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CAS No. : | 375853-82-0 | MDL No. : | MFCD11506075 |
Formula : | C11H20BNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AIPUNCFCQBDNDJ-UHFFFAOYSA-N |
M.W : | 209.09 | Pubchem ID : | 21105461 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
100% | With hydrogen In methanol; ethyl acetate for 14 h; | Method 4: General conditions for the reduction of tetrahydropyridines to piped dines in the presence of a boronate ester: The boronate ester is dissolved in ethyl acetate/methanol (1: 1 v/v) (0.4 M final ester concentration) after which Pd(OH)2 (0.35 equiv) is added and the reaction is allowed to stir under an atmosphere Of H2 for 14h. At this point the reaction is filtered through and concentrated in vacuo to provide the desired piperidine in quantitative yield.; Example 8: Piperidine 8 was prepared in 2 steps from compound 1 using Method 4 followed by pinacol ester deprotection using Method 2. [M-H]- = 228.2 m/z. Activity: B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In tert-butyl methyl ether at 20℃; | Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSψ4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B |
96% | With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; | To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the lH NMR spectrum were consistent with the structure of the compound. |
90% | With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃; | tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9. |
90% | With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃; | tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9. |
8 g | With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h; | Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+. |
8 g | With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h; | Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+. |
8 g | With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h; | Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium periodate; ammonium acetate; In water; acetone; at 20℃; | Intermediate 108 (1-[(1,1-Dimethylethyl) oxy] carbonyl}-1, 2,3, 6-tetrahydro-4-pyridinyl) boronic acid Sodium periodate (2.08 g, 9.75 mmol) was added in portions to a mixture of 1,1- dimethylethyl 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-3, 6-dihydro-1 (2H)-pyridine- carboxylate (1.0 g, 3.25 mmol, TDC Research Inc) and ammonium acetate (750 mg, 9.74 mmol) in acetone (40 mL) and water (40 mL) at room temperature, under nitrogen. The reaction was stirred overnight, filtered through a Celite pad, washed with acetone and the organic solvent removed. Brine (50 mL) was added and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated to give the title compound. MS calcd for (C10H18NO4 + H) + : 228 MS found (electrospray) : (M+H)'= 228 | |
With sodium periodate; ammonium acetate; In water; acetone; at 23℃; for 12h; | Method 1: General conditions for the conversion of boronate esters to boronic acids: The boronate ester (1.0 eq), sodium periodate (5.0 eq) and ammonium acetate (5.0 eq) are dissolved in acetone/water 2: 1 (0.05 M boronate ester) and stirred for 12 hours at 23 0C until TLC or LCMS indicated conversion to the boronic acid is complete. One option for isolation is to precipitate the product by dilution of the mixture with IN aqueous HCl and collection of the solid boronic acid by filtration. Alternately, the mixture is partitioned between water and ethyl acetate, and the organic layer washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified either by recrystallization and trituration (heptane, acetonitrile, or other solvents) or by flash silica gel chromatography (0.5% to 10% methanol/dichloromethane) to afford pure boronic acid.; Example 1: Tetrahydropyridine 1 was prepared in 1 step from commercially available 4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate using Method 1 and was isolated after precipitation from the reaction mixture. [M-H]- = 226.1 m/z. Activity: C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 18h; | A solution of <strong>[1532-71-4]1-<strong>[1532-71-4]bromoisoquinoline</strong></strong> (0.35 g, 1.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (US 2004/0186103) (0.5 g, 1.68 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) (0.065 g, 0.05 mol equiv.) and potassium carbonate (0.66 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) was heated at 80 °C for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was purified' by column chromatography on silica gel eluting with ethyl acetate: pentane 50 : 50 to afford the title compound as a pale yellow oil, 0.14 g. LRMS (APCI+): m/z [M+H]+ 311 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 20h; | Step 13BC: 3-Trifluoromethyl-3',6'-dihydro-2'H-t2J4']bipyridinyl-ll-carboxylic acid tert- butyl ester; A mixture of the boronate from Step 13BB (1.49 g, 4.82 mmol), Dichloro[l-1'- bis(diphenylphosphino)ferrocene]palladium (IT) dichloromethane adduct (703 mg, 0.96 mmol), 2- Bromo-3-(trifuloromethyl)pyridine (1.33 g, 5.78 mmol) and sodium carbonate (2.04 g, 19.28 mmol) in a 7:3:2 solution of dimethoxyethane/H2O/EtOH (30 ml) was degassed with N2 and heated at 800C. After 2Oh the mixture was cooled to room temperature and diluted with equal portions of EtOAc and H2O, the aqueous phase was then extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (elution with 0 to 30% EtO Ac-Hex) afforded the desired product (1.24 g), an orange oil, in 78% yield. IH NMR (400 MHz, CHLOROFORM-D) delta ppm 1.50 (s, 9 H), 2.51 (s, 2 H), 3.67 (s, 2 H), 4.07 (s, 2 H), 5.76 (s, 1 H), 7.34 (dd, J=8.1, 4.8 Hz, 1 H), 7.99 (d, J=8.1 Hz, 1 H), 8.75 (d, J=4.8 Hz, I H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; | 2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenyl-phosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85 C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil. | |
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; | Intermediate 1a): [Show Image] 2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenyl-phosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil. | |
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; | 2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenylphosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 160℃; for 0.25h;Microwave irradiation; | A solution containing <strong>[50998-17-9]6-bromo-quinoxaline</strong> (417 mg, 2.0 mmol), 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester (600 mg, 1.94 mmol), tetrakis [triphenylphosphine] palladium (108 mg, 0.1 mmol) and sodium carbonate (2 M solution, 3 mL) in 5 ml_ of dioxane/ethanol/water <n="265"/>(7:3:1 ) was heated at 160 C using microwave reactor for 15 minutes. After the reaction, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, the product was purified using column chromatography (5% methanol in dichloromethane) | |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 160℃; for 0.25h;Microwave irradiation; | A solution containing <strong>[50998-17-9]6-bromo-quinoxaline</strong> (417 mg, 2.0 mmol), 4-(4 ,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester (600 mg, 1.94 mmol), tetrakis [triphenylphosphine] palladium (108 mg, 0.1 mmol) and sodium carbonate (2 M solution, 3 ml_) in 5 ml_ of dioxane/ethanol/water (7:3:1 ) was heated at 160 C using microwave reactor for 15 minutes. After the reaction, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, the product was purified using column chromatography (5% methanol in dichloromethane) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; | A solution containing <strong>[857641-46-4]2-(4-bromo-pyrazol-1-yl)-pyrimidine</strong> (300 mg, 1.34 mmol), 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (280 mg, 1.34 mmol), PdCI2(dppf) (95 mg, 0.13 mmol) and potassium phosphate (800 mg, 4 mmol) in dioxane was heated at 80 C under argon for overnight. After removed the solvent, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, it was found the product was hard to separated from impurity and the crude product was treated with 90% of TFA for 20 min and TFA was removed under vacuum. The crude product was then purified using prep HPLC to give desired product as TFA salt (120 mg, 0.37 mmol) in 27 % overall yield. MS (ESMS, M+H 228) | |
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; | A solution containing <strong>[857641-46-4]2-(4-bromo-pyrazol-1-yl)-pyrimidine</strong> (300 mg, 1.34 mmol), 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (280 mg, 1.34 mmol), PdCI2(dppf) (95 mg, 0.13 mmol) and potassium phosphate (800 mg, 4 mmol) in dioxane was heated at 80 C under argon for overnight. After removed the solvent, ethylacetate was added and the mixture was filtered, washed with water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; | A mixture of <strong>[2516-40-7]2-bromo-benzothiazole</strong> (0.38 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (0.5 g, 1.62 mmol), potassium carbonate (0.67 g, 4.85 mmol), Pd(dppf)CI2 (0.132 g, 0.16 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 90 °C for overnight. Cooled to room temperature and diluted with EtOAc (200 ml_). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel to give the desired product 21 BB (0.4 g, 78percent). |
78% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; | A mixture of <strong>[2516-40-7]2-bromo-benzothiazole</strong> (0.38 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.62 mmol), potassium carbonate (0.67 g, 4.85 mmol), Pd(dppf)CI2 (0.132 g, 0.16 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 90 CC for overnight. Cooled to room temperature and diluted with EtOAc (200 ml_). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel to give the desired product 21 BB (0.4 g, 78percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 14h;Inert atmosphere; Reflux; | 3-Bromopyridine-2-carboxylic acid methyl ester (4.0 g, 18.6 mmol, 1.0 eq.) was combined with a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (5.8 g, 18.6 mmol, 1.0 eq.) in THF (100 mL), under nitrogen. A solution of Na2CO3 (7.9 g, 74.5 mmol, 4.0 eq.) in water (37 mL) was added, followed by the addition of PdCl2(PPh3)2 (650 mg, 930 mumol, 0.05 eq.). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), then washed with saturated aqueous NaCl (2*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3',6'-dihydro-2'H-[3,4]bipyridinyl-2,1'-dicarboxylic acid 1'-t-butyl ester 2-methyl ester (3.8 g) as colorless oil. H-NMR: (300 MHz, CDCl3, ppm) 8.67-8.64 (1H, dd, J=4.5 Hz), 7.60-7.63 (1H, dd, J=7.8 Hz), 7.42-7.46 (1H, t, J=7.8 Hz), 5.62 (1H, t), 4.06-4.07 (2H, d, J=2.4 Hz), 3.96 (3H, s), 3.67-3.69 (2H, t, J=12.1 Hz), 2.40 (2H, m), 1.52 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.4% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; toluene; at 90℃;Inert atmosphere; | Compound 105a. To a solution of ethyl 3-bromoisonicotinate (0.2 g, 0.925 mmol, 1.0 equiv) in Toluene (8 mL) and water (2 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.429 g, 1.39 mmol, 1.5 equiv), K2CO3 (0.255 g, 1.85 mmol, 2.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(PPh2)Cl2 (0.033 g, 0.046 mmol. 0.05 equiv). The resulting reaction mixture was heated at 90 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain 1?-(tert-butyl) 4-methyl 3?,6?-dihydro-[3,4?-bipyridine]-1?,4(2?H)-dicarboxylate (0.130 g, 44.4% Yield) as an yellow oil. (0848) LCMS 319.2 [M+H]+ (0849) 1H NMR (400 MHz, DMSO-d6) delta 8.65 (d, J=4.8 Hz, 1H), 8.59-8.52 (m, 1H), 7.63 (d, J=4.8 Hz, 1H), 5.68 (br. s., 1H), 3.96 (br. s., 2H), 3.87-3.69 (m, 3H), 3.52 (br. s., 2H), 2.27 (br. s., 2H), 1.53-1.25 (m, 9H), 1.07 (s, 3H). |
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 14h;Inert atmosphere; Reflux; | PdCl2(PPh3)2 (0.7 g, 1.03 mmol, 0.05 eq.) was added to a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (6.3 g, 20.5 mmol, 1.0 eq.) in THF (120 mL) under nitrogen. To this was added <strong>[59786-31-1]3-bromoisonicotinic acid methyl ester</strong> (4.4 g, 20.5 mmol, 1.0 eq.). This was followed by the addition of a solution of Na2CO3 (8.7 g, 82.1 mmol, 4.0 eq.) in water (41 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), and washed with saturated aqueous NaCl (2*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield 3',6'-dihydro-2'H-[3,4']bipyridinyl-4,1'-dicarboxylic acid 1'-t-butyl ester 4-methyl ester (5.6 g) as a yellow oil. H-NMR: (300 MHz, CDCl3, ppm): 8.65 (1H, d, J=4.8 Hz), 8.54 (1H, s), 7.65 (1H, d, J=4.8 Hz), 5.65 (1H, m), 4.08 (2H, m), 3.90 (3H, s), 3.65 (2H, m), 2.34 (2H, m), 1.51 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 1h;Reflux; | A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2/f-pyridine-l-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-r-carboxylic acid tert-hutyl ester (4.6 g) as a solid. MS (ES+) 294 (MEta+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH). | |
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 1h;Reflux; | Step A: A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2//-pyridine-l -carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-31,6'-dihydro-2'//-[2,4']bipyridinyl-lt- carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; | To a slurry of anhydrous potassium carbonate (3.50 g, 25.3 mmol) in dry degassed NN- dimethylformamide (35 mL) is added <strong>[1735-53-1]4-bromo-3-trifluoromethyl benzonitrile</strong> (2.00 g,8.00 mmol) followed by bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.92 g,1.25 mmol) and the reaction mixture is heated at 80 C overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and the solvent is removed in vacuo. The crude material is purified via silica gel chromatography using 4% ethyl acetate/petroleum ether as eluent to afford the desired product (1.2O g, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere; | Preparation 4 4-(4-Fluoro-2-hydroxymethylphenyl)piperidine-1-carboxylic Acid t-Butyl Ester Methyl 2-bromo-5-fluorobenzoate (1.8 g, 7.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.3 g, 7.5 mmol), THF (69 mL, 850 mmol) and 2 M of sodium carbonate in water (15.0 mL, 30.0 mmol) were combined, and the mixture was degassed and flushed with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (158 mg, 225 mumol) was added, and the mixture was again degassed and flushed with nitrogen. The mixture was heated at 80 C. for 1 hour. The mixture was then cooled and the layers separated, diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc in hexanes). A solution of the crude material and Pearlman's Catalyst (0.1:0.4, Palladium hydroxide:carbon black, 1.1 g, 1.5 mmol) in MeOH (60.8 mL, 150 mmol) was hydrogenated at 1 atm at room temperature overnight. The mixture was then evacuated, purged with nitrogen, filtered through Celite and concentrated to yield a colorless oil. This oil was dissolved in THF (30 mL, 400 mmol) and treated with borane-dimethyl sulfide complex (1.3 mL, 15.0 mmol) at room temperature. The mixture was heated to reflux for 5 hours. After cooling to room temperature, MeOH (20 mL) was slowly added and removed by rotary evaporation. Another 20 mL of MeOH was added and removed by rotary evaporation. The residue was then dissolved in EtOAc (100 mL) and washed with 1N HCl and sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The material was then purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound (924 mg) as a colorless sticky solid. 1H NMR (CDCl3) delta (ppm) 7.21 (br.s, 1H); 7.16 (m, 1H); 6.98 (m, 1H); 4.76 (br.s, 2H); 4.24 (m, 2H); 2.89 (m, 1H); 2.80 (m, 2H); 1.72 (m, 2H); 1.60 (m, 2H); 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen;palladium(II) hydroxide; In methanol; ethyl acetate; for 14h; | Method 4: General conditions for the reduction of tetrahydropyridines to piped dines in the presence of a boronate ester: The boronate ester is dissolved in ethyl acetate/methanol (1: 1 v/v) (0.4 M final ester concentration) after which Pd(OH)2 (0.35 equiv) is added and the reaction is allowed to stir under an atmosphere Of H2 for 14h. At this point the reaction is filtered through and concentrated in vacuo to provide the desired piperidine in quantitative yield.; Example 8: Piperidine 8 was prepared in 2 steps from compound 1 using Method 4 followed by pinacol ester deprotection using Method 2. [M-H]- = 228.2 m/z. Activity: B |
92% | With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 2585.81 Torr; for 10h; | 5 g (16.2 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-tert-butyl carboxylic acid is dissolved in methanol after (150 mL), Pd/C (1 g) was added at room temperature under H 2 (gas) 50 psi.The reaction was carried out at room temperature for 10 h, and the reaction was directly filtered after completion of the reaction.The filtrate is concentrated to obtain the product4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylic acid tert-butyl ester 4.6 g, yield 92 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; In tert-butyl methyl ether; at 20℃; | Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSpsi4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B |
100% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 4h; | To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-1(2H)-carboxylate (5g, 16 mmol) in dioxane (10 mL) was added 4N HCl dioxane solution (24.2 mL, 97 mmol) at RT, and the reaction was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to afford the title compound (4 g, yield 100percent) as a white solid.MS (ES+) C11H21BCINO2 requires: 209, found 210 [M+H]+. |
100% | With hydrogenchloride; In ethyl acetate; at 0 - 26℃; for 3h; | Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (ARK PHARMA, 25 g, 80.851 mmol) was dissolved in 250 mL of EtOAc and HCI 4N in EtOAc (SYMAX FINE CHEMICALS, 250 mL) was added at 0 °C. The mixture was allowed to 26 °C and stirred for 3 h. The reaction mixture was evaporated under reduced pressure. The crude was washed with diethyl ether and filtered to give title compound (20 g, quantitative). NMR (400 MHz, DMSO-d6) delta ppm: 9.30 (br s, 2H), 6.40-6.30 (m, 1 H), 3.64- 3.52 (m, 2H), 3.15-3.00 (m, 2H), 2.34-2.22 (m, 2H), 1.21 (s, 12H). |
96% | With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; | To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the lH NMR spectrum were consistent with the structure of the compound. |
90% | With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃; | tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9. |
90% | With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃; | tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9. |
With hydrogenchloride; In methanol; at 20℃; for 1h; | The mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (4.0 g, 12.9 mmol) in HCl/MeOH (20 mL) was stirred at room temperature for lhour. Then it was concentrated to give 4-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine hydyochloride (2.9 g, 11.8mmol, yield:91.4percent)which was used in the next step without further purification. ESI-MS (M+1): 210 calc. for CnH2oBN02 209 | |
8 g | With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h; | Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+. |
8 g | With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h; | Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+. |
8 g | With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h; | Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; barium hydroxide monohydrate; In water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; | nder argon, N- (4-bromo-2-nitrophenyl) acetamide 8a (7.00 g, 27.02 mmol),4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-Dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester8b (8.77 g, 28.37 mmol),1,1'-bis (diphenylphosphino) ferrocenepalladium dichloride dichloromethane complex (2.34 g, 2.70 mmol) and barium hydroxide monohydrate (5.12 g, 27.02 mmol)Was dissolved in a mixed solvent of 120 mL of N, N-dimethylformamide and water (V / V = 5/1)Heated to 100 ° C for 4 hours.The reaction mixture was cooled to room temperature, 150 mL of ethyl acetate and 150 mL of water were added,The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A)getTert-Butyl 4- (4-acetylamino-3-nitrophenyl) -5,6- dihydropyridine- 1 (2H) -carboxylate 8c (8.72 g,Orange solid), yield: 89.3percent. |
83.9% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tricyclohexylphosphine; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Under the protection of argon, the N - (4 - bromo -2 - nitrophenyl) acetamide 3 b (550 mg, 2 . 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 9 a (853 mg, 2 . 76 mmol), three-ring [...] (59 mg, 0 . 212 mmol), tris(dibenzylideneacetone)dipalladium (97 mg, 0 . 106 mmol) and cesium carbonate (2.08 g, 6 . 37 mmol) dissolved in 40 ml water and 1, 4 - dioxane (V/V=1/4) mixed solvent in, 80 °C reaction 2 hours. The reaction cooling to room temperature, concentrated under reduced pressure, adding 50 ml ethyl acetate and 20 ml water, layered, organic phase using saturated sodium chloride solution (20 ml) washing, drying with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, the obtained residue by silica gel column chromatography (eluant: B system) purification, to obtain 4-(4-acetyl-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 9 b (644 mg, yellow solid), yield: 83.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 16h;Reflux; | This example illustrates the preparation of 2-chloro-Lambda/-{5,6-dichloro-l'-[4-(5-chloro- pyrimidin-2-yl)-benzyl]- 1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-3-yl} -isonicotinamide (Compound B8 of Table B).The title compound was prepared from 3-amino-5,6-dichloro-3',4',5',6'-tetrahydro- 2'H-[2,4']bipyridinyl-r-carboxylic acid tert-butyl ester according to procedures analogous to those described in Example 5, Steps C-E. 3-Amino-5,6-dichloro-3',4',5',6'-tetrahydro-2'H- [2,4']bipyridinyl-r-carboxylic acid tert-butyl ester was prepared as follows:Step A: A degassed solution of <strong>[78607-32-6]2,5-dichloro-3-amino-pyridine</strong> (40.75 g), 4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (77.25 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)- palladium(II) chloride (8.76 g) in dioxane (1500 ml) was treated with a degassed solution of sodium carbonate (79 g) in water (800 ml). The reaction mixture was heated to reflux for 16 hours, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3- amino-5-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-r-carboxylic acid tert-butyl ester (60 g) as a yellow solid. MS (ES+) 310 / 311 (MEta+), 254 / 256 (MH+-isobutene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 80℃;Inert atmosphere; | 2-Bromothiophene-3-carboxylic acid methyl ester (3.0 g, 14.0 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g, 14.0 mmol, 1.0 eq.), THF (150 mL) and Na2CO3 (28 mL, 56 mmol, 4.0 eq.) were combined.The mixture was degassed and purged with nitrogen (3*). PdCl2(PPh3)2 (0.3 g, 0.4 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3*), then heated at 80° C. overnight.The mixture was then cooled and the layers were separated.The THF layer was diluted with EtOAc (150 mL), washed with saturated aqueous NaCl (50 mL) and dried over Na2SO4.The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1~10:1) to yield 4-(3-methoxycarbonylthiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; for 18h;Inert atmosphere; Reflux; | A solution of <strong>[78071-37-1]4-bromothiophene-3-carboxylic acid methyl ester</strong> (500 mg, 2.3 mmol, 1.0 eq.) in THF (40 mL) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.7 g, 2.3 mmol, 1 eq.) under nitrogen.A solution of Na2CO3 (960 mg) in water (4.5 mL) was added, followed by the addition of PdCl2(PPh3)2 (80 mg, 0.1 mmol, 0.4 eq.).The resulting solution was stirred for 18 hours while the temperature was maintained at reflux in an oil bath.The resulting solution was diluted with EtOAc (50 mL), then washed with saturated aqueous NaCl (2*100 mL).The organic layer was concentrated and the residue was applied onto a silica gel column and eluted with EtOAc/PE (1:30) to yield 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.4 g) as a light yellow oil.H-NMR: (300 MHz, CDCl3, ppm): 8.10 (1H, d, J=3.6 Hz), 7.05 (1H, d, J=3.6 Hz), 4.15 (2H, m), 3.85 (3H, s), 3.66 (2H, m), 2.38 (2H, s), 1.51 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 18h; | <strong>[36178-05-9]3-Bromo-2-fluoropyridine</strong> (1.5 g, 8.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (3.16 g, 10.2 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (0.48 g, 0.68 mmol), sodium carbonate (4.44 g, 41.9 mmol), and 6: 1 : 1 DME-H20-EtOH (20 mL) were combined in a sealed tube and stirred at 80 C for 18 h. The cooled reaction was diluted with CH2CI2 and washed with aqueous saturated NaHCC>3 solution; the aqueous layer was back-washed with CH2C12 (lx). The combined organic extracts were dried (MgSC>4), filtered, and concentrated in vacuo. Flash column chromatography (10% to 40% EtOAc/Hexanes) gave tert-butyl 4-(2-fluoropyridin-3-yl)- 5,6-dihydropyridine-l(2H)-carboxylate as a golden yellow oil. [M+l] = 279.2. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 20h; | A mixture of 160 <strong>[36178-05-9]3-bromo-2-fluoropyridine</strong> (1.8 g), 26 tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (3.4 g), 161 tetrakis(triphenylphosphine)palladium (0) (0.60 g), aqueous sodium carbonate (2M, 6.5 ml), and 46 1,4-dioxane (25 ml) was stirred at 110°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated. The resulting residue was purified via silica gel column chromatography to obtain 162 tert-butyl 2-fluoro-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate as a pale yellow solid (Compound (27-1)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium acetate;bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) dichloride; In 1,4-dioxane; water; at 120℃; for 1.5h;Sealed tube; microwave irradiation; | A 10 mL CEM microwave vessel was charged with <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (139 mg, 0.63 mmol, Alfa Aesar), 3,6-dihydro-2H-pyridine-l-A^-boc-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.), NaOAc (155 mg, 1.90 mmol) and a stirbar. The vessel was sealed, and transferred into a glove box using a standard antichamber evacuate-refill cycle (3 times). The vessel was charged with A-Phos (45 mg, 0.063 mmol, Sigma-Aldrich), and sealed. The vessel was then transferred to a standard hood, and treated with dioxane (4 mL), and water (0.4 mL). The slurry was sonicated and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was treated with a second aliquat of 3,6-dihydro-2H-pyridine-l-A x>c-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.) and was then heated in a microwave using a CEM explorer at 120 C for 30 min The solution was treated with dichlorobis(di-?er?-butylphenylphosphine)palladium(II) (20 mg, 0.032 mmol, Alfa Aesar) and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was cooled to RT overnight under a stream of N2. The residue was treated with dry THF (5 mL) and SiliaMetS TAAcOH (1.29 g, 0.63 mmol, Silicycle). The vessel was crimped with a PTFE lined seal, and heated at 60 C for 3 h. The slurry was N2- pressure filtered through a glass frit (10 mL Bohdan) fitted with a 0.22 muiotaeta PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The silica was washed with dry THF (5 x 5 mL), and concentrated in vacuo. The crude material was purified by silica gel chromatography (10% EtOH in DCE) to afford teri-butyl 3'-amino-5,6-dihydro-[4,4'- bipyridine]-l(2H)-carboxylate (77 mg, 0.28 mmol, 44 % yield). MS (ESI, pos. ion) m/z: 276.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 85℃;Inert atmosphere; | Step 1: To Methyl 3-(2-bromophenyl)propanoate (715 mg, 2.94 mmol) and 3,6- dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (1.0 g, 3.23 mmol) were added to a flask, followed by Pd(dppf)Cl2 (151 mg, 0.21 mmol) and K2C03 (1.22 g, 8.82 mmol). The reaction flask was purged with Ar (3x). Dry DMF (22 ml.) was added and the solution was degassed for 10 min. The reaction mixture was heated to 85 C overnight. The mixture was filtered through Celite and was concentrated. The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes) to give fert-butyl 4-(2-(3-methoxy-3- oxopropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (23) as a pale yellow oil (970 mg, 96% yield). 1H NMR (400 MHz, CDCfe): delta 7.21-7.16 (m, 3H), 7.09-7.06 (m, 1H), 5.57-5.55 (m, 1H), 4.03 (q, 2H), 3.67 (s, 3H), 3.63 (t, 2H), 2.95-2.91 (m, 2H), 2.59-2.55 (m, 2H), 2.37-2.33 (m, 2H), 1.50 (s, 9H). LC/MS RT (5 min method) = 2.10 min. Mass observed: 246.19 (M-Boc+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 70℃; for 18h;Inert atmosphere; | A solution of l-bromo-2-iodo-4-(trifluoromethyl)benzene (1.598 ml, 9.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)- carboxylate (3.00 g, 9.70 mmol), Pd(dppf)-CH2C12 adduct (0.396 g, 0.485 mmol), and potassium carbonate (2.329 g, 38.8 mmol) in 1,4-dioxane (36.4 ml) and water (12.13 ml) was stirred at 70 C for 18 hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (Redi-Sep Gold 80g silica gel column (Teledyne Isco, Lincoln, NE), gradient elution 0 to 100% Et20:Heptane) to afford tert- butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate as a light yellow oil. m/z (ESI) 428.1 (M+Na)+. | |
2.54 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 3h; | Intermediate J: tert-Butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6- dihydropyridine- 1 (2H)-carboxylate A solution of l-bromo-2-iodo-4-(trifluoromethyl)benzene (1.408 ml, 8.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (Frontier Scientific, Logan, UT, 2.78 g, 8.98 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, MA, 0.349 g, 0.427 mmol), and potassium carbonate (2.052 g, 34.2 mmol) in dioxane (32.1 ml) and water (10.69 ml) was stirred at 70 C for three hours. (LC-MS MH+ 430.1) The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel 80g, gradient elution 0 to 100% Et20:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine- 1 (2H)- carboxylate (2.54 g, 6.25 mmol) as a light yellow oil. [M+H]+ = 428.0. XH NMR (400 MHz, CHLOROFORM-d) delta ppm = 7.69 (d, J= 8.3 Hz, 1 H), 7.43 (d, J= 2.2 Hz, 1 H), 7.41 - 7.36 (m, 1 H), 5.69 (br. s., 1 H), 4.08 (q, J= 2.7 Hz, 2 H), 3.66 (t, J= 5.6 Hz, 2 H), 2.48 - 2.40 (m, 2 H), 1.52 (s, 9 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.44 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; for 0.25h;Microwave irradiation; | 6.01.04.02 4-(6-Methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 0.5 g tetrakis (triphenylphosphine) palladium was added to 1.3 g <strong>[26452-81-3]4-chloro-6-methoxy-pyrimidine</strong> and 4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester) and 9 mL 2 mol/L sodiumcarbonate in 40 mL dioxane. The reaction was stirred 15 min. under microwave conditions. Water was added and the reaction was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by HPLC to give 1.44 g of the desired product. Rt: 1.38 min (method L) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere; | Under inert gas atmosphere 5.00 g (23.3 mmol) <strong>[55849-30-4]5-bromo-2-ethoxy-pyridine</strong> are added to a mixture of 7.19 g (23.3 mmol) 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid terf-butyl ester, 95 mg (1 .2 mmol) PdCI2(dppf)xCH2CI2 and 15.2 g (46.5 mol) Cs2CO3 in 50 ml_ DMF and 10 ml_ H2O. The mixture is stirred for 12 h at 80C. After that time, the solvent is evaporated, the residue taken up in DCM and washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; gradient PE/EtOAc 20:1 -> 10:1 ) to yield the desired product which was directly used in the next step. Ci7H24N2O3 (M = 304.4 g/mol) | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere; | Under inert gas atmosphere 5.00 g (23.3 mmol) <strong>[55849-30-4]5-bromo-2-ethoxy-pyridine</strong> are added to a mixture of 7.19 g (23.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 95 mg (1.2 mmol) PdCl2(dppf)xCH2Cl2 and 15.2 g (46.5 mol) Cs2CO3 in 50 mL DMF and 10 mL H2O. The mixture is stirred for 12 h at 80 C. After that time, the solvent is evaporated, the residue taken up in DCM and washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; gradient PE/EtOAc 20:1->10:1) to yield the desired product which was directly used in the next step. C17H24N2O3 (M=304.4 g/mol) Rf (TLC): 0.30 (silica gel, PE/ethyl acetate 20:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.8 g | Example 36: 5-(2-(l,2,3,6-Tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2- yl)-3 ,4-dihydroisoquinoline-2( 1 H)-sulfonamide hydrochloride Step 1 : tert-Butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate A solution of Ci2Pd(dppf)-CH2Ci2 adduct (Strem Chemicals Inc., Newburyport, MA, 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.76 ml, 28.3 mmol), l-bromo-2-iodo-4-(trifluoromethyl)benzene (9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane, 40 mL water was heated to 100 C 3 hours. LC/MS showed complete consumption of starting material. Isoquinolin-5 -ylboronic acid (4.90 g, 28.3 mmol) and Ci2Pd(AmPhos) (Sigma-Aldrich, St. Louis, MO, 1.003 g, 1.416 mmol) were added, and the reaction mixture was again heated to 100 C for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgS04 and concentrated. Purification of the resulting residue by si81ica gel column chromatography (0 to 100% EtO Ac/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5- (trifluoromethyl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate (9.80 g, 21.56 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | Using similar reaction conditions as described in step i of intermediate 9, <strong>[112671-42-8]4-bromo-1-iodo-2-nitrobenzene</strong> (500mg, 1.53 mmol) was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine-1 (2H)-carboxylate ( 4 75 mg, 1.53 mmol) usingsodium carbonate (486mg, 4.59mmol) and Pd(PPh3) 2Clz (53mg, 0.07 mmol) in DME/water(10/2 ml) at 80C for 3 hours to afford 400mg (68.9%) of the product after purification with15 (601120 silica gel) column chromatography using 30% ethyl acetate in hexane as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere; | 11 A. 4-(3-Methoxy-4-methoxycarbonyl-henyl)-36-dihydro-2H-yridine-1 -carboxylic acid tert-butyl esterA solution of 4-bromo-2-methoxy-benzoic acid methyl ester (4.0 g, 16.5 mmol), 1-Boc- piperidine-4-boronic acid pinacol ester (5.1 g, 16.5 mmol) and K2C03 (6.6 g, 49.5mmol) in DMF (25 mL) was degassed with nitrogen for 15 minutes. PdCI2(dppf).DCM(1 .0 g, 0.6 mmol) was added at room temperature then the mixture was heated to90C and stirring continued for 5 hours. Water (100 mL) was added and the mixtureextracted with EtOAc (2 x 50 mL) then the combined organic extracts were washedwith brine (50 mL), dried (Na2504) and evaporated under reduced pressure. Theresidue was purified by column chromatography on neutral silica gel using 10-15% EtOAc/hexanes as the eluent to give the title compound (5.0 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 14h;Inert atmosphere; | General procedure: To a nitrogen flushed flask containing the boronate 22(1.39 g, 4.5 mmol), KOAc (1.86 g, 13.5 mmol) andPdCl2dppf (0.23 g, 0.28 mmol) was added a solution of thebromide 14 (1.07 g, 4.7 mmol) in DMF (30 mL). The mixturewas deoxygenated by continued flushing with nitrogen.The mixture was then heated to 80C and stirred under N2overnight when TLC indicated completion of the reaction.After cooling ethyl acetate (40 mL) and water (20 mL) wereadded and the organic phase was separated. The water phasewas extracted with ethyl acetate (20 mL). The combinedorganic phases were washed with brine, dried over Na2SO4,filtered over a short plug of celite and evaporated under reducedpressure. Column chromatography on silica gel,eluting with hexanes:ethyl acetate (6:4) and then changing to(4:6)) afforded 0.39 g (28%) of compound 23 as an off-whitesolid, m.p. 183-184 C; IR (KBr) max. cm-1: 3261, 3155(NH), 3052 (Ar-H), 1695 (C=O), 1616, 1518, 1415 (C=C).1H-NMR (500 MHz, CDCl3) = 1.49 (s, 9H, (CH3)3C); 1.72(br. s, 2H, CH2); 2.47 (br. s, 2H, CH2); 3.63 (m, 2H, CH2);4.07 (s, 2H, CH2); 5.97 (br. s, 1H, CH); 6.76 (d, J = 8.2 Hz,1H, H-5); 7.12 (br. s, 1H, H-8); 7.28 (m, 1H, H-6); 7.65 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) = 27.39 (CH2),28.48 (CH3)3C), 29.71 (CH2), 41.90 (CH2), 68.73 (CH2),79.80 (CH3)3C), 113.87 (aromatic-C), 118.03 (aromatic-C),120.92 (aromatic-C), 125.75 (aromatic-C), 134.49 (aromatic-C), 136.34 (aromatic-C), 152.59 (C=O), 154. 88 (C=O). Calculated(%) for C18H23N3O3 (329.17); C: 65.63, H: 7.04, N:12.76, found (%); C: 65.57, H: 7.09, N: 12.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation; Inert atmosphere; | Step 1: tert-Butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate To a 5 mL microwave vial was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (247 mg, 0.8 mmol), <strong>[55981-29-8]2,5-dibromo-1,3,4-thiadiazole</strong> (98 mg, 0.4 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min, then heated to 100 C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+2)=348.1; 1H NMR (400 MHz, CHLOROFORM-d) delta 6.46 (td, J=3.0, 1.9 Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H), 1.49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 17h;Inert atmosphere; | c) tert-Butyl 4-(4-amino-3-methyl-5-nitrophenyl)-3, 6-dihydropyridine- 1 (2W )-carboxylate (A 11 1) 4-Bromo-2-methyl-6-nitroaniline A1 10 (320 mg, 1.39 mmol), ferf-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (471 mg, 1.52 mmol) and PdCI2(dppf) (57 mg, 5 mol%) were loaded into a flask. 1 ,4-Dioxane (10 mL) was added, followed by a solution of potassium carbonate (383 mg, 2.77 mmol) in water (5 mL). The mixture was degassed by bubbling nitrogen through the reaction mixture then stirred for 17 hours at 80 C under nitrogen. The cooled mixture was concentrated, the aqueous residue diluted with water (50 mL) and extracted with CHCI3 (3 chi 50 mL). The pooled CHCI3 extracts were washed with brine (50 mL), dried over Na2S04 and evaporated. Column chromatography (12 g Si02 cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) gave the title compound as a viscous orange syrup (321 mg, 70% yield). H NMR (400 MHz, CDCI3) 5 8.01 (s, 1 H), 7.39 (s, 1 H), 6.19 (s, 2H), 5.99 (s, 1 H), 4.08 - 4.04 (m, 2H), 3.62 (t, J = 5.7 Hz, 2H), 2.51 - 2.44 (m, 2H), 2.26 (s, 3H), 1.49 (s, 9H). LCMS-B: rt 6.87 min; m/z (positive ion) 278.2 [M-tBu+2H]+, 234.1 [M-Boc+2H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 80 - 90℃; for 20.0h; | a) tert-Butyl 2'-amino-3'-nitro-5,6-dihydro-[4,4'-bipyridine]- 1(2H)-carbox (A27) An aqueous solution of 2 M Na2C03 (3.44 mL, 6.88 mmol) was added to a degassed mixture of fert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate A26 (1.42 g, 4.59 mmol), <strong>[84487-10-5]2-amino-4-bromo-3-nitropyridine</strong> A25 (0.500 g, 2.29 mmol) and PdCI2(PPh3)2 (0.080 g, 0.12 mmol) in 1 ,4-dioxane (30 mL). The reaction mixture was stirred at 80 - 90 C for 20 hours. The resulting mixture was concentrated in vacuo and partitioned between EtOAc (50 mL) and water (30 mL), then filtered through a pad of Celite. The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with 1 : 1 water: saturated brine (30 mL), dried (MgS04), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica cartridge, 0-80% EtOAc in petroleum benzine 40-60 C) to give the title compound (0.583 g, 79%) as a bright yellow solid. H NMR (400 MHz, cfe-DMSO) delta 8.15 (d, J = 4.9 Hz, 1 H), 7.23 - 6.93 (s, 2H), 6.54 (d, J = 4.9 Hz, 1 H), 5.68 (s, 1 H), 3.97 - 3.75 (m, 2H), 3.58 - 3.40 (t, J = 5.5 Hz, 2H), 2.29 - 2.14 (td, J = 5.5, 2.5 Hz, 2H), 1.42 (s, 9H), LCMS- A rt 5.51 min, m/z (positive ion) 321 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere; Sealed tube; | a) tert-Butyl 6-amino-5-nitro-5 6'-dihydro-[3 '-bipyridine]-1 ^ (A31) 5-Bromo-3-nitropyridin-2-amine A30 (2.50 g, 11.5 mmol), ferf-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (3.90 g, 12.6 mmol) and PdCI2(dppf) DCM solvate (474 mg, 5 mol%) were loaded into a flask, the flask was sealed and flushed with nitrogen. Dioxane (100 mL) was added, followed by a solution of K2C03 (4.76 g, 34.4 mmol) in water (50 mL). The mixture was degassed with three vacuum/nitrogen cycles, heated to 80 C for 16 hours, and allowed to cool. The mixture was concentrated, the aqueous residue diluted with water (400 mL) and chloroform (250 mL). The aqueous phase was extracted with chloroform (2 x 150 mL), the combined chloroform extracts washed with brine (200 mL), dried over Na2S04, filtered and evaporated. Column chromatography (0-80% EtOAc/hexanes) gave the title compound (3.058 g, 83%) as a yellow-orange solid. H NMR (400 MHz, CDCIs) delta 8.45 (d, J = 2.3 Hz, 1 H), 8.37 (d, J = 2.2 Hz, 1 H), 6.73 (br s, 2H), 6.06 (s, 1 H), 4.13 - 4.04 (m, 2H), 3.65 (t, J = 5.7 Hz, 2H), 2.48 (s, 2H), 1.49 (s, 9H). LCMS-A: rt 5.58 min; m/z (positive ion) 321.2 [M+H]+, 265.1 [M-tBu+2H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; | Step 1. tert-butyl 4-(lH-imidazol-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate [0253] A mixture of 2-bromo-lH-imidazole (1.2 g, 8.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (3.0 g, 9.70 mmol), sodium carbonate (2.1 g, 19.8 mmol), and [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro methane adduct (0.120 g, 0.16 mmol) in 1 ,4-dioxane (30 mL) and water (10 mL) stirred overnight at 100 C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford tert-butyl 4-(lH-imidazol-2-yl)- 5,6-dihydropyridine-l(2H)-carboxylate (0.300 g, 15%) as a light yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere; | A mixture of Example 135B (260.0 mg, 0.561 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (191 mg, 0.618 mmol), Pd(Ph3P)4 (32.4 mg, 0.028 mmol), and saturated sodium bicarbonate solution (2 mL, 0.561 mmol) in N,N-dimethylformamide (8 mL) was purged with nitrogen and heated at 80 C. for 4 hours. The mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 306 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.7 g | With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | A mixture of <strong>[40197-20-4]5-bromo-1H-benzimidazol-2-carboxylic acid</strong> (3.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.7 g), dichloro[1,1?-bis(di-tert-butylphosphino)ferrocene]palladium (410 mg), 2 M aqueous sodium carbonate solution (50 ml), and dioxane (75 ml) was stirred at 95 C. overnight in an argon atmosphere, and then cooled to room temperature. After water (170 ml) and ethyl acetate (200 ml) were added to the reaction mixture, the reaction mixture was stirred for 20 minutes, and then subjected to liquid-liquid partition. The aqueous layer was washed with ethyl acetate (50 ml), and then citric acid was added thereto to adjust pH to be 6 to 7. The resulting solid was collected by filtration, and then dried under reduced pressure, thereby obtaining 5-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-benzimidazole-2-carboxylic acid (2.7 g) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; | Intermediate 2-20-A. fert-butyl 4-(2-chloro-4-hydroxyphenyl)-5,6-dihydropyrid 1 (2H)-carboxylateTo a solution of <strong>[13631-21-5]4-<strong>[13631-21-5]bromo-3-chlorophenol</strong></strong> (CAS 13631 -21 -5) (1 .44 g, 6.94 mmol) in DMF (35 mL) were added te/ -butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1 (2H)-carboxylate (CAS 286961 -14-6) (2.79 g, 9.02 mmol), PdCI2(dppf) CH2CI2 adduct (0.28 g, 0.35 mmol) and 2 M potassium phosphate (10.41 mL, 20.82 mmol). The mixture was then degassed and placed under nitrogen atmosphere, and then the mixture was stirred at 100 C for 1 h. The reaction mixture was cooled to room temperature, and then diluted with EtOAc. The mixture was then washed with H20, dried over Na2S04, filtered, and then concentrated. The resulting residue was purified by silica gel flash column chromatography (0-50% EtOAc / heptane) to afford the title compound. MS (ESI+) m/z 254.1 (M-t-butyl+2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | [00651] Step 1: To a solution of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylic acid tert-butyl ester (1.0 g, 3.23 mmol) and <strong>[82257-09-8]3-bromo-4-methoxy-pyridine</strong> (552 mg, 2.94 mmol) in dioxane/H20 (30 mL + 10 mL) were added Pd(dppf)Cl2 (108 mg, 0.14 mmol) and K2C03 (1.62 g, 11.8 mmol). The resulting mixture was stirred at 80 C under N2 atmosphere overnight. Then the reaction mixture was poured into H20 (100 mL) and extracted with EtOAc (20 mL x 3). The extracts were washed with brine (20 mL x 3), dried over Na2S04 and concentrated in vacuu to give a residue, which was purified by a silica gel column with DCM : MeOH = 50 : 1 as eluent to afford 4-methoxy-3',6'-dihydro- 2'H-[3,4']bipyridinyl-r-carboxylic acid tert-butyl ester (721 mg, yield: 85%) as a yellow oil. NMR (400 MHz, CDC13): delta = 8.40 (d, J= 5.2 Hz, 1H), 8.27 (s, 1H), 6.79 (d, J= 4.8 Hz, 1H), 5.81 (s, 1H), 4.12- 4.02 (m, 2H), 3.87 (s, 3H), 3.66-3.54 (m, 2H), 2.53-2.43 (m, 2H), 1.49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In tetrahydrofuran; water;Reflux; | A mixture of 2-bromo-3-(tri r1uoromethyl)benzenamine (9.6 g; 40 mmol), 3,6-dihydro- 4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl )- 1.1-dimethylethylester- 1(2H)- pyridinecarboxilic acid (14.84 g; 48 mmol ). [l. l "-bis|bis( 1.1- dimethylethyl )phosphinoJferrocene]dichloro-palladium (652 mg; 1 mmol) and sodium carbonate (16.96 g; 160 mmol) in water (100 ml .) and THF (300 ml, ) was heated at reflux overnight. The solvent was removed under reduced pressure and the residue was solubilized with EtOAc and H20. The organic layer was separated, dried over MgSO.i, filtered and evaporated. The residue was purified by chromatography over silica gel (eluent: from 100% petrol ether to 50% petrol ether, 50% EtOAc). The pure fractions were collected and the solvent was evaporated to give 12 g (95%, white crystals) of intermediate 152 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; for 12.0h;Inert atmosphere; Reflux; | Compound 21 (leq) was added compound 22 (leq), followed by potassium carbonate (3eq), [1,1 '_ bis (diphenylphosphino) ferrocene] dichloropalladium (O.leq), was added 1 , 4-dioxane: water = 4: 1, vacuum pumping, replace the nitrogen, under the protection of nitrogen reflux 12h, TLC the reaction was complete after filtration, the filter cake was washed with chloroform, the filtrate was collected, concentrated, and column chromatographed to give intermediate 23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.0% | With bis(triphenylylphosphine)palladium(II) dichloride; sodium carbonate; In water; acetonitrile; at 90℃; for 12h;Inert atmosphere; | Under the protection of nitrogen, the 2-bromo-1-iodo-4 - (trifluoromethyl) benzene (0.50g, 1 . 42mmol), 4 - (4, 4, 5, 5-tetramethyl -1, 3, 2- two oxygen boron fifth heavenly stem link -2-yl) - 5,6-dihydropyridine -1 (2H)-carboxylic acid tert-butyl (0.48g, 1 . 57mmol), Pd (PPh3)2Cl2(25 mg, 36 mumol) and sodium carbonate (0.23g, 2 . 14mmol) into acetonitrile (10 ml) and water (3 ml) in the mixed solvent. Reaction solution is heated to 90 C stirring for 12 hours, cooling to the room temperature and adding water (20 ml), then with ethyl acetate (20 ml × 3) extraction. Combined organic phase dried with anhydrous sodium sulfate, filter, and concentrating under reduced pressure, the resulting residue by a silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=20/1) to obtain the title compound as a yellow oily liquid (470 mg, 81.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 2nd step: under the protection of nitrogen, the 1M isopropyl magnesium chloride-lithium chloride (88 ml, 88mmol) into the reaction bottle, temperature control -15 C to -5 C, dropwise N-Boc-1, 2, 5, 6-tetrahydro-pyridine-4-bromo, 2-methyl tetrahydrofuran (90 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding isopropoxy boric acid pinacone ester (16.4g, 88mmol), subsequently maintain the reaction at room temperature overnight. Adding 10% hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 160 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 5:1 obtained after pulping 18.9g N-Boc-1 needle-like white crystals, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 99.6%, yield: 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.7% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 70℃; for 3h;Inert atmosphere; | A mixture of 1 -bromo-3 -methyl-S-nitro-benzene; (3.1 8g, 14.7mM) and t-butyl 4- (4,4,5 ,S-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylate, (Sg, 16.17mM) in dry dioxane (80 mL) was purged with N2 for several minutes. Na2CO3 (20 mL;2M) and Pd(dppf)C12.DCM (1.08g, 1.47mM) was added and the reaction was heated at 70 C for3 hours. Pumped down solvent and the residue was partitioned between EtOAc and water. Organic phase was washed with water, brine, dried (Na2SO4) and solvent was removed under reduced pressure. Crude product was purified on Si02 with DCM => EtOAc 0 -50% to give tbutyl 4-(3 -methyl-S-nitro-phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylate, YL-1 2a (2.7 g, 46.7%) ?HNMR (400 MHz, CDC13) oe 8.02 (s, 1H), 7.92 (s, 1H), 7.49 (s, 1H), 6.16 (s, 1H), 4.11 (t, J = 7.1 Hz, 3H), 3.66 (t, J = 5.6 Hz, 2H), 2.54 (s, 2H), 2.46 (s, 3H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 318.16, found 320.0 (M+1)+; Retention time: 0.93 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+. Step 3. tert-But l 4-(l-methyl-lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l- methyl-lH-imidazol-5-yl)piperidine-l-carboxylate (1209) [00396] A -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine- l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (5 g, 19.01 mmol) and palladium on carbon (10 wt. %, 5 g) in MeOH (100 mL) was evacuated and backfilled with hydrogen several times and was then charged with hydrogen. The resulting mixture was stirred for 1 h at ambient temperature before being filtered and concentrated under vacuum, resulting in 1.7 g (34%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl- lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5- yl)piperidine-l-carboxylate as a yellow oil. MS (ESI) m/z 266 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+. Step 3. tert-But l 4-(l-methyl-lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l- methyl-lH-imidazol-5-yl)piperidine-l-carboxylate (1209) [00396] A -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine- l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (5 g, 19.01 mmol) and palladium on carbon (10 wt. %, 5 g) in MeOH (100 mL) was evacuated and backfilled with hydrogen several times and was then charged with hydrogen. The resulting mixture was stirred for 1 h at ambient temperature before being filtered and concentrated under vacuum, resulting in 1.7 g (34%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl- lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5- yl)piperidine-l-carboxylate as a yellow oil. MS (ESI) m/z 266 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; | Compound 135 (2.00 g, 6.39 mmol) and Compound 170 (2.174 g, 7.03 mmol) were dissolved in 1,4-dioxane (20 ml), to which were then added tetrakis(triphenylphosphine)palladium (0.739 g, 0.639 mmol) and 2 mol/L aqueous solution of potassium carbonate (4.79 ml, 9.59 mmol), and the reaction mixture was stirred at 100C. After completion of the reaction, chloroform and water were added to the reaction mixture, and the resulting mixture was filtered. The obtained filtrate was extracted with chloroform. The obtained organic layer was dried over magnesium sulfate, and then the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Compound 171. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | [0285] Step 1: tert-butyi 4-(5-(pyrimidin-2-yl)pyridin-2-yl)-5,6- dihydropyridine-1(2H)-carboxylate : To a stirred and degassed solution of 6- bromopyridin-3-ylboronic acid (6 g, 29.73 mmol), 2-bromo pyrimidine (4.7 g, 29.73 mmol) in 1,2-dimethoxy ethane:water (9: 1, 160 mL) was added cesium carbonate (38.6 g, 118.92 mmol). The mixture was degassed for 10 mins. Bis(triphenylphosphine)palladium(II) dichloride (2.0 g, 2.973 mmol) was added. The mixture was degassed for 10 min and then refiuxed for 2 h. Tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (9.1 g, 29.73 mmol) was added. The mixture was degassed for 10 mins and then refluxed for 16 h. The mixture was cooled to rt and filtered through a Celite pad. To the filtrate was added cold water, and the mixture was extracted with ethyl acetate (3 X 100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (100-200 silica) using 50% ethyl acetate in hexanes as eluent and further purified by Reveleris C-18 reversed phase column using 95% acetonitrile in aqueous formic acid (0.1%) to afford tert-butyl 4-(5-(pyrimidin-2-yl)pyridin-2-yl)-5,6-dihydropyridine-l(2H)- carboxylate (1.04 g, 3.07 mmol, 10% yield ). XH NMR (400 MHz, DMSO-d6) delta 9.47 (d, J = 1.5 Hz, 1H), 8.95 (d, J = 4.9 Hz, 2H), 8.65 (dd, J = 2.0, 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H), 6.86 (br s, 1H), 4.09 (br s, 2H), 3.57 (t, J = 5.6 Hz, 2H), = 1.5 Hz, 2H), 1.44 (s, 9H). LCMS: 339.17 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation; | III.1665-methoxy-2-(4-piperidyl)pyrimidine A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate. Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+ |
83% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation; | A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 - carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate.Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; | (1429) [00457] Into a 100-mL round-bottom flask that was purged and maintained under an inert atmosphere of nitrogen was added <strong>[499983-13-0]2-<strong>[499983-13-0](4-bromo-3-fluorophenyl)acetonitrile</strong></strong> (0.500 g, 2.34 mmol), feri-butyl 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate (1.09 g, 3.53 mmol), potassium carbonate (0.972 g, 7.03 mmol), Pd(dppf)Cl2 CH2CI2 (0.384 g, 0.47 mmol), DM (20 mL) and H2O (2 mL). The reaction mixture was stirred at 80 C for 3h and then cooled and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 :5) to afford fcrt-butyl 4-(4-(cyanomethyl)-2-fluorophenyl)-3,6- dihydropyri dine- 1 (2H)-carboxylate as a yellow solid (0.7 g, 95%). lH-NMR (300 MHz, CDC ) delta ppm 7.33-7.23 (m, 1H), 7.18-7.00 (m, 2H), 5.97 (s, 1H), 4. 1 7-4.06 (m, 2H), 3.81-3.70 (m, 21 1), 3.64 (t, J = 5.5 Hz, 2H), 2.51-2.46 (m, 2H), 1.5 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 75℃; for 18h;Inert atmosphere; | To a mixture of <strong>[10075-48-6]5-bromo-3-methyl-1H-indole</strong> (0.4 17 g, 1.985 mmol), PdC12(dppf)-CH2C12 adduct (0.041 g, 0.050 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (0.675 g, 2.183 mmol) in a 40 ml reaction vial was added THF (10 mL) followed by a 3M aqueous solution of tripotassium phosphate (1.985 mL, 5.95 mmol). The vial was fitted with a Teflon-linedseptum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and back-filled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (125 mL). The mixture was poured into a separatory funnel and washed withwater (2X 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel (24 g) column, which was eluted over 20 minutes using a gradient of 0-50% ethyl acetate/heptane. The combined fractions were concentrated to give tert-butyl4-(3 -methyl- 1H-indol-5-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (0.510 g, 82 % yield) as a tan oil. LC retention time 1.10 mm [Method Al]. MS (E) m/z: 313 (M-H). |
82% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 75℃; for 18h;Inert atmosphere; | To a mixture of <strong>[10075-48-6]5-bromo-3-methyl-1H-indole</strong> (0.417 g, 1.985 mmol),PdCl2(dppf)-CH2Cl2 adduct (0.041 g, 0.050 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.675 g, 2.183 mmol) in a 40 mL reaction vial were added THF (10 mL) followed by a 3 M aqueous solution of tripotassium phosphate (1.985 mL, 5.95 mmol). The vial was fitted with a Teflon-lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and back-filled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (125 mL). The mixture was poured into a separatory funnel and washed with water (2 x 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel (24 g) column, which was eluted over 20 minutes using a gradient of 0-50% ethyl acetate/heptane. The combined fractions were concentrated to give tert-butyl 4-(3-methyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.510 g, 1.632 mmol, 82% yield) as a tan oil. MS (M+1) m/z: 257.1 (MH+-tertbutyl). LC retention time 1.08 min [A1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.93 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere; | To <strong>[92992-85-3]2-bromo-3,5-dimethylpyridine</strong> (6.62 g) were added N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (10 g),sodium carbonate (7.54 g),1,4-dioxane (50 mL),water (50 mL) and tetrakis(triphenylphosphine)palladium(0)(1.87 g) and the mixture was stirred under a nitrogen stream at 100c for 5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine,dried over sodium sulfate,and treated with activated carbon. The solvent was evaporated and the obtained residue was purified by column chromatography (hexane:ethyl acetate)to give 3,5-dimethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (8.93 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 50.0℃; for 5.0h;Inert atmosphere; | General procedure: To an oven dried 5 mL microwave vessel was addedPd(dppf)Cl2·CH2Cl2 (4 mol%), halide/pseudohalide (1 equiv),boron coupling partner (1 equiv), and Cs2CO3 (3 equiv). Thevessel was then capped and purged with N2 before addition ofCyrene (1 mL, 0.25 M) and H2O (1.8 mL). The reaction mixturewas heated to 50 C and maintained at this temperature withstirring for 5 h before the vessel was vented and decapped. Thesolution was then diluted with Et2O (10 mL) and washed withwater (2 × 20 mL) and brine (2 × 20 mL). The organics were thenpassed through a hydrophobic frit and concentrated underreduced pressure to give a residue, which was purified by flashchromatography (silica gel) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100.0℃; for 3.0h;Inert atmosphere; | Compound 1 (2.0 g, 7.8 mmol, 1 eq), PB03145 (2.89 g, 9.36 mmol, 1.2 eq)Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.1 eq),Potassium phosphate (4.97 g, 23.4 mmol, 3 eq) was added to a 100 ml single-mouth bottle.Add dioxane (10 ml), water (2 ml), and replace with nitrogen three times.The temperature was raised to 100 ° C, and the reaction was carried out for 3 hours, and the reaction was terminated by TLC.The reaction solution was cooled to room temperature and EA (100 mL) was added.Water (30 ml), the organic phase was separated and washed with saturated brine (50 ml).The organic phase was dried over magnesium sulfate and dried.Add n-heptane (100 ml) and filter to give a yellow solid (2.3 g crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16h;Inert atmosphere; | To a stirred solution of ethyl 6-chloroimidazo[l,2-b]pyridazine-2-carboxylate (A50, 1.5 g, 6.64 mmol) in l,2-dimethoxy ethane(30 mL) and H20(6 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate(1, 3.08 g, 9.97 mmol) and Na2C03(2.11 g, 19.94 mmol). The reaction mixture was purged with N2 gas for 20 min. To the above reaction mixture was added[l, T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane PdCl2(dppf).DCM(0.54 g, 0.664 mmol), and the resulting solution was further purged with N2 gas for 10 min then stirred for 16 h at 80C. The reaction mixture was filtered over celite bed and washed with ethylacetate/water mixture. The filtrate was washed with water, brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude was purified by column chromatography using 0-10% MeOH in DCM as eluent to afford ethyl 6-(l-(tert-butoxycarbonyl)-l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-b]pyridazine-2-carboxylate A51 as a brown solid. Yield: 2.0 g(8l%).LC-MS m/z: 370.98[M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In 1,4-dioxane; water; at 120℃; for 3h; | To a solution of <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (475 mg, 2.34 mmol) in dioxane (6 mL) was added tert-butyl 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6-tetrahydropyridine-l-carboxylate (1425 mg, 4.61 mmol), Pd(OAc)2 (55 mg, 0.24 mmol), 5- Phos (203 mg, 0.49 mmol) and K3PO4 solution (1570 mg in 2 mL water, 7.40 mmol) at room temperature. The resulting mixture was stirred for 3 h at 120 C. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0 % to 60 % gradient) to yield tert-butyl 4-(6- amino-2-methoxypyridin-3-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate as an yellow oil (437 mg, 61 %). MS: m/z = 306.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; Sealed tube; | The reaction is performed underan argon-atmosphere. 6-Chloro-5-methylpyridazin-3-amine (3.00 g; 20.90 mmol), ie/f-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,6- tetrahydropyridine-1 -carboxylate (7.1 1 g; 22.98 mmol) and sodium carbonate (2 mol/L, aq. solution; 41 .79 mL; 83.58 mmol) in 1 ,4-dioxane (150 mL) is purged with argon. After 5 minutes Xphos 2nd Gen. (0.49 g; 0.63 mmol) is added and the mixture is stirred over night in a sealed vial at 100C. The reaction mixture is concentrated under reduced pressure. The residue is taken up in water and extracted several times with EtOAc. The combined organic layers are washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM/MeOH). (1086) Yield: 5.20 g (86%) ESI-MS: m/z = 291 [M+H]+ Rt(HPLC): 0.79 min (method 10) |
86% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; In 1,4-dioxane; water; at 100℃; | The reaction is performed under an argon atmosphere. 6-Chloro-5-methylpyridazin-3-amine (3.00 g; 20.90 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine-l-carboxylate (7.11 g; 22.98 mmol) and sodium carbonate (2 mol/L; aq. solution; 41.79 mL; 83.58 mmol) in l,4-dioxane (150 mL) are purged with argon. Xphos 2nd generation catalyst (0.49 g; 0.63 mmol) is added and the reaction mixture is stirred at l00C overnight. The reaction mixture is concentrated under reduced pressure. The residue is taken up in water and extracted several times with EtOAc. The combined organic layers are washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM/MeOH). Yield: 5.20 g (86%) ESI-MS: m/z = 291 [M+H]+ Rt(HPLC): 0.79 min (method 2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
178 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation; | General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation; | General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation; | General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation; | General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120°C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation; | General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120°C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere; Sealed tube; | To a solution of 5-bromo-lH-pyrrolo[2,3-c]pyridine (3.2 g, 16.24 mmol) in dioxane (60 mL) and water (20.00 mL) solvent mixture were added tert-butyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (5.02 g, 16.24 mmol) and potassium phosphate tribasic (10.34 g, 48.7 mmol). The reaction mixture was degassed with nitrogen for 5 min., PdCl2(dppf)-CH2Cl2 adduct (1.326 g, 1.624 mmol) was added, and the reaction mixture was stirred in a sealed tube at 90 C for 3 h. The reaction mass was concentrated, then the residue was diluted with EtOAc (20 mL), the solids were filtered, the filtrate was collected and concentrated to get crude compound. The crude compound was purified by silica gel chromatography on an ISCO instrument using 40 g silica column, the compound was eluted in 15% EA in hexanes, the fractions were collected and concentrated to afford tert-butyl 4-(lH-pyrrolo[2,3-c] pyridin-5-yl)-5,6-dihydropyridine-l(2H)-carboxylate (2.5 g, 8.35 mmol, 51% yield) as a pale brown solid. LCMS retention time 0.95 min [L] MS m/z 300.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 mg | To a mixture of 6-bromo-2-iodopyridin-3-amine (100 mg, 0.34 mmol), 1,2-dimethoxy-4-(prop-1-yn-1-yl)benzene (74 mg, 0.42 mmol), lithium chloride (18 mg, 0.42 mmol), sodium carbonate (180 mg, 1.68 mmol) and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol) in a screw cap vial was added DMF (2 mL). The vial was fitted with a Teflon-lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 100 C. for 16 h. LCMS analysis shows formation of two isomers, in approximately 3:1 ratio. 1H NMR analysis suggested the major product to be 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (5A-1). The reaction mixture was diluted with EtOAc (50 mL), poured into a separatory funnel and washed with 10% aqueous LiCl solution (2*10 mL) and saturated aqueous NaCl solution (10 mL), dried (Na2SO4), filtered and the filtrate was concentrated. The crude product was dissolved in a small amount of DCM and purified on a silica gel column chromatography with a 15 min gradient from 0%-100% DCM/EtOAc to afford 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 5A-1) that was contaminated with Intermediate 5A-2, 5-bromo-3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridine, m/z (303, M+1), 80 mg (67%). To a mixture containing 5-bromo-2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 5A-1) and Intermediate 5A-2 (100 mg, 0.29 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (111 mg, 0.36 mmol), and Pd(dppf)C12 (10.5 mg, 0.014 mmol) in a screw cap vial was added THF (2.5 mL) followed by 3M aqueous solution of tripotassium phosphate (0.10 mL, 0.3 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C. for 3 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3*10 mL). The extracts were combined, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified on silica gel column chromatography eluting with a 10 min gradient from 5%-100% DCM/EtOAc. No separation was observed. A mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5B) and the regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate was isolated (100 mg, 77% yield), m/z (550, M+1) and was used as such in subsequent step. A mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5B) and regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (95 mg, 0.21 mmol) was dissolved in MeOH (5 mL) and transferred to a Parr bottle. The mixture was purged with nitrogen. Pearlman's Catalyst (25 mg, 0.036 mmol) was added and the bottle was pressurized with hydrogen gas (50 psi) and shaken for 22 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated. The resulting residue was dissolved in a small amount of DCM and charged to a silica gel column, which was eluted over a 10 min gradient with 1%-5% MeOH/DCM to afford a mixture of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 5C) and the regioisomer tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (82 mg, 80%), m/z (452, M+H). The mixture of isomers (tert-butyl 4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (Intermediate 5C) and tert-butyl 4-(3-(3,4-dimethoxyphenyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)piperidine-1-carboxylate (80 mg, 0.18 mmol) were suspended in 4 N HCl in dioxane (4 mL, 16.00 mmol), stirred for 30 min, and concentrated to dryness. The resulting residue was suspended in diethyl ether (1 mL) and the solids were filtered and dried to give a mixture of 2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine (Intermediate 5D) and 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as bis HCl salts (50 mg, 65%), m/z (352, M+H). To a solution containing a mixture of 3-(3,4-dimethoxyphenyl)-2-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine 2 HCl (Intermediate 5D) and 2-(3,4-dimethoxyphenyl)-3-methyl-5-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine, 2 HCl (30 mg, 0.07 mmol) in DMF (1 mL) was added 1-isobu... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(I) oxide; lithium methanolate; triphenylphosphine; In N,N-dimethyl-formamide; at 45 - 55℃;Inert atmosphere; | Under nitrogen protection, in the reaction bottle,<strong>[159503-91-0]N-Boc-1,2,5,6-tetrahydropyridine-4-bromo</strong> (26.3 g, 0.1 mol),Boronic acid pinacol ester (25.4g, 0.1mol),Cuprous oxide (1.43g, 0.01mol),Triphenylphosphine (5.24 g, 0.02 mol),Lithium methoxide (7.2 g, 0.2 mol) was dissolved in N,N-dimethylformamide (130 g).The temperature is controlled from 45 C to 55 C to stir the reaction;After the GC reaction is completed, the reaction mixture is filtered through a pad of diatomaceous earth.The filter cake was rinsed with toluene (50 g) and the filtrate was diluted with toluene (50 g).The filtrate was washed with water (100 g) and layered.The organic layer was detected by GC without N,N-dimethylformamide.The organic layer was washed with saturated brine (100 g) and evaporated to dryness.Add heptane / ethanol = 5:1 beating,After filtration, 20.1 g of a white solid N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester was obtained, HPLC: 99.2%, yield 65%. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; at 65℃; for 1.0h; | In a four-necked bottle, add a certain amount of toluene, alkenyl bromide compound, potassium acetate, stir and mix, then raise the temperature to 65 C, add toluene solution of bis-boronic acid pinacol ester, add heat for 1 h, cool down and filter, mother liquor concentrate After that, petroleum ether is beaten to obtain the target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester (26.7 g, 86.2 mmol) and <strong>[88497-27-2]6-bromo-pyridazin-3-ylamine</strong> (15.0 g, 86.2 mmol) in n-BuOH/H20 (306 ml_/70 mL) is added K3P04 (64.0 g, 301 mmol) and degassed with argon for 5 min. Then XPhos (4.1 1 g, 8.62 mmol) and tris(dibenzylideneacetone) dipalladium (3.95 g, 4.31 mmol) is added. The resultant mixture is stirred at 115C for 15h. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude mixture is purified by column chromatography (MeOH/DCM) to provide the title compound. (0438) Yield: 23.1 g (97%) ESI-MS: m/z = 277 (M+H)+ Rt(HPLC): 0.44 min (Method 1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | tei -Butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2/-/)- carboxylate (Intermediate 7) (395 mg, 1.28 mmol) and Cs2C03 (1.03 g, 3.19 mmol) were added to a solution of <strong>[182275-70-3]2-iodo-6-methoxypyridine</strong> (Intermediate 8) (300 mg, 1.28 mmol) in 1 ,4-dioxane (10 mL) and the resulting mixture was degassed under a nitrogen atmosphere for 20 min. (9,9-Dimethyl-9/-/-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos, 36 mg, 0.06 mmol) and palladium(ll) acetate (29 mg, 0.13 mmol) were added and the resulting reaction mixture was stirred at 80 C for 18 h. The solvents were removed in-vacuo and residue was partitioned between H20 (80 mL) and EtOAc (60 mL). The aqueous layer was further extracted with EtOAc (60 mL) and the combined organic layers were dried (Na2S04) and the solvent was removed in-vacuo. The residue was purified by column chromatography (normal phase neutral activated alumina, 10 % to 12 % EtOAc in hexane) to give tert- butyl 6- methoxy-3',6'-dihydro-2,4'-bipyridine-T(2'/-/)-carboxylate (310 mg, 84 %) as a gum. LCMS (System 3, Method D): m/z 291 (M+H)+ (ESI +ve), at 5.73 min, 202 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.9 g | In the third step, a Grignard exchange reaction of 26.21 g (0.1 mol) of N-Boc piperidin-4-enyl bromide with 12.9 g (0.105 mol) of isopropyl bromide in tetrahydrofuran, and then, under the protection of nitrogen, At 0 C, 19.03 g (0.11 mol) of pinacol methoxyboronic acid was added dropwise to the Grignard reaction solution, the reaction was held for 4 h, and then the temperature was raised to reflux for 1 h. After the reaction was completed, 10 ml of 10% dilute hydrochloric acid was added to quench the reaction. After the solvent was distilled off, 120 ml of ethanol was added for beating. The white solid was filtered to obtain 26.9 g, and the yield was 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 15h; | To a mixture of N-Boc-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-pyridine (41.0 g), dimethoxyethane (221 mL), and water (111 mL) were added <strong>[189278-27-1]2-bromo-6-(trifluoromethyl)pyridine</strong> (30.0 g), sodium carbonate (70.3 g), and tetrakis(triphenylphosphine)palladium(0) (7.67 g). The reaction mixture was stirred at 80 C. for 15 hours, and then concentrated hydrochloric acid (300 mL) was slowly added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hour, and then filtrated on Celite. The filtrate was washed with chloroform. To the aqueous layer was added 20% aqueous sodium hydroxide (375 mL), and extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo to give the title compound (26.9 g). (0232) 1H-NMR (400 MHz, CDCl3) delta: 2.53-2.59 (2H, m), 3.11 (2H, t, J=5.7 Hz), 3.59 (2H, q, J=3.0 Hz), 6.81-6.84 (1H, m), 7.48 (1H, d, J=7.8 Hz), 7.51 (1H, d, J=8.0 Hz), 7.78 (1H, dd, J=7.9, 7.9 Hz) |
Tags: 375853-82-0 synthesis path| 375853-82-0 SDS| 375853-82-0 COA| 375853-82-0 purity| 375853-82-0 application| 375853-82-0 NMR| 375853-82-0 COA| 375853-82-0 structure
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Precautionary Statements-General | |
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P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
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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