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CAS No. : | 1142943-96-1 | MDL No. : | MFCD28502349 |
Formula : | C10H9BrN4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XLBCMNCPMMPNHH-UHFFFAOYSA-N |
M.W : | 281.11 | Pubchem ID : | 59179473 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501 | UN#: | N/A |
Hazard Statements: | H302-H312-H332 | 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 |
---|---|---|
11 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 12 h; | 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1,1-dioxo(Intermediate 1A) (20.18 g, 53 mmol),N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7A) (16.45 g, 59 mmol),Pd(dppf)Cl2 (3.91 g, 5 mmol),2CO3 (22.06 g, 160 mmol) was added in turn to a 250 mL three-vial flask.Then add 1,4-dioxane (100 mL),Water (25mL),The temperature was raised to 90° C. under argon protection for 12 hours.After the reaction is over,Cool to room temperatureAdd 300 mL of dichloromethane to the reaction mixture.Then wash twice with water,500mL each time,Drying the organic phase with anhydrous sodium sulfate,The organic phase is concentrated to dryness,The residue is subjected to column chromatography (eluent:Dichloromethane:methanol = 50:1) was purified to give the title product as a pale yellow solid, 11 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate In 1,4-dioxane; ISOPROPYLAMIDE at 140℃; for 0.5h; | 8 Synthesis 8; Cyclopropanecarboxylic acid [5-(4-methoxy-phenylamino)-[1 ,2,4]triazolo[1 ,5-a]pyridin-2- yl]-amide (WW-127)A microwave tube was charged with cyclopropanecarboxylic acid (5-bromo- [1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl)-amide (0.05g, 0.178mmol), p-anisidine (0.044g, 0.356mmol), bis(dibenzylideneacetone)palladium (0.008g, 0.009mmol), xantphos (0.01Og, 0.018mmol) and sodium terf-butoxide (0.038g, 0.392mmol) in dioxane (1 mL). A couple of drops of dimethylacetamide were added to assist with microwave absorption. The mixture was heated at 14O0C for 30min. The mixture was filtered and concentrated in vacuo. The crude product was purified by preparatory HPLC. LCMS method: 2, RT: 3.49min, Ml: 324 [M+1]. NMR (1 H, DMSO, 300MHz): 10.88 (brs, 1 H), 8.73 (s, 1 H), 7.43 (4, 1 H), 7.33 (d, 2H), 6.99 (d, 2H), 6.95 (d, 1 H), 6.24 (d, 1H), 3.11 (s, 3H), 2.08 (brs, 1 H), 0.83 (d, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ISOPROPYLAMIDE at 150℃; for 0.25h; Microwave irradiation; | 7 Svnthesis 7; Cyclopropanecarboxylic acid {5-[(pyridin-2-ylmethyl)-amino]-[1 ,2,4]triazolo[1 ,5-a]pyridin-2- yl}-amide (WW-075)To a solution of cyclopropanecarboxylic acid (5-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl)- amide (0.05g, 0.178mmol) in dimethylacetamide (1mL) in a microwave vial, 2- aminomethylpyridine (0.096g, 0.89mmol) was added and the solution was heated in the microwave at 15O0C for 15min. The crude was purified straight away by preparatory chromatography after filtration. LCMS method: 2, RT: 2.07min, Ml: 309 [M+1]. NMR (1 H, DMSO, 300MHz): 10.91 (s, 1H), 8.57 (d, 1 H), 7.77 (t, 1H), 7.30-7.49 (m, 4H), 6.85 (d, 1 H), 6.08 (d, 1 H), 4.67 (d, 2H), 2.07 (brs, 1 H)1 0.83 (d, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; at 150℃; for 0.166667h; | Synthesis 6; Cyclopropanecarboxylic acid [5-(1-propyl-1/-/-pyrazol-4-yl)-[1 ,2,4]triazolo[1 ,5-a]pyridin-2- yl]-amide (WW-124)Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1 ,5-a]pyridin-2-yl)-amide (0.05g, 0.178mmol), 1-propyl-1H-pyrazole-4-boronic acid, pinacol ester (0.054g, 0.231mmol) and dimethylacetamide (1mL) were added to a microwave tube containing a stirrer bar, potassium phosphate solution (0.5M in water, 0.7mL, 0.356mmol) and tetrakis(triphenylphosphine)palladium (0.02g, 0.018mmol). The reaction was heated to 15O0C for 10min under microwave heating. The crude was purified straight away by preparatory chromatography after filtration. LCMS method: 2, RT: 3.75min; Ml: 311 [M+1]; NMR 1H (DMSO): 0.80-0.88 (m, 7H)1 1.78-1.90 (m, 2H), 2.05 (brs, 1 H), 4.16 (t, 2H), 7.52 (dd, 1 H), 7.55 (d, 1 H), 7.66 (t, 1H), 8.51 (s, 1H), 8.86 (s, 1 H), 11.11 (brs, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In 1,2-dichloro-ethane; at 20℃; | <strong>[1010120-55-4]5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (10 g, 50 mmol) and triethylamine (10 g, 100 mmol) in dichloroethane (200 mL) Cyclopropionyl chloride (5.7 g, 55 mmol) was added and stirred at room temperature overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purification by silica gel column chromatography gave white solid (10 g, 76%) |
58% | Step (Hi)5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (10.7g, 50mmol) was suspended in acetonitrile (200mL) and DIPEA (9.6mL, 55mmol). Cyclopropanecarbonyl chloride (5.0mL, 55mmol) and 4-(Dimethylamino)pyridine (287mg, 2.35mmol) were added in one portion and the suspension heated at 80C for 18h. After this time the solvents were removed in vacuo and the resulting solid was stirred in ammonia/methanol (2M) for 2h at rt. The solvents were removed in vacuo and the resulting solid was triturated, filtered and washed with diethyl ether (3 x lOOmL) to afford the desired compound as a white solid (8.12g, 58% ). LCMS (method A), (M+H+) 281/283, RT = 0.78min. | |
56.64% | To <strong>[1010120-55-4]5-bromo-[1,2,4] triazolo[1,5-a]pyridin-2-amine</strong>(15.00 g, 70.41 mmol) and triethylamine(21.4 g, 211.2 mmol), dissolved in acetonitrile(150 mL) was added dropwise cyclopropanecarboxylic acid chloride(8.8 g, 84.5 mmol) at 0C. After adding, the mixture was warmed to room temperature for the reaction for 16 hours. After TLC showed that the reaction was completed through monitoring, the reaction mixture was distilled under reduced pressure. The resulting residue was dissolved in an alcoholic solution of methylamine(150 mL), heated to 80C for the reaction for 1 hour, cooled, distilled under reduced pressure. The resulting residue was dissolved in mixed solution of water(100 mL) and ethyl acetate(200 mL), and the layers were separated and extracted. The combined organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluting with ethyl acetate/petroleum ether =0?70%) to give N-(5-bromo-[1,2,4]triazolo[1,5-a] pyridin-2-yl)cyclopropyl carboxamide (7.2 g, 56.64% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta = 11.20 (br. s., 1 H), 7.68 - 7.73 (m, 1 H), 7.52 - 7.58 (m, 1 H), 7.46 - 7.51 (m, 1 H), 1.96 - 2.09 (m, 1 H), 0.82 (d, J=6.28 Hz, 4 H). MS (ESI) Calcd. for C10H9 BrN4O [M + H]+ 282, Found 282. |
To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 50C is added Et3N (11.6 mL, 83.3 mmol) followed by the appropriate acid chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and acid chloride (33.3 mmol) may be added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids may be collected by filtration, washed with H2O (2x50 rnL), acetone (50 rnL) and Et2O (50 rnL), then dried in vacuo to give the required intermediate (4). In some cases column chromatography (petrol/EtOAc) may be required to obtain pure compounds. | ||
To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by the appropriate acid chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and the acid chloride (33.3 mmol) may be added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids may be collected by filtration, washed with H2O (2×50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required acyl intermediate (4). In some cases column chromatography (petrol/EtOAc) may be required to obtain pure compounds. | ||
1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4) To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required bromo intermediate (4). | ||
With triethylamine; In acetonitrile; at 5 - 20℃; | Step iii : Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the desired compound. | |
Step iii : Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the desired compound. | ||
With triethylamine; In acetonitrile; at 5 - 20℃; | [0167] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5C is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1 h-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et20 (50 mL). The solids are collected by filtration, washed with H20 (2x50 mL), acetone (50 mL) and Et20 (50 mL), then dried in vacuo to give the desired compound | |
4.5 g | With pyridine; at -50℃; for 0.166667h; | Add 50mL pyridine to the reaction flask,Cyclopropane chloride (2.9 g, 28 mmol) was added dropwise to the reaction flask at -50C.Stir for 10 minutes,5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5 g, 23 mmol) was then added to the reaction flaskin,The reaction was stirred overnight at room temperature.After the reaction is completed,Add 100 mL of petroleum ether to the reaction solution.FilteringFilter cake washed twice with petroleum ether, Each time 100mL,Then wash once with 100mL of waterTo get the title product,Earth gray solid 4.5g |
4 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 5h; | 100 ml of 6 dichloromethane and 9 g of 12 diisopropylethylamine were added to 5 g of the product of Step 2. The mixture was cooled to 0 C in an ice bath. 6.1 g of 15 cyclopropanecarbonyl chloride was added dropwise. The mixture became clear after 1 hour of reaction. After the reaction was continued for 4 hours, the reaction system was concentrated to dryness to give an oily 16 solid. Then, a mixed solution of 7 ml of ammonia water and 43 ml of methanol was added to the oily solid under cooling in an ice salt bath, and stirred for about 3 hours. The system became a brown turbid liquid. After filtration by suction, the solid was washed with water and dried to obtain 4 g of the target. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; tripotassium phosphate tribasic In tetrahydrofuran; lithium hydroxide monohydrate at 90℃; for 12h; Inert atmosphere; | 5.5.1 Step 5.1 Preparation of Compound 7 N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxamide (Int-1) (325 mg, 1.15 mmol), 4-hydroxy Phenylboronic acid (SM6) (254 mg, 1.84 mmol) and potassium phosphate (585 mg, 2.76 mmol) were dissolved in tetrahydrofuran (10 mL) and water (5 mL), and 1,1-bis(diphenylphosphine) was added after nitrogen replacement three times. Ferrocene palladium chloride (50 mg, 0.07 mmol) was replaced with nitrogen three times and then raised to 90°C and stirred for 12 hours.30 mL of ethyl acetate was added to remove the insoluble solids, and the filtrate was concentrated and purified by column to obtain N-(5-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-2- yl]cyclopropaneamide (7) (220 mg, 75% yield, yellow solid). |
With potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 140℃; for 0.5h; Microwave irradiation; | A An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K2CO3 (2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (This reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over MgSO4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In 1,4-dioxane; water at 90℃; Inert atmosphere; | 176.1 5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyridine-2-carbonitrile (10 g, 0.03 mol, 1.1 equiv.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (7.6 g, 0.027 mol) in 1,4-dioxane/water (4:1; 70 mL). K2CO3 (7.45, 0.054 mol, 2 eq.) and PdCl2dppf (5%) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. under N2 until completion (monitored by LCMS). 1,4-Dioxane was removed under vacuum, and water/EtOAc were added and the solid was filtered. The obtained solid was dissolved in methanol/DCM, dried over MgSO4 and the final compound was obtained after purification by flash chromatography, eluted with neat EtOAc as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>tert</i>-butyl alcohol at 120℃; for 16h; | G.a Piperidine-4-carboxylic acid methyl ester (1.5 eq.) is added to a solution of cyclopropanecarboxylic acid (5-brorno-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (leq) in tert-butanol. The reaction is heated at 1200C for 16hr. The excess of solvent is evaporated. The crude is purified by flash chromatography 1:2 petrol/EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl alcohol; at 120℃; for 16h; | <strong>[3973-62-4]3-Phenyl-piperidin</strong>e (3 eq.) was added to a solution of Cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (leq) in tert-butanol. The reaction was heated at 1200C for 16hr. The excess of solvent was evaporated. The crude was purified by preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>tert</i>-butyl alcohol at 120℃; for 16h; | B.a Piperazine-1-carboxylic acid tert-butyl ester (1.5 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (leq) in tert-butanol. The reaction was heated at 1200C for 16hr. The excess of solvent was evaporated. The crude was purified by flash chromatography 1:4 petrol/EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 1h; Inert atmosphere; | 3.3.1 Step 3.1 Preparation of Compound 5 N-[5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (Int-1) (1.5 g, 5.34 mmol), [4- (Hydroxymethyl)phenyl]boronic acid (SM3) (1.62 g, 10.67 mmol) and potassium carbonate (2.21 g, 16.01 mmol) were dissolved in dioxane (15 mL) and water (3 mL) 3 times to replace nitrogen, then After adding 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (195 mg, 0.267 mmol), nitrogen was replaced again 3 times and added to 90 degrees and stirred for 1 hour.The reaction mixture was added with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was subjected to silica gel column chromatography ( Eluent: 2% to 5% methanol/dichloromethane) to give yellow solid N-[5-(4-(hydroxymethyl)phenyl]-[1,2,4]triazole[1,5-a] ]dopyridin-2-yl]cyclopropanecarboxamide (5) (1.4 g, 78% yield). |
68% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 7.2 Step 2: Preparation of N-(5-(4-(hydroxymethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7B) N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (2.8 g, 10 mmol),4-hydroxymethylphenylboronic acid (1.5g, 10mmol),1,1'-bisdiphenylphosphinoferrocene dichloropalladium (730 mg, 1 mmol),Potassium carbonate (2.8g, 20mmol) was sequentially added to the jar.Then 50 mL of 1,4-dioxane and 10 mL of water were added thereto.Under argon protection,The reaction was heated to 90 °C and stirred for 16 hours.Then, cool the reaction solution to room temperature.Add ethyl acetate extraction,Organic layer separation,Dry, concentrate.The residue was purified by column chromatography (eluent: dichloromethane:methanol = 25:1).The title product was obtained as a yellow solid 2.1 g, yield 68% |
With potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.1 Step 1:; 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO4 and evaporated in vacuo. The resulting mixture was used without further purification. |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; | ||
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1.1 1.2. Route 2 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 1.2. Route 2 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90° C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The resulting mixture is used without further purification. | |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1 1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4- hydroxymethyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyri-din-2-yl] -amide Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide 4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2 dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90° C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The resulting mixture is used without further purification. | |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; | 1.2.1 Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5- aJpyridin-2-ylJ-am [0170] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K2C03 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The resulting mixture is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate at 140℃; for 0.5h; Inert atmosphere; Microwave irradiation; | A Method APreparation of Compounds of the Invention Via Suzuki Coupling (5):An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K2CO3 (2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSO4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.; 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N2 atmosphere. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; ethanol at 115℃; for 0.25h; Microwave irradiation; | 1.iv Step (iv)N-(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxamide (150mg, 0.53mmol), (2-fluoro-4-methoxyphenyl)boronic acid (91mg, 0.53mmol) and [l,l 'bis(diphenylphosphino)ferrocene] dichloro-palladium (II) complex with DCM (4mg, 0.005 mmol) were heated, under microwave irradiation at 115 °C for 15 minutes in 2M Na2C03 (1.06mL), EtOH (0.75mL) and 1,4-dioxane (3mL). After this time the solvent was removed in vacuo and the residue portioned between DCM and 1M HC1. The phases were separated and the aqueous phase washed with further DCM. The combined organic extracts were washed with brine, dried over MgS04 and the solvent removed in vacuo to afford the title compound as a white solid. 1H NMR (d6-DMSO) δ 10.99 (s, 1H), 7.76-7.62 (m, 3H), 7.17 (dd 1H), 7.05 (dd, 1H), 6.97 (dd, 1H), 3.87 (s, 3H), 1.99 (br s, 1H), 0.79 (d, 4H); LCMS (method B), (M+H+) 327, RT = 8.19min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ethyl acetate / 24.25 h / 5 - 50 °C 2.1: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / 4 h / 20 °C / Reflux 3.1: N-ethyl-N,N-diisopropylamine / dmap / acetonitrile / 18 h / 80 °C 3.2: 2 h / 20 °C | ||
Multi-step reaction with 3 steps 1: dichloromethane 2: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol 3: triethylamine / acetonitrile | ||
Multi-step reaction with 3 steps 1: dichloromethane / 16 h / 5 - 20 °C 2: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / 3 h / Reflux 3: triethylamine / acetonitrile / 5 - 20 °C |
Multi-step reaction with 3 steps 1: dichloromethane / 16 h / 5 - 20 °C 2: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / methanol; ethanol / 3 h / Reflux 3: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1: dichloromethane / 16.25 h / 5 - 20 °C 2: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / ethanol; methanol / 20 °C / Reflux 3: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1: dichloromethane / 16 h / 5 - 20 °C 2: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / methanol; ethanol / 3 h / Reflux 3: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1: dichloromethane / 10 h / 5 - 20 °C 2: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol / 4 h / 20 °C / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 5 h / 0 °C | ||
Multi-step reaction with 3 steps 1: dichloromethane / 20 °C 2: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / Reflux 3: acetonitrile | ||
Multi-step reaction with 3 steps 1.1: dichloromethane / -20 - 20 °C 2.1: hydroxylamine hydrochloride; triethylamine / ethanol / 3 h / 70 - 100 °C 3.1: triethylamine / dichloromethane / 0.5 h / -20 - 0 °C 3.2: 20 °C 3.3: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / 4 h / 20 °C / Reflux 2.1: N-ethyl-N,N-diisopropylamine / dmap / acetonitrile / 18 h / 80 °C 2.2: 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol 2: triethylamine / acetonitrile | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / 3 h / Reflux 2: triethylamine / acetonitrile / 5 - 20 °C |
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / methanol; ethanol / 3 h / Reflux 2: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / ethanol; methanol / 20 °C / Reflux 2: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / methanol; ethanol / 3 h / Reflux 2: triethylamine / acetonitrile / 5 - 20 °C | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine / ethanol; methanol / Reflux 2: acetonitrile | ||
Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride; triethylamine / ethanol / 3 h / 70 - 100 °C 2.1: triethylamine / dichloromethane / 0.5 h / -20 - 0 °C 2.2: 20 °C 2.3: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | 1.1.2.4. Compound 1 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90 C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography. Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H2O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50 C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | 1.1.3. Compound 110271] 4-[4-(4,4,5,5-Tetramethyl-[ 1 ,3,2]dioxaborolan-2- yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4] triazolo[ 1 ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K2C03 (2 eq.) and PdC12 dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90 C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo.10272] The final compound is obtained after purification by flash chromatography.10273] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino) ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50 C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | [0168] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4: 1). K2C03 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90C for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography. [0169] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base. |
11 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h; | 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1,1-dioxo(Intermediate 1A) (20.18 g, 53 mmol),N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7A) (16.45 g, 59 mmol),Pd(dppf)Cl2 (3.91 g, 5 mmol),2CO3 (22.06 g, 160 mmol) was added in turn to a 250 mL three-vial flask.Then add 1,4-dioxane (100 mL),Water (25mL),The temperature was raised to 90 C. under argon protection for 12 hours.After the reaction is over,Cool to room temperatureAdd 300 mL of dichloromethane to the reaction mixture.Then wash twice with water,500mL each time,Drying the organic phase with anhydrous sodium sulfate,The organic phase is concentrated to dryness,The residue is subjected to column chromatography (eluent:Dichloromethane:methanol = 50:1) was purified to give the title product as a pale yellow solid, 11 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate / 1,4-dioxane; lithium hydroxide monohydrate / 90 °C 2: phosphorus tribromide / chloroform | ||
Multi-step reaction with 2 steps 1: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / chloroform / 20 h / 20 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / chloroform / 20 h / 20 °C |
Multi-step reaction with 2 steps 1: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / 1,4-dioxane; lithium hydroxide monohydrate / 16 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / chloroform / 20 h / 20 °C | ||
Multi-step reaction with 2 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate / 1,4-dioxane; lithium hydroxide monohydrate / 16 h / 90 °C / Inert atmosphere 2: triphenylphosphine; carbon tetrabromide / dichloromethane / 15 h / 20 °C | ||
Multi-step reaction with 2 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate / 1,4-dioxane; lithium hydroxide monohydrate / 1 h / 90 °C / Inert atmosphere 2: phosphorus oxytribromide / chloroform / 2 h / 10 - 15 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / 1,4-dioxane; lithium hydroxide monohydrate / 0.5 h / 140 °C / Microwave irradiation 2: sodium hydroxide / methanol; lithium hydroxide monohydrate; tetrahydrofuran / 1.5 h / 20 °C | ||
Multi-step reaction with 2 steps 1: tripotassium phosphate tribasic; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / 1,4-dioxane; lithium hydroxide monohydrate / 18 h / 95 °C / Inert atmosphere 2: lithium hydroxyde monohydrate; lithium hydroxide monohydrate / tetrahydrofuran / 1.5 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / chloroform / 20 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane; methanol / 16 h / 20 °C / Inert atmosphere 4: hydrogenchloride / methanol; tetrahydrofuran / 27 h / 25 - 50 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 2: hydrogenchloride / methanol; tetrahydrofuran / 22 h / 25 - 50 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 16 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / chloroform / 20 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane; methanol / 16 h / 20 °C / Inert atmosphere 4: hydrogenchloride / methanol; tetrahydrofuran / 22 h / 25 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; | 4 Step 4: Preparation of N-[5-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl] cyclopropane carboxamide (Intermediate 6) To N-(5-bromo-[1,2,4]triazolo[1,5-a] pyridin-2-yl)cyclopropane carboxamide(3.0 mg, 10.67 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.4 g, 12.9 mmol) and potassium carbonate(3.7 g, 26.7 mmol), dissolved in a mixed solution of dioxane(30 mL) and water(5 mL), was added Pd(dppf)Cl2(260 mg) in the nitrogen atmosphere. The resulting mixture was heated to 110°C for the reaction for 3 hours, then cooled to room temperature. After TLC showed that raw material was completely reacted, the reaction mixture was filtered. The filtrate was washed with water(150 mL) and extracted with ethyl acetate(150 mL*3). The combined organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluting with ethyl acetate/petroleum ether =50∼100%) to give N-[5-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl] cyclopropane carboxamide(2.1 g, 62.4% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ= 13.37 (br. s., 1H), 11.15 (br. s., 1H), 8.96 (s, 1H), 8.53 (s, 1H), 7.57-7.72 (m, 2H), 7.51 (d, J=8.28 Hz, 1H), 2.06 (br. s., 1H), 0.78-0.91 (m, 4H). MS (ESI) Calcd. for C13H12N6O [M + H]+ 269, Found 269. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 21.4 step 4: synthesis step of N-cyclo propylcarbonyl {5-4-[1-(1,1-dioxothiomorpholine-1- Dimethyl amino methyl)] methylphenyl - [1,2,4]triazolo[1,5-a]pyridin-2-}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-Dioxythiomorpholine-1-dimethylaminomethyl)]-p-toluic acid benzoate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10mL)And water (1mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water.The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.Purified by silica gel column chromatography,A white solid (54 mg, 53%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 22.3 step 3: synthesis step of N-cyclo propylcarbonyl {5-4-[1-((1,1-dioxothiomorpholine4-yl)-1-pyrazolemethyl)] methylphenyl - [1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-dioxothiomorpholin-1-pyrazolylmethyl)]methylene terephthalate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.Purified by silica gel column chromatography, A white solid (51 mg, 52%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 2.5 step 5: synthesis step of N-cyclopropylcarbonyl{5-4-[1-(1,1-dioxothiomorpholine-2,2,2-trifluoroethyl)]phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropanoyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridine_2-)amine (100 mg, 0 · 4 mmol),4_ [1-(1,1-Dioxythiomorpholine-2,2,2-trifluoroethyl)]benzoic acid benzoic acid ester (300 mg, 0 · 8 mmol), Pd (dppf) Cl 2 (10 mg, 0 ·04mmol)cesium carbonated(390 mg, 1 · 2 mmol) dissolved in 1,4-dioxane (10 mL)And water (lmL),Stir at 100 ° C overnight. After the reaction solution is diluted, it is washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate.Concentrated and evaporated to dryness. Purified by silica gel column chromatography,Obtained as a white solid (23 mg, 18%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 3.4 step 4: synthesis step of N-cyclopropylcarbonyl {5-4-[1-(1,1-dioxothiomorpholine-1-cyano)]methyl phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amine (100 mg, 0 · 4 mmol), 4-[1-(1,1-dioxothiomorpholine-1-cyano)]tolueneboronic acid pinacol ester (300 mg, 0 · 8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390 mg, 1.2 mmol) in 1,4-dioxane (10 mL) and water (1 mL), the mixture was dropped at 100 ° C overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purified by silica gel column chromatography, Obtained as a white solid (23 mg, 18%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 4.5 step 5: synthesis step of N-cyclopropylcarbonyl{5-[[1-(1,1-dioxothiomorpholine)]indane]phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amine (100 mg, 0 · 4 mmol), 5-[1-(1,1-dioxothiomorpholine)]indane boronic acid pinacol ester (300 mg, 0 ·8mmοi), Pd (dppf) Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390 mg, 1.2 mmol) Dissolved in 1,4-dioxane (10 mL) and water (1 mL) and stirred at 100 ° C overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purified by silica gel column chromatography to give a white solid (20mg, 16%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 5.3 step 3: synthesis step of N-cyclopropylcarbonyl {5-4-[1-(1,1-dioxothiomorpholine-amine)]phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amine (100 mg, 0 · 4 mmol), 4-[1-(1,1-dioxothiomorpholine-amino)]phenylboronic acid pinacol ester(300 mg, 0 · 8 mmol), Pd (dppf) Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390 mg, 1.2 mmol) dissolved in 1,4 -Dioxane (10 mL) and water (1 mL) were taken at 100 ° C overnight. After the reaction solution is diluted, it is washed with water and washed with saturated brine.After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness.Purified by silica gel column chromatography,A white solid (51 mg, 50%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 6.5 Step 5, synthesis step of N-cyclopropionyl{5-4-[3-(1,1-dioxothiomorpholinyl)]cyclobutylaminophenyl-[1,2,4]triazolo[1 , 5-a] Pyridine-2-} amine . N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[3-(1,1-dioxothiomorpholinyl)]cyclobutylaminophenylboronic acid pinacol ester (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10mg, 0.04mmol) And cesium carbonate (390 mg, 1.2 mmol) dissolved in 1,4-dioxane (10 mL) And water (1mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water.Washed with saturated saline,After drying anhydrous sodium sulfate,Concentrated and evaporated to dryness.Purified by silica gel column chromatography,A white solid (20 mg, 16%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 100℃; | 7.3 step 3, synthesis of N-Cyclopropylcarbonyl {5- 4[1-(1,1-dioxothiomorpholine-4-yl)-1,1-dimethyl] methylphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-Dioxythiomorpholine)-1,1-dimethyl]toluene borate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water and washed with saturated brine.After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness.Purified by silica gel column chromatography To a white solid (52 mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 100℃; | 8.3 step 3, synthesis of N- Cyclopropylcarbonyl {5- 4[1- (1,1- dioxothiomorpholine- )- 1,1- dimethylene] methylphenyl- [1,2,4]triazolo[1,5- a]pyridin- 2- }amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-dioxothiomorpholine)-1,1-dimethylene]toluene borate (300 mg, 0.8 mmol),Pd(dppf)Cl2 (10mg, 0.04mmol) and cesium carbonate(390 mg, 1.2 mmol) dissolved in 1,4-dioxane (10 mL) and water (1 mL).Stir at 100 ° C overnight.After the reaction solution is diluted,Washed with water, washed with saturated brine,After drying anhydrous sodium sulfate,Concentrated and evaporated to dryness.Purified by silica gel column chromatography,A white solid (51 mg, 50%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 100℃; | 9.4 step 4: synthesis step of N-cyclo propylcarbonyl {5-[3-(1,1-dioxothiomorpholine)]dihydro Indole-6-yl-[1,2,4]triazolo[1,5-a]pyridin-2-}amine N-cyclopropanoyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol), 3-(1,1-dioxothiomorpholine-4-yl)dihydroindole-6-boronic acid pinacol ester (300 mg, 0.8 mmol),Pd(dppf)Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390 mg, 1.2 mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight. After the reaction solution is diluted,Washed with water, washed with saturated brine, dried over anhydrous sodium sulfate,Concentrated and evaporated to dryness.Purified by silica gel column chromatography,A white solid (51 mg, 50%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 100℃; | 10.3 step 3: synthesis step of N-cyclopropylcarbonyl {5-[3-(1,1-dioxothiomorpholine-4-yl)]dihydro benzofuran-6-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),3-(1,1-Dioxythiomorpholine-) dihydrobenzofuran-6-boronic acid pinacol ester (300 mg, 0.8 mmol),Pd(dppf)Cl2 (10mg, 0.04mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight. After the reaction solution is diluted, it is washed with water.The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.Purified by silica gel column chromatography,A white solid (56 mg, 54%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 11.3 step 3, synthesis of N- Cyclopropylcarbonyl {5- 4- (1,1- dioxothiomorpholine-4yl)-1-hydroxymethyl hydroxymethyl)methylphenyl[1,2,4]triazolo[1,5- a]pyridin- 2-yl }amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-Dioxythiomorpholine-1-hydroxymethylhydroxymethyl)]-toluic acid benzoic acid ester (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water.Wash with saturated brine and dry over anhydrous sodium sulfate.Concentrated and evaporated to dryness.Purified by silica gel column chromatography,Obtained as a white solid (53 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 100℃; | 12.6 step 6: synthesis step of N-cyclopropylcarbonyl {5-[4-((1,1-dioxothiomorpholine-4-yl)-1,1-dimethyleneoxa)]methylphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-Dioxythiomorpholine)-1,1-dimethylene oxa]toluene borate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04) Mm)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight.After the reaction solution is diluted,Washed with water, washed with saturated brine,After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness.Purified by silica gel column chromatography,A white solid (51 mg, 50%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 13.5 step 5: synthesis step of N-cyclo propylcarbonyl {5-[1-(1,1-dioxothiomorpholine)]-2-methyl-5-bromo-2-hydroxy-indene-5 -[1,2,4]triazolo[1,5-a]pyridin-2-}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),1-(1,1-dioxothiomorpholine)-2-methyl-5-bromo-2-hydroxy-indole-5-boronic acid tablet (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg) , 0.04mmol)And cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),100 ° CStir overnight. After the reaction solution is diluted,Washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.Silica gel column chromatography purification,Obtained as a white solid (55 mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 14.4 step 4: synthesis step of N-cyclo propylcarbonyl {5-[5-(1,1-dioxothiomorpholine)] Benzodioxane-8-[1,2,4]triazolo[1,5-a]pyridin-2-}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),5-(1,1-dioxothiomorpholine)benzodioxan-8-borate tablet (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg,0.04 mmol) and cesium carbonate (390 mg, 1.2 mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight. After the reaction solution is diluted,Washed with water, washed with saturated brine,After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness.Purified by silica gel column chromatography,A white solid (51 mg, 52%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane; water at 100℃; | 15.3 step 3, synthesis of N- Cyclopropylcarbonyl {5- (1,1- dioxothiomorpholine)- isochroman- 7- [1,2,4]triazolo[1,5- a]pyridin- 2- }amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol), 4-(1,1-Dioxothiomorpholine)isochroman-7-borate tablet (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol) and Cesium carbonate (390 mg, 1.2 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). Stir at 100 ° C overnight.Reaction solution After release, wash,The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purified by silica gel column chromatography to give a white solid(54 mg, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 16.3 step 3: synthesis step of N-cyclo propylcarbonyl {5-[3-(1,1-dioxothiomorpholine-4-yl)] 2,2-dimethylbenzofuran]-6- [1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropanoyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol), 3-(1,1-Dioxathiomorpholine-2,2-dimethylbenzofuran-6-boronic acid pinacol ester (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390 mg, 1.2) Ment) dissolved in 1,4-dioxane (10 mL) and water (1 mL), 100 ° CStir overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Silica gel column chromatography Purification gave a white solid (54 mg, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 17.4 step 4: synthesis step of N-cyclopropylcarbonyl {5-4-[1-((1,1-dioxothiomorpholine-4-yl)-1-methoxycarbonyl)] methylphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-dioxothiomorpholine-1-methoxycarbonyl)]-p-toluate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol) and cesium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water.The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purified by silica gel column chromatography,Obtained as a white solid (73 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 1.6 step 6: synthesis step of N-cyclopropylcarbonyl {5-4-[1-(1,1-dioxothioethylmorpholine)]phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amine. N-cyclopropylcarbonyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100mg0 4mmol)4-[1-(1,1-Dioxythioethylmorpholine)] phenylboronic acid pinacol ester (300 mg, 0.8 mmol), Pd (dppf) CI2 (10 mg, 0.04 mmol) and Caesium carbonate (390 mg, 1.2 mmol) dissolved in 1,4-dioxane (100 mL) and water (1 mL), and stirred at 100 ° C for overnight. The reaction mixture was diluted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. Purified by silica gel column chromatography to give a white solid (20 mg, 16%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 18.3 step 3: synthesis step of N-cyclo propylcarbonyl {5-4-[1-((1,1-dioxothiomorpholine-4-yl)-1-hydroxy methyl)] methylphenyl - [1,2,4]triazolo[1,5-a]pyridin-2-yl}amine N-cyclopropionyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol),4-[1-(1,1-Dioxythiomorpholine-1-hydroxymethyl)]-toluene borate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg,0.04mmol)And cesium carbonate (390 mg, 1.2 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL).Stirred at 100 ° C night. After the reaction solution is diluted, it is washed with water and washed with saturated brine.After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness.Purified by silica gel column chromatography, obtained as a white solid (53 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 19.3 step 3, synthesis of N- Cyclopropylcarbonyl {5- 4- ((1,1- dioxothiomorpholine-4-yl) -1-methoxymethyl) methyl phenyl- [1,2,4]triazolo[1,5- a]pyridin- 2- yl}amine v |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 20.3 step 3: synthesis step of N-cyclo propylcarbonyl {5-4-[1-(1,1-dioxothiomorpholine-1,1-dimethyl-1-hydroxymethyl)] methylphenyl - [1,2,4]triazolo[1,5-a]pyridin-2-}amine N-cyclopropanoyl (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-)amine (100 mg, 0.4 mmol), 4-[1-(1,1-dioxothiomorpholine-1,1-dimethyl 1-hydroxymethyl)]methylene terephthalate (300 mg, 0.8 mmol), Pd(dppf)Cl2 (10 mg, 0.04 mmol) and Barium carbonate (390mg, 1.2mmol)Soluble in 1,4-dioxane (10 mL) and water (1 mL),Stir at 100 ° C overnight.After the reaction solution is diluted, it is washed with water.The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Silica gel column Chromatographic purification,A white solid (50 mg, 50%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.86 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 100℃; for 2h; | 1.4 Step 4, N-(5-(4-((3-(methylsulfonyl)azetidin-1-yl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]c yclopropanecarboxamide Step 4, N-(5-(4-((3-(methylsulfonyl)azetidin-1-yl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]c yclopropanecarboxamide 1 g of N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, 1.25 g of 3-(methylsulfonyl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine, 1.0 g of potassium carbonate, and 0.14 g of Pd(dppf)Cl2 were added in 30 ml of dioxane/water (5:1), and heated to 100 °C for 2 h. After filtration, the filtrate was rotary evaporated to dryness to remove the dioxane and diluted with water. After extracted with ethyl acetate, and purified by column chromatography the title compound (0.86 g) was obtained. 1HNMR (400MHz, DMSO-D6) δ 9.21 (s, 1H), 7.94 (m, 2H), 7.56-7.62 (m, 2H), 7.44 (m, 2H), 7.26 (s, 1H), 7.07 (d, 1H), 3.94 (m, 1H), 3.77 (s, 2H), 3.60-3.73 (m, 4H), 2.93 (s, 3H), 1.79 (s, 1H), 1.18 (m, 2H), 0.91 (m, 2H). MS (ESI): 426.16 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With tributyl-amine; 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)-2-trisilanol; C45H30N6 In N,N-dimethyl acetamide at 40℃; for 0.5h; Inert atmosphere; Irradiation; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 70 - 100℃; Inert atmosphere; | 1.4 Step 4 Synthesis of 4- (2- (cyclopropylcarboxamido)-[1,2,4] triazolo [1,5-a] pyridin-5-yl) benzoic acid (VI) Under the protection of nitrogen at room temperature, 1.0g (3.5mmol) of intermediate V, 1.2g (5.3mmol) of 4-carboxyphenylboronic acid pinacol ester, 1.0g (7mmol) of potassium carbonate and 0.14g (0.35mmol) of Pd (dppf) Cl2 was added to a mixed solvent of 10 mL dioxane / water (8: 1), and the temperature was slowly raised to 70-100 ° C with stirring, and the reaction was performed for 5-14 h. After the reaction was completed, part of the solvent was distilled off, 15 mL of water was added to the residue, and the aqueous layer was washed with DCM. The aqueous layer was adjusted to pH 2-3 with 4N HCl, suction filtered, and purified by column chromatography to obtain 0.86 g of white solid in 75% yield; |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 90 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90 - 100℃; for 12h; Inert atmosphere; | 1.1 General procedure for preparation of intermediate j-5 and j-6 The appropriate boronic pinacol ester (2 eq) is added to a solution of intermediate j-3 (2 g, 7.1 mmol) in 1,4-dioxane/water (5:1). K2CO3 (2 eq) and PdCl2dppf (0.1 eq) are added to the solution. The resulting mixture is then heated in an oil bath at 90-100 °C for 12 h under N2. After cooling, water is added and the solution is extracted with EtOAc. The organic layers are dried over anhydrous Na2SO4 and evaporated in vacuum. The compound is obtained after purification by flash chromatography 1.1.1 N-(5-(4-formylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2 yl) cyclopropane carboxamide (j-5) Yield: 75% (1.63 g), brown solid.1H NMR (400 MHz, DMSO-d6) δH 11.13 (s, 1H), 10.12 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.92 - 7.64 (m, 2H), 7.42 (m, 1H), 2.01 (s, 1H), 0.82 (d, J = 6.2 Hz, 4H); 13C NMR (100 MHz, DMSO-d6) δC 192.66, 171.23, 158.13, 150.25, 138.21, 137.22, 136.60, 130.22, 129.68, 129.25, 114.50, 114.31, 13.78, 7.62. HRMS calcd for C17H14N4O2, [M+H]+, 307.1196, found 307.1187. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90 - 100℃; for 12h; Inert atmosphere; | 1.1 General procedure for preparation of intermediate j-5 and j-6 General procedure: The appropriate boronic pinacol ester (2 eq) is added to a solution of intermediate j-3 (2 g, 7.1 mmol) in 1,4-dioxane/water (5:1). K2CO3 (2 eq) and PdCl2dppf (0.1 eq) are added to the solution. The resulting mixture is then heated in an oil bath at 90-100 °C for 12 h under N2. After cooling, water is added and the solution is extracted with EtOAc. The organic layers are dried over anhydrous Na2SO4 and evaporated in vacuum. The compound is obtained after purification by flash chromatography 1.1.1 N-(5-(4-formylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2 yl) cyclopropane carboxamide (j-5) Yield: 75% (1.63 g), brown solid. |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 5.1 Step 1: Preparation of Compound 5-1 A system consisted with a mixed solution of dioxane (20 mL) and water (5 mL) in which compound 1-4 (1 g, 3.56 mmol), (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.9 mmol), Pd(dppf)Cl2.CH2Cl2 (291 mg, 355.7 mol) and K2CO3 (1.47 g, 10.67 mmol) were dissolved, was purged 3 times with nitrogen. The suspension was stirred at 90° C. for 12 hours under nitrogen atmosphere. LCMS showed that the raw material was completely consumed, and the target molecular ion peak was detected. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain compound 5-1. LCMS (ESI) m/z: 384 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.2% | With tetrakis(triphenylphosphine) palladium(0); potassium <i>tert</i>-butylate In toluene at 110℃; for 16h; Sealed tube; Inert atmosphere; | 11 Step 1: Synthesis of N-(5-(1H-pyrrol-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanamide (Intermediate 11C ) The N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanamide (200mg, 0.71mmol, according to J.Med.Chem. 2014, 57 , 9323), (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid (190mg, 0.71mmol), Pd(PPh3)4 (82mg, 0.07mmol), t- BuOK (160mg, 1.4mol) was placed in a sealed tube, 10mL of toluene was added, nitrogen was replaced, sealed and heated to 110°C, and reacted for 16 hours. The reaction solution was quenched by adding brine, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. Purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 66 mg of the title product as a pale yellow solid, yield: 35.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 48h; Inert atmosphere; Sealed tube; | 12.5 Step 1: 5-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine Synthesis of (Intermediate 1B) Add (1-(4-(cyanomethyl)-1-(2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol Ester (1.00g, 2mmol), N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanamide (11A) (0.60g, 2mmol) , Potassium carbonate (0.55g, 4mmol), Pd(dppf)Cl2 (0.73g, 0.5mmol), dioxane (20mL), water (5mL) are placed in a sealed tube and reacted at 80 under nitrogen atmosphere 48 hours. The reaction solution was concentrated to dryness and purified by column chromatography (eluent: dichloromethane: methanol = 3: 1) to obtain 520 mg of the title product as a yellow solid, yield: 49.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.14 g | With methanol; potassium carbonate at 20℃; for 1h; | 1.1.2 Step 1.2 Preparation of compound Int-1 N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (1) (3.3g crude product, 9.4mmol)Dissolve in methanol (30 mL) solution, add potassium carbonate (3.9 g, 28.2 mmol), and stir at room temperature for 1 hour.The reaction solution was concentrated in vacuo at room temperature, and the obtained crude product was dissolved and dispersed in ethyl acetate (250 mL) and then filtered.The filter cake was washed successively with dichloromethane (250 mL) and tetrahydrofuran (250 mL), and the filtrate was collected and concentrated in vacuo.Use petroleum ether/ethyl acetate (22mL, 10:1v/v) to improve the slurry to obtain the productN-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Int-1)(2.14g, yield 80%, purity 99%), yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 85℃; for 0.5h; Inert atmosphere; | 3.3.3 Step 3.3 Preparation of compound EXP-4 N-(5-bromo-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Int-1) (20mg, 0.071mmol),4-[[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-)thiazole-2-]methyl]-1,4-thiazine1, 1-Dioxide (4) (76.5mg, 0.213mmol),Potassium carbonate (29.5mg, 0.213mmol) was suspended in dioxane (1mL) and water (0.2mL), and the reaction liquid was replaced with nitrogen three times.Then, 1,1-bis(tert-butylphosphorus)ferrocene palladium chloride (9.3mg, 0.014mmol) was quickly added, and the reaction solution was replaced with nitrogen three times again.Stir at 85°C for half an hour. The reaction solution was concentrated in vacuo,Rapid purification by column machine (eluent: 0%0.5% methanol/dichloromethane) to obtain crude product, Alkaline machine points to get the target moleculeN-[5-[2-[(1,1-Dioxy-1,4-thiazine-4-)methyl]thiazole-5-]-[1,2,4]triazole[1,5- a)pyridine-2-]cyclopropylformamide (EXP-4)(5.6 mg, 6% yield, 93% purity, yellow solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 0.5h; Inert atmosphere; | 1.1.3 Step 1.3 Preparation of Compound 2 N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Int-1) (300mg, 1.1mmol),(5-formyl-2-thienyl)boronic acid (SM3) (332.9mg, 2.1mmol) andPotassium carbonate (442.5mg, 3.2mmol) is dissolved in dioxane (5mL) and water (1mL),After replacing nitrogen for three times, quickly add 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (39.0mg, 53.4umol),The nitrogen was replaced three times again, and stirred at 90°C for 30 minutes under the protection of nitrogen.The reaction solution was diluted with water (20mL) and dichloromethane for extraction (20mL×3), and the organic phase was washed with saturated brine (20mL).After drying with anhydrous sodium sulfate and filtering, the filtrate was concentrated in vacuo to obtain a crude product.Purify by silica gel column chromatography (eluent: 1%2% methanol/dichloromethane) to obtain the productN-[5-(5-Formyl-2-thienyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (2)(350mg semi-pure product, containing part of raw material 1, conversion yield 49.4%), yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 2100℃; Inert atmosphere; | 9.9.1 Step 9.1 Preparation of compound 17 N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxamide (Int-1) (100mg, 0.36mmol),5-carboxy-2-thiophene boronic acid (SM13) (122mg, 0.71mmol) and sodium carbonate (113mg, 1.07mmol) are dissolved in tetrahydrofuran (10mL) and water (5mL),After nitrogen replacement for three times, 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (50mg, 0.07mmol) was added,After nitrogen replacement three times, it was raised to 100°C and stirred for 2 hours.The reaction solution was added with water (10 mL) and extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL),After drying with anhydrous sodium sulfate and filtering, the filtrate is concentrated in vacuo to obtain5-(2-Formyl)-thiophene-[1,2,4]triazole[1,5-a]pyridine-2-cyclopropanecarboxamide (17) (50mg, crude product) yellow solid,Used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 1.5h; Inert atmosphere; | 1.4 Step 4: Preparation of Compound 1-5 A system consisted with a mixed solution of dioxane (120 mL) and water (30 mL) in which N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]amino carbamic acid tert-butyl ester (11 g, 34.0 mmol), compound 1-4 (7.6 g, 27.2 mmol), K2CO3 (14.11 g, 102.09 mmol) and Pd(dppf)Cl2 (2.49 g, 3.4 mmol) were dissolved was purged 3 times with nitrogen. The mixed solution was stirred at 90° C. for 1.5 hours under nitrogen atmosphere. After TLC monitoring showed the raw material was completely consumed, and the target molecular peak was detected. The reaction solution was concentrated under reduced pressure, then dispersed in 100 mL water, and extracted with ethyl acetate ((150 mL*3)). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20-70% elution) to obtain compound 1-5. LCMS (ESI) m/z: 398 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 2h; Inert atmosphere; | 2.1 Step 1: Preparation of Compound 2-1 A system consisted with a mixed solution of dioxane (12 mL) and water (3 mL) in which 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (0.3 g, 1.02 mmol), compound 1-4 (300 mg, 1.07 mmol), K2CO3 (421.39 mg, 3.05 mmol) and Pd(dppf)Cl2 (74.36 mg, 101.63 umol) were dissolved, was purged 3 times with nitrogen. And the mixture was stirred at 90° C. for 2 hours under nitrogen atmosphere. LCMS showed that the raw material was completely consumed, and the target molecular ion peak was detected. The reaction solution was concentrated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain compound 2-1. LCMS (ESI) m/z: 370 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 3h; Inert atmosphere; | 2.3 Step 3: In nitrogen atmosphere, mixed dioxane (40 ml) and water (10 ml) solution containing N-(5-bromo-[1,2,4]triazole[1,5-a] pyridine-2-yl) cyclopropyl formamide (2 g, 7.1 mmol), compound 3-3 (3.49 g, 9.3 mmol), potassium carbonate (2.95 g, 21.3 mmol), and [1,1-Bis (diphenylphosphine) ferrocene]palladium dichloride dichloromethane (581 mg, 711.5 μmol) was replaced by nitrogen for 3 times, and the reaction solution was heated to 90° C. for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was separated by a rapid silica gel column (0 4% methanol/dichloromethane) to provide compounds 3-4. LCMS (ESI) m/z: 452.4[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 4.3 Step 3: The solution of dioxane (4 mL) and water (1 mL) containing compound 5-3 (0.13 g, 357.8 μmol), N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropane formamide (101 mg, 357.8 μmol), K2CO3 (149 mg, 1.1 mmol), and Pd(dppf)Cl2 (26 mg, 35.8 μmol) was replaced by nitrogen gas. The mixture was stirred in nitrogen atmosphere for 12 hours at 90° C. LCMS showed reaction was complete, and target molecular ion peaks were detected. The reaction solution was removed of the solvent by concentrating, then dispersed in 10 mL water, and extracted by DCM/MeOH (10:1, 30 mL*3). Organic phases were combined, washed by the saturated saline solution (40 mL) and dried by anhydrous sodium sulfate, then filtered to provide filtrate, which was distillated under reduced pressure to provide a coarse product. The coarse product was purified by the chromatographic column method (SiO2, DCM:MeOH=1:0 to 20:1) to provide compound 5-4. LCMS (ESI) m/z: 438.3[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 5.3 Step 3: Dioxane (4 mL) and water (1 mL) solution containing compound 6-3 (186 mg, 512 μmol), N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropane formamide (144 mg, 512 μmol), K2CO3 (212 mg, 1.5 mmol), Pd(dppf)Cl2.CH2Cl2 (42 mg, 51.2 μmol) was replaced by nitrogen for 3 times. In nitrogen condition, the mixture was stirred for 12 hours at 90° C. LCMS showed raw materials were consumed completely, and target molecular ion peaks were detected. The reaction solution was removed of solvent, dispersed in 10 mL water, and extracted by DCM:MeOH (10:1, 30 mL*3). Organic phases were combined, washed by saturated saline solution (40 mL), dried by anhydrous sodium sulfate, filtered, and then distillated under reduced pressure to provide a coarse product. The coarse product was purified by chromatographic column method (SiO2, DCM:MeOH=1:0 20:1) to provide compound 6-4. LCMS (ESI) m/z: 438.7[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 6.3 Step 3: Dioxane (4 mL) and water (1 mL) solution containing compound 7-3 (0.15 g, 447.43 μmol), N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropane formamide(126 mg, 447.43 μmol), K2CO3(186 mg, 1.34 mmol), and Pd(dppf)Cl2.CH2Cl2 (37 mg, 44.7 μmol) was replaced by nitrogen for 3 times. The mixture was stirred in nitrogen atmosphere for 12 hours at 90° C. LCMS showed that raw materials were consumed completely, and target molecular ion peak were detected. The reaction solution was concentrated to remove solvent, then dispersed in 10 mL water, and extracted by DCM:MeOH (10:1, 30 mL*3). Organic phases were combined, washed by saturated saline solution (40 mL), dried by hydrous sodium sulfate, filtered, and distillated under reduced pressure to provide coarse product, which was purified by chromatographic column method (SiO2, DCM:MeOH=1:0 20:1) to provide compound 7-4. LCMS (ESI) m/z: 410.2[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 3h; Inert atmosphere; | 1.3 Step 3: In a nitrogen atmosphere, potassium carbonate (3.8 g, 27.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (744 mg, 911.0 μmol) were added into the solution of dioxane (60 mL) and water (15 mL) containing compound 1-3 (3.5 g, 10.0 mmol) and N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl) cyclopropane formamide (2.6 g, 9.1 mmol). This reaction solution was stirred for 3 hours at 90° C. LCMS showed the raw materials were consumed completely, and there were target molecular ion peaks detected. The reaction solution was concentrated to provide a coarse product, which was purified and separated by chromatography to provide compound 1-4. LCMS (ESI) m/z: 424.3[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.91% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; tripotassium phosphate tribasic In 1,4-dioxane; lithium hydroxide monohydrate at 95℃; for 18h; Inert atmosphere; | 2.2.1 Step 2.1 Preparation of Compound 3 4-Methoxycarbonylbenzeneboronic acid (SM1) (1.67 g, 8.98 mmol) was added to N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl) - To a mixed solution of cyclopropanecarboxamide (Int-1) (1.83 g, 6.51 mmol) in 1,4-dioxane (26 mL) an d water (5 mL), potassium phosphate (2.07 g, 9.76 g) was added under nitrogen flow mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (262 mg, 0.358 mmol). After the reaction liquid was replaced with nitrogen several times, it was heated to 95° C. under a nitrogen atmosphere, and stirring was continued for 18 hours. The obtained dark red reaction solution was filtered to remove the insoluble residue while hot, and then concentrated. The residue was slurried with ethyl acetate/methanol (30 mL, v/v=5/1). The insoluble solids were collected by filtration, washed with ethyl acetate (5 mL×2) and dried in vacuo to obtain the target product 4-[2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]benzoic acid methyl ester (3) (1.98 g, 95% purity, 5.59 mmol, 85.91% yield, grey solid). |
Tags: 1142943-96-1 synthesis path| 1142943-96-1 SDS| 1142943-96-1 COA| 1142943-96-1 purity| 1142943-96-1 application| 1142943-96-1 NMR| 1142943-96-1 COA| 1142943-96-1 structure
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H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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