acetate/hexane ( I ; 1 ) to give 2.5 g (72percent) title compound as a solid. LC/MS (Method D, ESI): RT= 1.1 min, m/z = 198.0 [M+H] |
72% | With pyridine; hydroxylamine-O-sulfonic acid In methanol at 0 - 20℃; for 12 h; Inert atmosphere | To a solution of N'-(5- bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 1 7.54 mmol, 1 .00 equiv) in methanol (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2,00 equiv) and (aminooxy)sulfonic acid (3 , 6 g, 31 .83 mmol, 1 .30 equiv). The resulting solution was stirred for 1 2 h at rt. After the reaction completed, the mixture was concentrated under vacuum The residue was diluted with 1 50 mL of ethyl acetate then washed with 1 x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a sil ica gel column eluted with ethyl acetate/hexane ( I ; 1 ) to give 2.5 g (72percent) title compound as a solid. LC/MS (Method D, ESI): RT= 1 . 1 min, m z = 198.0 [M+H] " |
72% | With pyridine; hydroxylamine-O-sulfonic acid In methanol at 0 - 20℃; for 12 h; Inert atmosphere | To a solution of N'-(5-bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in MeOH (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonic acid (3.6 g, 31 .83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1 : 1 ) to give 2.5 g (72percent) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 min, m/z = 198.0 [M+H] +. |
72% | at 0 - 20℃; for 12 h; Inert atmosphere | [0206] Step 2. 6-Bromo-[1,2,4ltriazolo[1,5-alpyridine. To a solution of N’-(5-bromo- pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in methanol (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonic acid (3.6 g, 31.83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1:1) to give 2.5 g (72percent) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 mi m/z = 198.0 [M+H]. |
72% | With pyridine; hydroxylamine-O-sulfonic acid In methanol at 0 - 20℃; for 12 h; Inert atmosphere | Step 2. 6-Bromo-rL2,41triazolorL5-alpyridine. To a solution of N'-(5-bromo- pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in methanol (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2.00 equiv) and (aminooxy) sulfonic acid (3.6 g, 31.83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1: 1) to give 2.5 g (72percent) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 min, m/z = 198.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Inert atmosphere | The A48-1 (180mg, 0.91mmol), bis (pinacolato) borate (348mg, 1.37mmol), 1,1'- bis (diphenylphosphino) ferrocene palladium (II)(37mg, 0.045mmol), potassium acetate (180mg, 1.83mmol) was dissolved in tetrahydrofuran (10mL). Under nitrogen for 8h at 80 , cooled toAt room temperature, filtered through celite, the solvent was evaporated under reduced pressure to give a dark solid (300mg, content: 74percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 9.27 G (16.8 mmol) of the compound from Step C in 200 mL of ethanol/toluene (1 : 1) was added 6.7 g (33.6 mmol) OF 6-BROMO [1, 2, 4] TRIAZOL6 [1, 5-A] pyridine (Intermediate 18), 2.9 g (3.6 mmol) of [1, 1'-BIS (diphenylphosphino) ferrocenedichloropalladium (II) (complex with dichloromethane, L : 1), and 42 mL (84 mmol) of 2N aqueous sodium carbonate solution. The reaction mixture was stirred at 90 C under nitrogen for 12 h. After cooling to ambient temperature, 600 mL of ethyl acetate was added to the mixture and the organic phase was washed sequentially with 0.5N aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC on a KILOPREP 100 G system (Kromasil C8 16 micron, isocratic elution, 40% acetonitrile/water with 0.1% TFA) to afford the coupled product. The above intermediate was then dissolved in a 1 : 1 mixture of dichloromethane and TFA, stirred for 30 min at room temperature, then concentrated in vacuo. The product was purified by reverse phase HPLC on a KILOPREP@ 100 G system (Kromasil C8 16 micron, gradient elution, 0% to 65% acetonitrile/water with 0. 1 % TFA) to afford the product as A TFA salt. This salt was then dissolved in water, and the aqueous solution adjusted to pH 2 via addition of 2N aqueous sodium carbonate solution. After extracting the aqueous mixture with 3: 1 chloroform : isopropanol (5 x 300 mL), the combined organic layers were washed once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The resultant amine was then dissolved in dichloromethane and 30 ML of 2N hydrogen chloride in ether was added to the solution. After stirring for 60 min, the solution was evaporated to afford the title compound as a white hydrochloride salt. The compound was further purified by recrystallization (ethanol/ether) then LYOPHILIZATION from water/acetonitrile (40: 60,100 mL) to afford the title compound. MS 443.2 (M+1). 500 MHZ'H NMR (CD30D) 5 9.12 (s, 1 H), 8.48 (s, 1 H), 8.06 (dd, J = 9.4, 1.6 Hz, 1 H), 7.87 (d, J=9. 3HZ, LH), 7. 85 (d, J = 8. 0 HZ, 2 H), 7.58 (dd, J = 8. 2,1. 6 HZ, 2 H),. 4.69 (dd, J = 57.4, 8.4 Hz, 1 H), 4.58 (dd, J = 13.8, 8.2 Hz, 1 H), 4.52-3. 74 (M, 6 H), 2.96 (s, 3 H), 2.94 (d, J = 1.1 Hz, 3 H), 2.69-45 (M, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 100℃; for 18h; | To the boronate from Step A in 80 mL of ETHANOL/TOLUENE (1 : 1) was added 6.0 g (11. 4 mmol) OF 6-BROMO [1, 2,4] triazolo [1, 5-a] pyridine (Intermediate 18), 400 mg (0.49 mmol) of [L, 1'-BIS (diphenylphosphino) FERROCENE] DICHLOROPALLADIUM (II) (complex with dichloromethane, 1 : 1), and 37 mL (74 mmol) of 2N aqueous sodium carbonate solution. The reaction mixture was stirred at 100 C under nitrogen for 18 h. After cooling to ambient temperature, 600 ML of ethyl acetate was added to the mixture and the organic phase was washed sequentially with 1N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 10 to 90% ACETONITRILE/WATER with 0.1% TFA) to afford the pure coupled product as a mixture of diastereomers at the benzylic position. MS 516.4 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of N'-(5-bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 1 7.54 mmol, 1 .00 equiv) in methanol (40 mL) maintained under nitrogen at 0 C was added pyridine (4 mL, 2,00 equiv) and (aminooxy)sulfonic acid (3 , 6 g, 31 .83 mmol, 1 .30 equiv). The resulting solution was stirred for 1 2 h at rt. After the reaction completed, the mixture was concentrated under vacuum The residue was diluted with 1 50 mL of ethyl acetate then washed with 1 x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a sil ica gel column eluted with ethyl acetate/hexane ( I ; 1 ) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1.1 min, m/z = 198.0 [M+H] |
72% | With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of N'-(5- bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 1 7.54 mmol, 1 .00 equiv) in methanol (40 mL) maintained under nitrogen at 0 C was added pyridine (4 mL, 2,00 equiv) and (aminooxy)sulfonic acid (3 , 6 g, 31 .83 mmol, 1 .30 equiv). The resulting solution was stirred for 1 2 h at rt. After the reaction completed, the mixture was concentrated under vacuum The residue was diluted with 1 50 mL of ethyl acetate then washed with 1 x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a sil ica gel column eluted with ethyl acetate/hexane ( I ; 1 ) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1 . 1 min, m z = 198.0 [M+H] " |
72% | With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of N'-(5-bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in MeOH (40 mL) maintained under nitrogen at 0 C was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonic acid (3.6 g, 31 .83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1 : 1 ) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 min, m/z = 198.0 [M+H] +. |
72% | With pyridine; hydroxylamine-O-sulfonic acid; at 0 - 20℃; for 12h;Inert atmosphere; | [0206] Step 2. 6-Bromo-[1,2,4ltriazolo[1,5-alpyridine. To a solution of N?-(5-bromo- pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in methanol (40 mL) maintained under nitrogen at 0 C was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonic acid (3.6 g, 31.83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1:1) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 mi m/z = 198.0 [M+H]. |
72% | With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; for 12h;Inert atmosphere; | Step 2. 6-Bromo-rL2,41triazolorL5-alpyridine. To a solution of N'-(5-bromo- pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in methanol (40 mL) maintained under nitrogen at 0 C was added pyridine (4 mL, 2.00 equiv) and (aminooxy) sulfonic acid (3.6 g, 31.83 mmol, 1.30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1: 1) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1.15 min, m/z = 198.0 [M+H]+. |
With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; | To an ice-cooled, stirred solution of the crude product from Step A (3.94 g, 17.3 mmol) in methanol (30 mL) and pyridine (2.73 g, 35.6 mmol) was added HYDROXYLAMINE-O- sulfonic acid (2.54 g, 22.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (100 ML) and saturated aqueous brine solution (100 mL), dried (magnesium sulfate) and concentrated in vacuo to yield a brown solid, which was recrystallized from dichloromethane to afford the title compound as an orange solid. LC/MS 197.9 and 199.9 (M+1). | |
With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; | Step B: 6-Bromo [1,2,4]triazolo[1,5-al]pyridine; To an ice-cooled, stirred solution of the crude product from Step A (3.94 g, 17.3 mmol) in methanol (30 mL) and pyridine (2.73 g, 35.6 mmol) was added hydroxylamine-O-sulfonic acid (2.54 g, 22.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (100 mL) and saturated aqueous brine solution (100 mL), dried (magnesium sulfate) and concentrated in vacuo to yield a brown solid, which was recrystallized from dichloromethane to afford the title compound as an orange solid. LC/MS 197.9 and 199.9 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 14h; | Step C: tert-Butyl I( lS,25)-1 -I(3,3-difluoropYrrolidin-I-yl)carbonyll-3-(dimethylaminol-3-oxo-2- (4-f 1,2,41triazolof 1,5-alpyridin-6-(at)yclohex-3-en-1-,(at)l)pronyllcarbamate; The material from Step B (2.0 g, 3.6 mmol) was combined with [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.43 g, 0.53 mmol), potassium carbonate (1.5 g, 11 mmol), and 6-bromo [1,2,4]triazolo[1,5-a]pyridine pure, 1.1 g, 4.3 mmol) and the flask was flushed with nitrogen. DMF (35 mL) was added, and the resulting mixture was heated at 80 C for 14 h. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography twice (0-5% methanol in dichloromethane, then 0-5% methanol in ethyl acetate) to afford the title compound. LC/MS 547.3 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.6% | 6-Bromo-[1,2,4] triazolo[1,5-a] pyridine (D6) D5 (16.2 g, ~56.6 mmol, 1 eq) was dissolved in methanol (90 ml) and pyridine (10 ml) under argon and cooled down to 0 C. To this was added, with stirring, hydroxylamine-O-sulfonic acid (7.3 g, 75.2 mmol, 1.3 eq) to form a purple suspension. This was allowed to reach room temperature and stirred for 16 h. After removing the solvents, the residue was suspended in aqueous sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate (2*200 ml). The organic layer was then washed with water and brine (100 ml of each), dried (MgSO4) and the solvent removed. Purification by flash chromatography on silica, eluding with a gradient solvent system of first 2:1 40-60 C. petroleum ether:ethyl acetate to 1:1 40-60 C. petroleum ether:ethyl acetate afforded the product as a pale yellow solid (5 g, 44.6%); 1H NMR (250 MHz, CDCl3) delta: 7.65 (1H, d), 7.69 (1H d), 8.34 (1H, s), 8.77 (1H, s),; m/z [APCIMS]: 198/200 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of the boronate ester (0.45 g, 0.76 mmol, partial pure) from step C above, 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (0.18 g, 0.92 mmol), and cesium carbonate (0.74 g, 2.3 mmol) in a solution of DMF (8 mL) and water (2 mL) was purged with argon for about 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (56 mg, 0.076 mmol) was added to the mixture, which was then heated at 80 0C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was purified by flash column chromatography (dichloromethane/methanol 99:1 to 96:4), followed by preparative thin layer chromatography (dichloromethane/methanol 95:5) to give benzazepine (0.27 g, partially pure) as a yellow solid, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | (b) 6-Ethenyl[l,2,4]triazolo[l,5-.]pyridine; 6-Bromo[l,2,4]triazolo[l,5-alpha]pyridine (0.5g, 2.5mmol) was dissolved in degassed DME (2OmL) under argon and tetrakis triphenylphosphine palladium (58mg, 0.05mmol) was added under argon and the orange solution was stirred at room temperature under argon for about 40 minutes. Potassium carbonate (345mg, 2.5mmol), water (4mL) and triethenylboroxin pyridine complex (for a synthesis see Kerins, F.; O'Shea, D. J. Org. Chem. (2002), 67(14), 4968-4971) (162mg, lmmol) were then added and the mixture was stirred at reflux for 4h (the colour of the reaction changed to yellow). The reaction was stirred at reflux overnight. A further 1% of tetrakis triphenylphosphine palladium, 0.2eq of triethenylboroxin pyridine complex and lOOmg of potassium carbonate were added and the reaction was stirred at reflux for Ih. The reaction was cooled to room temperature, diethylether was added and the aqueous was extracted (3x80mL).The organics were dried (magnesium sulphate), filtered and reduced to afford a solid which was subjected to silica chromatography (0-5% methanol in dichloromethane) to afford the title compound (340mg, 93%). MS (ES+) m/z 146 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydroxylamine-O-sulfonic acid; In methanol; at 0 - 20℃; | Intermediate 4; [l,2,4]triazolo[l,5-alpha]pyridine-6-carbaldehyde; <n="115"/>(a) 6-Bromo[l,2,4]triazolo[l,5-alpha]pyridine; To a stirred solution of 2-amino-5-bromo-pyridine(5g, 28.9mmol) in DMF (12 rnL) was added DMF-DMA (12mL) and the solution was heated at 1300C overnight. The reaction was then cooled to room temperature and the volatiles removed to afford the desired intermediate N-(5-bromo-2-pyridinyl)imidoformamide. 1H NMR(400MHz) delta(DMSO) 6.76 (IH, d), 7.73 (IH, ), 8.24 (IH, m), 8.45 (IH, s) The intermediate was dissolved in methanol (4OmL), treated with pyridine (4.6mL) and cooled to O0C. Hydroxylamine-o-sulfonic acid (4.52g) was added and the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The solvents were then removed and the residue was partitioned between a saturated solution of sodium bicarbonate and 20% methanol in dichloromethane. The phases were separated and the aqueous layer was extracted again with 20% methanol in dichloromethane (2x250mL). The organics were washed with water, brine, dried (magnesium sulphate), filtered and reduced to afford 4.7g of crude product. This was dissolved in 20% methanol in dichloromethane and washed with brine, then dried, filtered and evaporated to afford 4g of impure product. The residue was subjected to column chromatography on silica gel to afford 2.37g of the title compound. MS (ES+) m/z 198/200 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 110℃; for 23h; | To a solution of <strong>[356560-80-0]6-bromo[1,2,4]triazolo[1,5-a]pyridine</strong> (400 mg) in DMF were added tris(dibenzylideneacetone)dipalladium (0), 1'-bis(diphenylphosphino)ferrocene, and Zn(CN)2 under a nitrogen atmosphere, followed by stirring at 110C for 23 hours. It was cooled to room temperature, and saturated NH4Cl (12 ml), a saturated NH3 solution (6 ml), and H2O (12 ml) were added thereto. The reaction mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 5% CH3OH/chloroform)[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile as a dark red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); potassium acetate;Inert atmosphere; | The A48-1 (180mg, 0.91mmol), bis (pinacolato) borate (348mg, 1.37mmol), 1,1'- bis (diphenylphosphino) ferrocene palladium (II)(37mg, 0.045mmol), potassium acetate (180mg, 1.83mmol) was dissolved in tetrahydrofuran (10mL). Under nitrogen for 8h at 80 , cooled toAt room temperature, filtered through celite, the solvent was evaporated under reduced pressure to give a dark solid (300mg, content: 74%). |
A solution of 6-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridine (0.15 g, 0.75 mmol), bispinacolatodiboron (0.29 g, 1.14 mmol) and KOAc (0.11 g, 1.13 mmol) in 1 ,4- dioxane (5.0 ml_) was degassed by flushing with nitrogen for 15 min. Tricyclohexylphosphine (0.025 g, 0.09 mmol) and tris(dibenzyledineacetone) dipalladium (0) (0.038 g, 0.037 mmol) was then added to the reaction mixture, which was again degassed by nitrogen for 15 min. The resulting reaction mixture was heated to 1000C for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite bed and the filtrate was concentrated to get the crude residue that was carried forward to the next step without further purification. MS: 246.10 (M+H)+. | ||
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80.0℃;Inert atmosphere; | Under an argon atmosphere, 277 mg (0.303 mmol) of tris-(dibenzylidene-acetone)-dipalladium(0) and 224 mg (0.727 mmol) of tricyclohexylphosphine were dissolved in 30 ml dioxane. J410 mg(5.555 mmol) of 4,4,4'4'5,5,5'5'-octamethyl-2,2'-bi-l,3,2-dioxaborolan, 1000 mg (5.050 mmol) of the compound from example 49 A and 743 mg (7.575 mmol) potassium acetate were added and the mixture was stirred overnight at 800C. After cooling, dioxane was added to the reaction mixture and it was filtered on Celite. The filtrate was concentrated in a rotary evaporator at reduced pressure and dried under high vacuum. We obtained 2520 mg of 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)[l,2,4]triazolo[l,5-a]pyridine as raw product, which was reacted further without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 4h; | To a solution of 6-bromo-[l,2,4]triazolo[1,5-a]pyridine (700 mg, 3.5350 mmol), diphenylmethanimine (1.28 g, 7.06 mmol) and t-BuONa (680 mg, 7.076 mmol) in toluene (50 mL) were added BINAP (221 mg, 0.3549 mmol) and Pd2(dba)3 (167 mg, 0.1769 mmol). The mixture was degassed for 5 min and refilled with N2 and then stirred at 100 C for 4 h. The reaction was quenched with water (100 mL), and extracted with EtOAc (100 mLx 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1 to 1/1) to give the title compound as a yellow solid (1.01 g, 95.8%) .MS (ESI, pos. ion) m/z: 299.2 [M+H]+;1H NMR (400 MHz, CDCl3) d (ppm): 8.21 (s, 1H), 8.04 (d, 7 = 1.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.50 (dd, J= 8.4, 2.9 Hz, 2H), 7.42 (t, J= 7.5 Hz, 2H), 7.31 (t, J= 6.2 Hz, 3H), 7.14 (dd, J= 7.7, 1.7 Hz, 2H), 7.03 (dd, J= 9.4, 2.0 Hz, 1H). |
95.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 4h;Inert atmosphere; | To <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (700 mg, 3.5350 mmol),Benzophenone imine (1.28g, 7.06mmol)And t-BuONa (680mg, 7.076mmol)Intoluene (50mL) solutionBINAP (221mg, 0.3549mmol)And Pd2(dba)3 (167 mg, 0.17690 mmol).The resulting mixture was degassed for 5 minutes.And charge N2,It was then stirred at 100 C for 4 hours.After the reaction,The reaction was quenched with water (100 mL).Extracted with EtOAc (100 mL×3).The combined organic phases were dried over anhydrous Na 2 SO 4 .Filter and concentrate under reduced pressure.The residue obtained was purified by silica gel column chromatography (EtOAc/EtOAc (v/v)The title compound was obtained as a yellow solid (1.01 g, 95.8%). |
69% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; | 6-Bromo-[l,2,4]triazolo[l,5-a]pyridine (300 mg, 1.5 mmol), bezophenone imine (326 mg, 1.8 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), BINAP (14 mg, 0.02 mmol) and sodium terf-butoxide (202 mg, 2.1 mmol) were combined in toluene and heated at 80 0C overnight. The mixture was concentrated under reduced pressure and purified by Biotage SP4 (ethyl acetate / petroleum ether gradient) to give the desired product as a yellow crystalline solid (310 mg, 69 %). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.21 (dd, J=9.39, 2.06 Hz, 1 H), 7.24 - 7.29 (m, 2 H), 7.32 - 7.40 (m, 3 H), 7.47 - 7.54 (m, 2 H), 7.55 - 7.62 (m, 1 H), 7.66 (d, J=8.70 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 8.35 (s, 1 H), 8.41 (d, J=I.83 Hz, 1 H); m/z (ES+APCI)+ : 299 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step C: tert-Butyl [(1S,2S)-1-[(3S)-3-fluoropyrrolidin-1-yl]carbonyl 1-2-(4-hydroxy-4- f 1,2,41triazolof 1,5-alpyridin-6-ylcyclohexyl(at)pro(at)(at)lcarbamate; To a solution of <strong>[356560-80-0]6-bromo[1,2,4]triazolo[1,5-a]pyridine</strong> prepared in Step B (0.11 g, 0.56 mmol) in THF (1.8 mL) at-78 C was added a solution of n-butyllithium in hexane (2.4 M, 0.45 mL, 1.1 mmol). The resulting solution was stirred at-78 C for 40 min, whereupon Intermediate 11 (0.068 g, 0.18 mmol) was added as a solution in THF (1 mL). After an additional 1 h at -78 C, saturated aqueous ammonium chloride was added and the mixture was allowed to warm to ambient temperature. A small amount of water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to deliver the title compound. LC/MS 512.5 (M+Na), 390.4 (M+I-Boc), 372.4 (M+1-Boc-water). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | EXAMPLE 3(S)-3-((S)-l -(4-([1 ,2,4]triazolo[l ,5-a]pyridin-6-yl)phenyl)ethyl)-6-(2-hydroxy-2- methylpropyl)-6-phenyl- 1 ,3-oxazinan-2-one To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-l-(4- (4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-l ,3-oxazinan-2-one (300 mg, 0.63 mmol) and 6-bromo-[l,2,4]triazolo[l,5-a]pyridine (149 mg, 0.75 mmol) in dry 1,4-dioxane (15 mL) were added 2M aq Cs2CO3 (2 mL) and Pd(PPh3)Cl2 (40 mg, 0.056 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (50 mL) and EtOAc (100 mL), the mixture was extracted with EA (3x50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-3-((S)-l-(4-([l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl- 1 ,3 -oxazinan-2- one (188 mg, yield: 63.5%). LC-MS Method tR = 1.18 min, m/z = 471, 418; 1H NMR (CDCl3): deltal.05 (s, 3H), 1.12 (s, 3H), 1.49-1.51 (m, 3H), 2.15-2.18 (m, 2H), 2.21-2.23 (m, IH), 2.32-2.37 (m, IH), 2.82-2.87 (m, IH), 3.01-3.06 (m, IH), 5.63-5.68 (m, IH), 7.01-7.06 (m, 2H), 7.19-7.22 (m, 3H), 7.29-7.32 (m, 3H), 7.33-7.36 (m, 2H),7.36-7.38 (m, IH), 7.75-7.78 (m, IH), 7.11-7.13 (m, IH), 8.79 (s, IH). |
63.5% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; for 2h;Inert atmosphere; Reflux; | To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (18, 300 mg, 0.63 mmol) and <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (149 mg, 0.75 mmol) in dry 1,4-dioxane (15 mL) were added 2M aq Cs2CO3 (2 mL) and Pd(PPh3)Cl2 (40 mg, 0.056 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (50 mL) and EtOAc (100 mL), the mixture was extracted with EA (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-3-((S)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (12m, 188 mg, yield: 63.5%). LC-MS Method tR = 1.18 min, m/z = 471, 418; 1H NMR (CDCl3): delta1.05 (s, 3H), 1.12 (s, 3H), 1.49-1.51 (m, 3H), 2.15-2.18 (m, 2H), 2.21-2.23 (m, 1H), 2.32-2.37 (m, 1H), 2.82-2.87 (m, 1H), 3.01-3.06 (m, 1H), 5.63-5.68 (m, 1H), 7.01-7.06 (m, 2H), 7.19-7.22 (m, 3H), 7.29-7.32 (m, 3H), 7.33-7.36 (m, 2H),7.36-7.38 (m, 1H), 7.75-7.78 (m, 1H), 7.11-7.13 (m, 1H), 8.79 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 1h;Inert atmosphere; | 6-Bromo-[l,2,4]triazolo[l,5-alpha]pyridine (600 mg, 3.03 mmol) was added to a mixture of the boronate ester from step E (873 mg, 1.68 mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12 mL). The reaction mixture was deoxygenated with argon. Dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.10 mmol) was added and the reaction mixture was stirred at 900C for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:ldichloromethane/methanol /concentrated ammonium hydroxide solution in dichloromethane) gave the desired 4-(3,4-dichlorophenyl)-7-([l,2,4]triazolo[l,5- alpha]pyridin-6-yl)-l,l-dimethyl-l,2,3,4-tetrahydroisoquinoline (431 mg, 50% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) delta 8.79 (s, IH), 8.38 (s, IH), 7.84 (d, J= 9.0 Hz, IH), 7.77 (dd, J= 8.0, 1.5 Hz, IH), 7.48 (s, IH), 7.39 (d, J= 8.5 Hz, IH), 7.31 (dd, J = 8.0, 1.5 Hz, IH), ), 7.21 (d, /= 1.5 Hz, 1H),6.996.92 (m, 2H), 4.08 (t, J = 5.5 Hz, IH), 3.45 (dd, J= 13.5, 5.5 Hz, IH), 3.10 (dd, J= 13.5, 5.5 Hz, IH), 1.68 (s, 3H), 1.60 (s, IH), 1.57 (s, 3H); ESI MS m/z 423 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In water; dimethyl sulfoxide; at 45℃; | Step C: To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),6-bromo-[l,2,4]triazolo[l,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600 mL) and water (50 mL) was added Pd(dppf)Cl2 (5.83 g, 7.14 mmol) and Cs2CO3 (116 g, 357 mmol). The reaction temperature reached 45 0C after the addition. HPLC showed that starting materials were consumed after 15 min. The reaction was diluted with water (400 mL). The black precipitate was collected by filtration and dissolved in DCM (300 mL), and washed with brine (200 mL). The aqueous layer was back extracted with DCM (100 mL). The combined organic layers were filtered through a Celite pad and the filtrate was concentrated to give a black solid mixture. The product was recrystallized in methanol to give 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol, 86 % yield) as a pale grey solid: m/z = 224.0 [M+l]; 1H NMR (400 MHz, DMSO-D6) delta ppm 7.74 (t, J=7.68 Hz, 1 H), 7.91 - 8.02 (m, 2 H), 8.11 (dd, J=9.19, 1.89 Hz, 1 H), 8.17 (d, J=7.81 Hz, 1 H), 8.36 (s, 1 H), 8.57 (s, 1 H), 9.45 (s, 1 H), 10.11 (s, 1 H). |
86% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; at 45℃; for 0.25h; | To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),6-bromo-[l,2,4]triazolo[l,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600 mL) and water (50 mL) was added Pd(dppf)Cl2 (5.83 g, 7.14 mmol) and Cs2CO3 (116 g, 357 mmol). The reaction temperature reached 45 0C after the addition. HPLC showed that starting materials were consumed after 15 min. The reaction was diluted with water (400 mL). The black precipitate was collected by filtration and dissolved in DCM (300 mL), and washed with brine (200 mL). The aqueous layer was back extracted with DCM (100 mL). The combined organic layers were filtered through a Celite pad and the filtrate was concentrated to give a black solid mixture. The product was recrystallized in methanol to give 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol, 86 % yield) as a pale grey solid: m/z = 224.0 [M+l]; 1H NMR (400 MHz, DMSO-D6) delta ppm 7.74 (t, J=7.68 Hz, 1 H), 7.91 - 8.02 (m, 2 H), 8.11 (dd, J=9.19, 1.89 Hz, 1 H), 8.17 (d, J=7.81 Hz, 1 H), 8.36 (s, 1 H), 8.57 (s, 1 H), 9.45 (s, 1 H), 10.11 (s, 1 H). |
86% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; at 45℃; for 0.25h; | To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),6-bromo-[l,2,4]triazolo[l,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600 mL) and water (50 mL) was added Pd(dppf)Cl2 (5.83 g, 7.14 mmol) and Cs2CO3 (116 g, 357 mmol). The reaction temperature reached 45 0C after the addition. HPLC showed that starting materials were consumed after 15 min. The reaction was diluted with water (400 mL). The black precipitate was collected by filtration and dissolved in DCM (300 mL), and washed with brine (200 mL). The aqueous layer was back extracted with DCM (100 mL). The combined organic layers were filtered through a Celite pad and the filtrate was concentrated to give a black solid mixture. The product was recrystallized in methanol to give 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol, 86 % yield) as a pale grey solid: m/z = 224.0 [M+l]; 1H NMR (400 MHz, DMSO-D6) delta ppm 7.74 (t, 7=7.68 Hz, 1 H), 7.91 - 8.02 (m, 2 H), 8.11 (dd, 7=9.19, 1.89 Hz, 1 H), 8.17 (d, 7=7.81 Hz, 1 H), 8.36 (s, 1 H), 8.57 (s, 1 H), 9.45 (s, 1 H), 10.11 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Example 2 - Alternate Synthesis of Example 1[0133] Step A: To a solution of the triflate (9.5 g, 21.6 mmol) from step G inExample 1 and bis(pinacolato)diboron (6.6 g, 25.9 mmol) in dimethyl sulfoxide (200 mL) was added potassium acetate (6.4 g, 64.8 mmol). The solution was degassed with argon for 5 minutes and then dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) (1.6 g, 2.2 mmol) was added to it. The reaction mixture was degassed with argon for 5 minutes, heated at 80 0C for 1 hour, and then cooled to room temperature. To this solution were added 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (4.8 g, 23.8 mmol) and an aqueous solution of cesium carbonate (21.1 g, 64.8 mmol in 87 mL of water). The resultant solution was degassed with argon and then dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) (0.8 g, 1.1 mmol) was added to it. The reaction mixture was degassed with argon and heated at 80 0C for 1 hour. A dark sticky oil formed during the reaction. The dark supernatant solution was poured out, diluted with water, and extracted with ethyl acetate (3x), which was dried over sodium sulfate and concentrated in vacuo. The oil left was dissolved in dichloromethane and the resultant solution was washed with water, dried over sodium sulfate, and concentrated in vacuo. The combined crude product was purified by flash column chromatography (100% ethyl acetate to 92:7.2:0.8 ethyl acetate/methanol/ammonium hydroxide) to give 7- ([l,2,4]triazolo[l,5-alpha]pyridin-6-yl)-4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinoline (7.7 g, 87%, AUC HPLC 97.6%) as a brown foam: 1H NMR (500 MHz, CDCl3) delta 8.77 (s, IH), 8.37 (s, IH), 7.82 (d, J= 9.0 Hz, IH), 7.76 (d, J= 9.0 Hz, IH), 7.39-7.32 (m, 4H), 7.09 (d, J= 8.0 Hz, IH), 7.01 (d, J= 8.5 Hz, IH), 4.26 (t, J= 6.5 Hz, IH), 3.75 (app s, 2H), 3.01 (dd, J= 11.5, 5.5 Hz, IH), 2.64 (dd, J= 11.5, 6.5 Hz, IH), 2.46 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere; Sonication; | A dry flask was loaded with the boronate ester (0.8 g, 1.59 mmol) from Step J, 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (0.35 g, 1.78 mmol), cesium carbonate (0.97 g, 2.98 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed with argon then, DMF (20 mL) and water (4 mL) were added followed by a short sonication. The reaction mixture was heated to 800C for 1 hour. The cold reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 x 60 mL). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 1 : 1 : 1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 7- ([l,2,4]triazolo[l,5-alpha]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.86 g, quantitative) as a white foam. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere; | Step K: A dry flask was loaded with the boronate ester (0.8 g, 1.59 mmol) from Step J, 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (0.35 g, 1.78 mmol), cesium carbonate (0.97 g, 2.98 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed with argon then, DMF (20 mL) and water (4 mL) were added followed by a short sonication. The reaction mixture was heated to 80 0C for 1 hour. The cold reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 x 60 mL). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 1 :1 :1 to 1 :1 :2 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 7- ([l,2,4]triazolo[l,5-alpha]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.86 g, quantitative) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of the triflate (9.5 g, 21.6 mmol) from step G inExample 1 and bis(pinacolato)diboron (6.6 g, 25.9 mmol) in dimethyl sulfoxide (200 mL) was added potassium acetate (6.4 g, 64.8 mmol). The solution was degassed with argon for 5 minutes and then dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) (1.6 g, 2.2 mmol) was added to it. The reaction mixture was degassed with argon for 5 minutes, heated at 80 0C for 1 hour, and then cooled to room temperature. To this solution were added 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (4.8 g, 23.8 mmol) and an aqueous solution of cesium carbonate (21.1 g, 64.8 mmol in 87 mL of water). The resultant solution was degassed with argon and then dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) (0.8 g, 1.1 mmol) was added to it. The reaction mixture was degassed with argon and heated at 80 0C for 1 hour. A dark sticky oil formed during the reaction. The dark supernatant solution was poured out, diluted with water, and extracted with ethyl acetate (3x), which was dried over sodium sulfate and concentrated in vacuo. The oil left was dissolved in dichloromethane and the resultant solution was washed with water, dried over sodium sulfate, and concentrated in vacuo. The combined crude product was purified by flash column chromatography (100% ethyl acetate to 92:7.2:0.8 ethyl acetate/methanol/ammonium hydroxide) to give 7- ([l,2,4]triazolo[l,5-alpha]pyridin-6-yl)-4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinoline (7.7 g, 87%, AUC HPLC 97.6%) as a brown foam: 1H NMR (500 MHz, CDCl3) delta 8.77 (s, IH), 8.37 (s, IH), 7.82 (d, J= 9.0 Hz, IH), 7.76 (d, J= 9.0 Hz, IH), 7.39-7.32 (m, 4H), 7.09 (d, J= 8.0 Hz, IH), 7.01 (d, J= 8.5 Hz, IH), 4.26 (t, J= 6.5 Hz, IH), 3.75 (app s, 2H), 3.01 (dd, J= 11.5, 5.5 Hz, IH), 2.64 (dd, J= 11.5, 6.5 Hz, IH), 2.46 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere; | A dry flask was loaded with the boronate ester (0.8 g, 1.59 mmol) from Step J, 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (0.35 g, 1.78 mmol), cesium carbonate (0.97 g, 2.98 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed with argon then, DMF (20 mL) and water (4 mL) were added followed by a short sonication. The reaction mixture was heated to 80 0C for 1 hour. The cold reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 x 60 mL). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 1 :1 :1 to 1 :1 :2 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 7- ([l,2,4]triazolo[l,5-alpha]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.86 g, quantitative) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 110℃; for 2h;Inert atmosphere; Microwave irradiation; Sealed vial; | 62. Compound 62: 5-([l,2,4]Triazolo[l,5-a]pyridin-6-yl)-l'- cyclobutyl-3H-spiro[benzofuran-2,4'-piperidine][00364] A microwave vial was charged with intermediate 1-7 (100 mg, 0.27 mmol, 1.0 eq), 6-bromo-[l,2,4]triazolo[l,5-a]pyridine (54 mg, 0.27 mmol, 1.0 eq), Pd(dppf)2Cl2 (22 mg, 0.027 mmol, 0.1 eq), EtOH (1.5 mL), toluene (1.5 mL) and aqueous sodium carbonate (0.75 mL, 2.0 M in water). The vial was sealed, evacuated and purged three times with nitrogen. The reaction mixture was heated under microwave irradiation at 1100C for 2 hrs, and the solids were removed by filtration and washed with ethyl acetate. Water was added, and the crude reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried with sodium sulfate. The solids were removed by filtration, the filtrate was concentrated and the residue was purified by preparative TLC to give compound 62 (66 mg, 68%). 1U NMR (400 MHz, CD3OD) delta: 9.32 (s, 1 H), 9.12 (d, / =3.2Hz, IH), 8.45 (d, /=8.8Hz, IH), 8.10 (d, /=8.8Hz, IH), 7.68 (s, 1 H), 7.60 (/ =7.2Hz, IH), 6.96 (/=8.0Hz, IH), 3.72-3.81 (m, IH), 3.49-3.61 (m, 2H), 3.10-3.27 (m, 4H), 2.31-2.44 (m, 4H), 2.13-2.30 (m, 4H), 1.81-1.97 (m, 2H). MS (ESI): m/z 375.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; at 80℃; for 1h;Inert atmosphere; | To a solution of the triflate (9.5 g, 21.6 mmol) from step G inExample 36 and bis(pinacolato)diboron (6.6 g, 25.9 mmol) in dimethyl sulfoxide (200 mL) was added potassium acetate (6.4 g, 64.8 mmol). The solution was degassed with argon for 5 minutes and then dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (1.6 g, 2.2 mmol) was added to it. The reaction mixture was degassed with argon for 5 minutes, heated at 800C for 1 hour, and then cooled to room temperature. To this solution were added 6-bromo- [l,2,4]triazolo[l,5-alpha]pyridine (4.8 g, 23.8 mmol) and an aqueous solution of cesium carbonate (21.1 g, 64.8 mmol in 87 mL of water). The resultant solution was degassed with argon and then dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.8 g, 1.1 mmol) was added to it. The reaction mixture was degassed with argon and heated at 800C for 1 hour. A dark sticky oil formed during the reaction. The dark supernatant solution was poured out, diluted with water, and extracted with ethyl acetate (3x), which was dried over sodium sulfate and concentrated in vacuo. The oil left was dissolved in dichloromethane and the resultant solution was washed with water, dried over sodium sulfate, and concentrated in vacuo. The combined crude product was purified by flash column chromatography (100% ethyl acetate to 92:7.2:0.8 ethyl acetate/methanol/ammonium hydroxide) to give 7-([l,2,4]triazolo[l,S-alpha]pyridin-6-yl)-4- (3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.7 g, 87%, AUC HPLC 97.6%) as a brown foam: 1H NMR (500 MHz, CDCl3) delta 8.77 (s, IH), 8.37 (s, IH), 7.82 (d, J = 9.0 Hz, IH), 7.76 (d, J = 9.0 Hz, IH), 7.397.32 (m, 4H), 7.09 (d, J = 8.0 Hz, IH), 7.01 (d, J = 8.5 Hz, IH), 4.26 (t, J = 6.5 Hz, IH), 3.75 (app s, 2H), 3.01 (dd, J= 11.5, 5.5 Hz, IH), 2.64 (dd, J= 11.5, 6.5 Hz, IH), 2.46 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 2.5h;Inert atmosphere; | A mixture of the boronate ester from Step F (350 mg, 0.80 mmol, prepared in Step F), 6-bromo-[l,2,4]triazolo[l,5-alpha]pyridine (191 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and iV^V-dimethylformamide (4 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.040 mmol) was added. The mixture was degassed again and then heated to 900C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2x), brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-7-([l,2,4]triazolo[l,5- alpha]pyridin-6-yl)-4-(3,4-dicMorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetiota^ydroisoquinoline was obtained in 54% yield as a brown oil: ESI MS m/z 428 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step C: A mixture of the boronate ester (372 mg, 0.94 mmol) from Step B above, <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (223 mg, 1.13 mmol) and cesium carbonate (919 mg, 2.82 mmol), in water (1 mL) and N,N-dimethylformamide (5 mL) was degassed with argon. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (38 mg, 0.047 mmol) was added, the mixture was degassed again and heated to 90 C. for 3 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2*25 mL). The combined organics were washed with water (2*20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide) to give 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine (77 mg, 21%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step G: A mixture of bis(pinacolato)diboron (690 mg, 1.49 mmol), potassium acetate (482 mg, 4.91 mmol) and 5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl trifluoromethanesulfonate (690 mg, 1.49 mmol) from Step F above in DMF (6 mL) was purged with nitrogen for 5 min. Next, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (182 mg, 0.22 mmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80 C. for 2 h. After the completion of reaction, as monitored by LC-MS, <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (318 mg, 1.61 mmol), cesium carbonate (1.56 g, 4.81 mmol), and water (2 mL) were sequentially added. The reaction mixture was purged with nitrogen and then dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (178 mg, 0.21 mmol) was added. The mixture was degassed again and heated to 90 C. for 3 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2*25 mL). The combined organics were washed with water (2*20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine, (60 mg, 10%) as a brownish solid (AUC HPLC >95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Step A: A mixture of bis(pinacolato)diboron (388 mg, 1.592 mmol), potassium acetate (346 mg, 3.53 mmol) and 5-(3-chloro-4-fluorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl trifluoromethanesulfonate from Step A of Example 53 (529 mg, 1.176 mmol) in DMF (5.5 mL) was purged with nitrogen for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (96 mg, 0.118 mmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80 C. for 2 hours. After the completion of reaction, as monitored by LC-MS, <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (251 mg, 1.268 mmol), cesium carbonate (1.127 g, 3.46 mmol), and water (2 mL) were sequentially added. The reaction mixture was purged with nitrogen and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (94 mg, 0.115 mmol) was added. The mixture was degassed again and heated to 90 C. for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organics were washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3-chloro-4-fluorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine (100 mg, 21%) as a brownish solid (AUC HPLC >95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere; | Step G: A mixture of bis(pinacolato)diboron (622 mg, 2.45 mmol), potassium acetate (611 mg, 6.22 mmol) and 5-(3,4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl trifluoromethanesulfonate (800 mg, 1.9 mmol) from Step F above in DMF (16 mL) was purged with nitrogen for 5 min. Next, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (231 mg, 0.28 mmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80 C. for 2 h. After the completion of reaction, as monitored by LC-MS, <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (409 mg, 2.1 mmol), cesium carbonate (2.02 g, 6.2 mmol), and water (3 mL) were sequentially added. The reaction mixture was purged with nitrogen and then dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (230 mg, 0.28 mmol) was added. The mixture was degassed again and heated to 90 C. for 3 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2*25 mL). The combined organics were washed with water (2*20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3,4-dichlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine, (350 mg, 54%) as a brownish solid: ESI MS (m/z) 421 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Step A: A mixture of bis(pinacolato)diboron (606 mg, 2.386 mmol), potassium acetate (540 mg, 5.51 mmol), and 5-(3-chloro-4-fluorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl trifluoromethanesulfonate (800 mg, 1.836 mmol), which was prepared using a similar procedure described in Step A of Example 3, in DMF (16 mL), was purged with nitrogen for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (150 mg, 0.184 mmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80 C. for 2 horns. After the completion of reaction, as monitored by LC-MS, <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (388 mg, 1.96 mmol), cesium carbonate (1.74 g, 5.34 mmol), and water (3 mL) were sequentially added. The reaction mixture was purged with nitrogen and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (145 mg, 0.178 mmol) was added. The mixture was degassed again and heated to 90 C. for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organics were washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford the racemic mixture of 8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3-chloro-4-fluorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine (216 mg, 30%) as a brownish solid: ESI MS (m/z): 405 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; ruphos;palladium diacetate; In water; toluene; at 115℃;Inert atmosphere; Sealed tube; | In an open sealed tube, a stirred mixture of 6-bromo[l,2,4]triazolo[4,3- a]pyridine (Ark Pharm, Inc., Libertyville, IL) (50 mg, 0.25 mmol), palladium(II) acetate (5.5 mg, 0.025 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (23 mg, 0.05 mmol), K2CO3 (138 mg, 1.0 mmol) and ira/i5,-2-(trifluoromethyl)cyclopropylboronic acid MIDA ester (99 mg, 0.38 mmol) in toluene (1.5 mL) and H20 (0.5 mL) was de-gassed with N2 for 15 minutes, then the reaction mixture placed under nitrogen, heated to 115 C and stirred overnight. After allowing to cool, the reaction mixture was diluted with EtOAc (30 mL) and H20 (30 mL), then filtered through Celite and the filter cake washed with EtOAc (3 x 10 mL). The aqueous and organic layers of the filtrate were partitioned and the aqueous extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried (Na2S04), filtered and the solvent concentrated under vacuum to leave a crude residue. The residue was purified by preparative thin-layer chromatography (4 prep TLC plates used) using CH2C12 / MeOH (95:5) as eluent to give the product (31.8 mg, 56%) as a solid.[00235] 1H NMR (CDC13, 300MHz): delta 8.82 (s, 1H), 8.08 (s, 1H), 7.76 (d, / = 9.5 Hz, 1H), 7.09 (dd, J = 9.5, 1.4 Hz, 1H), 2.43-2.36 (m, 1H), 1.95-1.82 (m, 1H), 1.51-1.44 (m, 1H), 1.30-1.22 (m, 1H). 13C NMR (CDC13, 75MHz): delta 149.1, 135.8, 127.5 (q, / = 269 Hz), 126.1, 121.3, 116.7, 22.5 (q, / = 37.3 Hz), 17.1 (q, / = 2.9 Hz), 9.9 (q, / = 2.5 Hz). 19F NMR (CDCI3, 282 MHz): -66.9 (d, / = 6.2 Hz), m/z = 228.01 (M+H)+ . HRMS (EI): [M+H]+ calc'd for C10H8F3N3 m/z 228.0749, found 228.0721. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In dimethyl sulfoxide; at 100℃; for 20h; | [0207] Step 3. [1,2,4lTriazolo[1,5-alpyridine-6-carboxylic acid methyl ester. A mixture of 6-bromo-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine (2.4 g, 12.12 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1.14 mmol, 0.10 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO (1.6 g, 20.48 mmol, 1.67 equiv) and methanol (50 mL) was stirred under carbon monoxide (10 atm) for 20 h at 100 C. The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1:1) to give 0.98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1.04 mi m/z = 178.0 [M+H]. |
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In dimethyl sulfoxide; at 100℃; for 20h; | A mixture of <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (2 4 g, 1 2.12 mmol, 1 .00 equiv), bis(tnphenylphosphine)palladium(II) dichloride (800 mg, 1 . 14 mmol, 0.1 0 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO ( 1 .6 g, 20.48 mmol, 1 .67 equiv) and methanol (50 mL) was stirred under carbon monoxide ( 10 atm) for 20 h at 100 C. The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane ( 1 : 1 ) to give 0 98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1 .04 min, m z = 178.0 [M+H] . | |
With bis-triphenylphosphine-palladium(II) chloride; dimethyl sulfoxide; triethylamine; at 100℃; for 20h; | A mixture of <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (2 4 g, 1 2.12 mmol, 1 .00 equiv), bis(tnphenylphosphine)palladium(II) dichloride (800 mg, 1 . 14 mmol, 0.1 0 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO ( 1 .6 g, 20.48 mmol, 1 .67 equiv) and methanol (50 mL) was stirred under carbon monoxide ( 10 atm) for 20 h at 1 00 C. The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane ( 1 : 1 ) to give 0 98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1 .04 min, m z = 178.0 [M+H] ' . |
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In dimethyl sulfoxide; at 100℃; under 7600.51 Torr; for 20h; | A mixture of <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (2.4 g, 12.12 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1 .14 mmol, 0.10 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO (1.6 g, 20.48 mmol, 1 .67 equiv) and MeOH (50 mL) was stirred under carbon monoxide (10 atm) for 20 h at 100 C. The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1: 1) to give 0.98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1 .04 mm, m/z = 178.0 [M+H]+. | |
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In dimethyl sulfoxide; at 100℃; under 7600.51 Torr; for 20h; | 0215] Step 3. rL2,41TriazolorL5-alpyridine-6-carboxylic acid methyl ester. A mixture of 6-bromo-[l,2,4]triazolo[l,5-a]pyridine (2.4 g, 12.12 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1.14 mmol, 0.10 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO (1.6 g, 20.48 mmol, 1.67 equiv) and methanol (50 mL) was stirred under carbon monoxide (10 atm) for 20 h at 100 C. The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1: 1) to give 0.98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1.04 min, m/z = 178.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 100℃; for 40h;Inert atmosphere; | Step 1: A suspension of <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (CAS 356560-80-0, 0.5 g, 2.52 mmol), tert-butyl carbamate (CAS 4248-19-5 , 0.592 g, 5.05 mmol), Pd2(dba)3 (0.185 g, 0.202 mmol), Cs2C03 (1.645 g, 5.05 mmol) and Xantphos (0.234 g, 0.404 mmol) in dioxane (8.5 mL) was degassed and refilled with argon twice. The reaction was heated to 100 C for 40h. The reaction was cooled and partitioned between EtOAc and water. The organic was collected, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by flash chromatography (0-70% EtOAc in petrol on basic silica) to afford tert-butyl[1,2,4]triazolo[1,5-a]pyridin-6-yl carbamate. 1H NMR (400 MHz, DCM- delta ppm 1.57 (s, 9 H) 6.57- 6.71 (m, 1 H) 7.34 - 7.40 (m, 1 H) 7.70 - 7.78 (m, 1 H) 8.31 (s, 1 H) 9.14 - 9.25 (m, 1 H) MS ES+: 179 (M-u) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; water; at 75℃; for 16h;Inert atmosphere; | a stirred solution of tert-butyl (2081) 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-5-yl)piperidine- 1-carboxylate (50 mg, 0.107 mmol), 6-bromo-[l,2,4]triazolo[l,5-a]pyridine (31.7 mg, 0.160 mmol) in tetrahydrofuran (5 mL), and water (0.5 mL) was added potassium phosphate tribasic (68.0 mg, 0.320 mmol). The solution was degassed with nitrogen for 10 mins. Next, PdCb(dppf) (7.81 mg, 10.67 mupiiotaomicron) was added and the solution was degassed again for 10 mins. The reaction mixture was heated to 75 C for 16 h. The reaction progress was monitored by LCMS. The reaction mass was filtered through a celite bed, washed with EtOAc, and concentrated to afford tert-butyl (2082) 4-(2-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-3-isopropyl-lH-indol-5-yl) (2083) piperidine-l-carboxylate (50 mg, 0.109 mmol). The material was carried on directly into the subsequent step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.5 g | In a 1 L three-neck round bottom flask 23.6 g of the compound C-2 was added, 450 mL of anhydrous tetrahydrofuran was added, the mixture was stirred under an argon atmosphere, and the temperature of the mixture was lowered to -78 C. 47.7 mL of 2.5M n-butyllithium was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. Then, 20 mL of triethyl borate was added thereto, and the mixture was stirred at room temperature for 8 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The material formed by concentration was dissolved in dichloromethane and precipitated with hexane to give 14.5 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
After dissolving 1-bromo-[1,2,4]triazolo[1,5alpha ]pyridine (1.1 g, 5.6 mmol) in N,N-dimethylformamide (15 mL) in a sealed tube, n-butyl vinyl ether (3.6 mL, 27.8 mmol), 1,3-bis(diphenylphosphino)propane (161 mg, 0.4 mmol), palladium(II) acetate (37 mg, 0.2 mmol), potassium carbonate (922 mg, 6.7 mmol) and water (1.6 mL) were added thereto, and the result was heated under reflux for 16 hours. After lowering the temperature to room temperature, an aqueous 2 N-hydrochloric acid solution (10 mL) was added thereto, and the result was stirred for 30 minutes at room temperature. After terminating the reaction, the result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (410 mg). 1H NMR (300 MHz, CDCl3) delta 9.23 (s, 1H), 8.46 (s, 1H), 8.09 (d, 1H), 7.81 (d, 1H), 2.67 (s, 3H). MS (ESI+): m/z 162 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.5% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 88℃;Inert atmosphere; | A mixture of the compound 6-bromo-1,2,4-triazolo[1,5-alpha]pyridine (0.2 g, 1.0 mmol), compound 13-a (0.32 g, 1.5 mmol), Pd(dppf)Cl2 (0.21 g, 0.26 mmol), sodium carbonate (0.22 g, 2.0 mmol), dioxane (6 mL) and water (2 mL) was stirred under nitrogen atmosphere at 88C overnight. The reaction solution was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE/EA= 1/1) to give compound 15 (90 mg, 31.5%). LC-MS (ESI): m/z = 287.1 [M+H]+. 1H NMR (400 MHz, CDCl3): delta 8.66 (s, 1H), 8.39 (s, 1H), 7.64 (m, 6H), 7.36 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 2.43 (s, 3 H). |
[ 746668-59-7 ]
6-Bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 7169-95-1 ]
6-Bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 947248-68-2 ]
6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine
Similarity: 0.91
[ 1053655-66-5 ]
7-Bromo-[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 882521-63-3 ]
7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine
Similarity: 0.83
[ 746668-59-7 ]
6-Bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 7169-95-1 ]
6-Bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 947248-68-2 ]
6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine
Similarity: 0.91
[ 1053655-66-5 ]
7-Bromo-[1,2,4]triazolo[1,5-a]pyridine
Similarity: 0.91
[ 274-85-1 ]
[1,2,4]Triazolo[1,5-a]pyridine
Similarity: 0.86
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