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Structure of 626-55-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 626-55-1 |
Formula : | C5H4BrN |
M.W : | 158.00 |
SMILES Code : | BrC1=CC=CN=C1 |
MDL No. : | MFCD00006373 |
InChI Key : | NYPYPOZNGOXYSU-UHFFFAOYSA-N |
Pubchem ID : | 12286 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Class: | 3 |
UN#: | 1993 |
Packing Group: | Ⅱ |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 31.94 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.58 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.6 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.69 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.46 |
Solubility | 0.545 mg/ml ; 0.00345 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.48 |
Solubility | 5.21 mg/ml ; 0.0329 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.86 |
Solubility | 0.217 mg/ml ; 0.00137 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.13 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.14 |
* 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% | Stage #1: at 30℃; for 0.0166667 h; Flow reactor Stage #2: With sodium hydroxide In N,N-dimethyl-formamide at 30℃; for 0.0433333 h; Flow reactor |
General procedure: All reactions were performed using a commercially available Vapourtec R-series set-up equipped with four pumps.(E)-Ethyl N-(mesitylsulfonyl)oxyacetimidate 7 was dissolved in MeCN (1M) and filtered. Perchloric acid (neat, 11.6M) was mixed with the first inlet via a Y-piece with flow rates of 1.228 mL/min and 0.106 mL/min respectively.Pyridine 2 was dissolved in MeCN (2M), filtered and introduced in a second Y-piece at flow rate 0.614 mL/min.Sodium hydroxide (1 M) was diluted with DMF to 0.667 M and introduced in a third Y-piece at flow rate 1.840mL/min. The stoichiometric ratio of all four inlets was 1:1:1:1. The system solvent was MeCN for the first threeinlets and H2O/DMF (2:1) for the fourth inlet. The PFA (polyfluoroalkoxy alkane polymer) reactor coils, withvolumes 20 mL, 2 mL and 10 mL respectively, were all set to temperature 30 °C. The reaction mixture from the firsttwo inlet streams spent 15 minutes residency time in the first reactor, the second 1.02 minutes and the third 2.64minutes.In all cases the power trace for the third reactor (where amination was occurring) showed that an exotherm took place(less power was required to heat to 30 °C). The operating pressure was 7-8 bar at beginning with just the first twopumps and rose to 9-10 bar with all 4 pumps. The reaction set-up was flushed afterwards with 33 percent aq. HCl (conc.)in MeOH followed by IPA. The total flow rate at the outlet was 3.788 mL/min.1-Amino-3-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate (3a): The reaction was performed using generalflow procedure reacting 3-bromopyridine 2a with MSH 1. The outlet solution (25 mL, collected over 3.6 mins) wasconcentrated in vacuo to give an orange solid (3.6 mins collection time, >99percent). 1H NMR (400 MHz, d6-DMSO)2.18 (9H, s, 3 x CH3), 6.77 (2H, s, NH2), 7.93 (1H, dd, J = 4 and 8 Hz, ArH), 7.95 (s, 2H, ArH), 8.49 (1H, d, J = 8Hz, ArH), 8.81 (1H, d, J = 8 Hz, ArH), 9.17 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 20.3, 22.7, 121.4,128.6, 129.9, 135.8, 136.4, 138.6, 141.4, 142.5, 166.0 ppm. HRMS (FAB) calcd for C5H6BrN2+ 172.97144, found172.97105 and C9H11O3S- 199.04289 found 199.04277. DSC showed small exotherm with 61 J/g onset 249 °C andlarger exotherm with 573 J/g onset 299 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | General procedure: All reactions were performed using a commercially available Vapourtec R-series set-up equipped with four pumps.(E)-Ethyl N-(mesitylsulfonyl)oxyacetimidate 7 was dissolved in MeCN (1M) and filtered. Perchloric acid (neat, 11.6M) was mixed with the first inlet via a Y-piece with flow rates of 1.228 mL/min and 0.106 mL/min respectively.Pyridine 2 was dissolved in MeCN (2M), filtered and introduced in a second Y-piece at flow rate 0.614 mL/min.Sodium hydroxide (1 M) was diluted with DMF to 0.667 M and introduced in a third Y-piece at flow rate 1.840mL/min. The stoichiometric ratio of all four inlets was 1:1:1:1. The system solvent was MeCN for the first threeinlets and H2O/DMF (2:1) for the fourth inlet. The PFA (polyfluoroalkoxy alkane polymer) reactor coils, withvolumes 20 mL, 2 mL and 10 mL respectively, were all set to temperature 30 C. The reaction mixture from the firsttwo inlet streams spent 15 minutes residency time in the first reactor, the second 1.02 minutes and the third 2.64minutes.In all cases the power trace for the third reactor (where amination was occurring) showed that an exotherm took place(less power was required to heat to 30 C). The operating pressure was 7-8 bar at beginning with just the first twopumps and rose to 9-10 bar with all 4 pumps. The reaction set-up was flushed afterwards with 33 % aq. HCl (conc.)in MeOH followed by IPA. The total flow rate at the outlet was 3.788 mL/min.1-Amino-3-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate (3a): The reaction was performed using generalflow procedure reacting 3-bromopyridine 2a with MSH 1. The outlet solution (25 mL, collected over 3.6 mins) wasconcentrated in vacuo to give an orange solid (3.6 mins collection time, >99%). 1H NMR (400 MHz, d6-DMSO)2.18 (9H, s, 3 x CH3), 6.77 (2H, s, NH2), 7.93 (1H, dd, J = 4 and 8 Hz, ArH), 7.95 (s, 2H, ArH), 8.49 (1H, d, J = 8Hz, ArH), 8.81 (1H, d, J = 8 Hz, ArH), 9.17 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 20.3, 22.7, 121.4,128.6, 129.9, 135.8, 136.4, 138.6, 141.4, 142.5, 166.0 ppm. HRMS (FAB) calcd for C5H6BrN2+ 172.97144, found172.97105 and C9H11O3S- 199.04289 found 199.04277. DSC showed small exotherm with 61 J/g onset 249 C andlarger exotherm with 573 J/g onset 299 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile;Reflux; | Example 163 A3-(pyridin-3-yl)benzoic acid; To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 3-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g of 3-(pyridin-3-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+. |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 90℃; for 14.0h; | 20 ml of 0.4 M sodium carbonate aqueous solution,3.2 g of 3-bromopyridine (21), 3.3 g of 3-carboxyphenylboronic acid and 1.15 g of tetrakis (triphenylphosphine) palladium (0) were added to 100 ml of acetonitrile,And the mixture was stirred at 90 C. for 14 hours. After completion of the reaction,Filter through Celite, add 1N dilute hydrochloric acid to the filtrate, Extracted with ethyl acetate, and washed with saturated brine.The organic layer was dried over anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure.The precipitated crystals were washed with hexane and filtered,3- (Pyridin-3-yl) benzoic acid (22)Was obtained. To the solid,50 ml of ethanol and 5 ml of concentrated sulfuric acid were added.After heating under reflux for 12 hours,Sodium bicarbonate was added to the reaction solution to quench. After distilling off ethanol under reduced pressure,An aqueous sodium hydrogen carbonate solution was addedAnd extracted three times with ethyl acetate. The organic layers were combined,Washed with saturated brine,After drying with anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1)Ethyl 3- (pyridin-3-yl) benzoate(23) was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Preparation of 2-chloro-4-pyridin-3-yl-pyrimidine lll-a To a solution of n-butyllithium (2.5 molar in hexane, 13.5 mL, 34 mmol) in anhydrous diethylether (50 mL) under argon at -78 ' was added 3-bromo pyridine (3 mL, 31 mmol). The mixture was stirred for 1 h, then a suspension of 2-chloro pyrimidine (3.6 g, 31 mmol) in anhydrous diethylether (30 mL) was added portionwise over 10 min. The resulting mixture was stirred at -30 C for 30 min, and then allowed to warm to 0 C for 1 h, at which point the reaction was successively quenched by addition of water (1 mL) in THF (10 mL) and DDQ (7.6 g, 34 mmol) in THF (25 mL). The resulting brown suspension was stirred at room temperature for 15 min, then cooled to 0 ', and treated with hexane (25 mL) and aqueous NaOH (3N, 25 mL). The mixture was stirred at 0 ' for 5 min, diluted with water (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with water, dried on MgS04, and concentrated to a minimum volume to afford after filtration lll-a as a pale brown solid (3.14 g, 53 %). H NMR (400 MHz, DMSO- de) delta 9.35 (dd, J = 2.3, 0.8 Hz, 1 H), 8.90 (d, J = 5.3 Hz, 1 H), 8.79 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.54 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 8.26 (d, J = 5.3 Hz, 1 H), 7.62 (ddd, J = 8.0, 4.8, 0.8 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N,N,-tetramethylethylenediamine;(9-benzylfluoren-9-yl)dicyclohexylphosphine; palladium diacetate; at 115℃; under 18751.9 Torr; for 20.0h;Autoclave;Product distribution / selectivity; | (i) Alkoxycarbonylation reactions of different aryl bromides using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salt) and 0.385 mmol TMEDA were diluted with n-butanol to a total volume of 10 ml. 0.5 mmol of each substrate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with carbon monoxide the pressure was set to 25 bar CO and the autoclave was stirred while warming up to 115°C. The reactions were hold at 115°C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.166667h;Microwave irradiation; | B) A Schlenck flask was charged with <strong>[31785-05-4]5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester</strong> (0.33 g, 1.80 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.15 g, 0.26 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.08 g, 0.08 mmol). Degassed dioxane (6.00 ml) was added, followed by 3-bromopyridine (0.23 g, 1.50 mmol). The flask was subjected to 5 cycles of evacuation and backfiring with argon. The reaction mixture was then transferred under argon to a microwave vial containing cesium carbonate (0.84 g, 2.60 mmol). The vial was then irradiated in a microwave oven at 150 C. for 10 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (ethyl acetate/methanol) to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.25 g, 65%) as a light yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With oxalic acid; potassium carbonate; triphenylphosphine; copper(I) bromide; In ethanol; | EXAMPLE 26 3-((1-methyl-2-piperidinyl)methoxy)pyridine oxalate salt 1-Methyl-2-piperidinemethanol (0.857 g, 6.65 mmol) was allowed to react with 3-bromopyridine (0.67 mL, 6.98), cuprous bromide (0.257 g, 1.33 mmol), triphenylphosphine (0.698 g, 2.66 mmol) and potassium carbonate (0.919 g, 6.65 mmol). The reaction mixture was heated to 90° C. and stirred for 120 hr, then cooled to 25° C., acidified with HCl (1.5 M; 35 mL) and washed with ethyl acetate (4*50 mL). The aqueous layer was basified with saturated aqueous potassium carbonate, and the product was extracted with chloroform (6*100 mL), dried (MgSO4) and concentrated in vacuo to an oil. The crude product was purified to yield the free base of the title compound after chromatography on silica gel (CHCl3 /MeOH/NH4 OH 1500:30:3). The amine was dissolved in EtOH (1 mL) and treated with oxalic acid (ca. 65 mg) to yield after recrystallization (EtOH/Et2 O) the title compound (0.088 g, 4percent) as a hygroscopic white solid. MS (DCI/NH3) m/e: 207 (M+H)+. 1 H NMR (D2 O,300 MHz) 5: 8.46 (d, J=2.9 Hz, 1H), 8.37 (dd, J=5.2, 1.1 Hz, 1H), 7.94 (ddd, J=8.8, 2.9, 1.1 Hz, 1H), 7.80 (dd, J=8.8, 5.9 Hz, 1H), 4.69 (dd, J=11.2, 3.1 Hz, 1H), 4.35 (dd, J=11.2, 2.0 Hz, 1H), 3.56 (m, 2H), 3.18 (dt, J=12.7, 3.0 Hz, 1H), 2.93 (s, 3H), 2.05-1.65 (m, 6H). Anal. calcd for C14 H20 N2 O5 Omega0.4 C2 H2 O4: C, 53.49; H, 6.31; N, 8.43. Found: C, 53.39; H, 6.09; N, 8.19. |
4% | With oxalic acid; potassium carbonate; triphenylphosphine; copper(I) bromide; In ethanol; | EXAMPLE 26 3-((1-methyl-2-piperidinyl)methoxy)pyridine oxalate salt 1-Methyl-2-piperidinemethanol (0.857 g, 6.65 mmol) was allowed to react with 3-bromopyridine (0.67 mL, 6.98), cuprous bromide (0.257 g, 1.33 mmol), triphenylphosphine (0.698 g, 2.66 mmol) and potassium carbonate (0.919 g, 6.65 mmol). The reaction mixture was heated to 90° C. and stirred for 120 hr, then cooled to 25° C., acidified with HCl (1.5 M; 35 mL) and washed with ethyl acetate (4*50 mL). The aqueous layer was basified with saturated aqueous potassium carbonate, and the product was extracted with chloroform (6*100 mL), dried (MgSO4) and concentrated in vacuo to an oil. The crude product was purified to yield the free base of the title compound after chromatography on silica gel (CHCl3 /MeOH/NH4 OH 1500:30:3). The amine was dissolved in EtOH (1 mL) and treated with oxalic acid (ca. 65 mg) to yield after recrystallization (EtOH/Et2 O) the title compound (0.088 g, 4percent) as a hygroscopic white solid. MS (DCI/NH3) m/e: 207 (M+H)+. 1 H NMR (D2 O, 300 MHz) delta: 8.46 (d, J=2.9 Hz, 1H), 8.37 (dd, J=5.2, 1.1 Hz, 1H), 7.94 (ddd, J=8.8, 2.9, 1.1 Hz, 1H), 7.80 (dd, J=8.8, 5.9 Hz, 1H), 4.69 (dd, J=11.2, 3.1 Hz, 1H), 4.35 (dd, J=11.2, 2.0 Hz, 1H), 3.56 (m, 2H), 3.18 (dt, J=12.7, 3.0 Hz, 1H), 2.93 (s, 3H), 2.05-1.65 (m, 6H). Anal. calcd for C14 H20 N2 O5.0.4 C2 H2 O4: C, 53.49; H, 6.31; N, 8.43. Found: C, 53.39; H, 6.09; N, 8.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; In diethyl ether; | Reference Example 35 n-Butyllithium (1.6N hexane solution, 108 ml) was added dropwise to a diethyl ether solution (400 ml) of 3-bromopyridine (25.7 g) at -78 C. over 1 hour under nitrogen atmosphere. After stirring for 30 minutes, a diethyl ether solution (100 ml) of diethyl oxalate (28.6 g) was added dropwise thereto at -78 C. over 1 hour. The reaction mixture was further mixed for 30 minutes, allowed to warm to 0 C., and 1N hydrochloric acid (200 ml) was added thereto. After stirring for 30 minutes, sodium bicarbonate was added thereto to neutralize the reaction mixture. The organic layer was separated, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 3-pyridylglyoxylate (13.1 g, yield 45%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; at 110℃; for 24h;Inert atmosphere; | Example B; Stage 1: Ethyl 3-methyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate; 3.765 g (27.24 mmol) of potassium carbonate, 0.124 g (0.649 mmol) of copper iodide, 0.296 g (2.595 mmol) of trans-N,N'-dimethyl-1,2-cyclohexanediamine and 2.000 g (12.97 mmol) of <strong>[85290-78-4]ethyl 3-methylpyrazole-4-carboxylate</strong> were dissolved in 5.0 ml (51.90 mmol) of 3-bromopyridine under argon. The mixture was heated to 110 C. for 24 hours and then cooled to room temperature. Dichloromethane was added and the solids were filtered off. The filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 4:1).Yield: 2.18 g (73% of theory), logP1) (HCOOH) 1.83. Contains 13% regioisomer (logP1) (HCOOH) 1.63).1H NMR((CD3)2SO): 1.31 (t, 3H), 2.46 (s, 3H), 4.27 (q, 2H), 7.53 (m, 1H), 8.26 (m, 1H), 8.55 (m, 1H), 8.96 (s, 1H), 9.11 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B; Stage 1: Ethyl 3-methyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate; 3.765 g (27.24 mmol) of potassium carbonate, 0.124 g (0.649 mmol) of copper iodide, 0.296 g (2.595 mmol) of trans-N,N'-dimethyl-1,2-cyclohexanediamine and 2.000 g (12.97 mmol) of <strong>[85290-78-4]ethyl 3-methylpyrazole-4-carboxylate</strong> were dissolved in 5.0 ml (51.90 mmol) of 3-bromopyridine under argon. The mixture was heated to 110 C. for 24 hours and then cooled to room temperature. Dichloromethane was added and the solids were filtered off. The filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 4:1).Yield: 2.18 g (73% of theory), logP1) (HCOOH) 1.83. Contains 13% regioisomer (logP1) (HCOOH) 1.63).1H NMR((CD3)2SO): 1.31 (t, 3H), 2.46 (s, 3H), 4.27 (q, 2H), 7.53 (m, 1H), 8.26 (m, 1H), 8.55 (m, 1H), 8.96 (s, 1H), 9.11 (m, 1H); Stage 2: 3-Methyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid; 2.180 g (9.427 mmol) of ethyl 3-methyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate (contaminated with approx. 10% regioisomer) was dissolved in approx. 50 ml of dioxane, and admixed with approx. 15 ml of water and 2.011 g of a 45% aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 12 h. Since the conversion was incomplete, the reaction mixture was additionally heated under reflux for 5 h. The solution was cooled to room temperature and the dioxane was removed under reduced pressure. The residue was admixed with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase was adjusted to pH 3 at 0 C. with 1N HCl and extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. This gave 1.56 g of the desired acid. After 12 h, a solid had precipitated out in the aqueous phase; it was filtered off with suction and gave 0.090 g of additional product.Yield: 1.65 g (86% of theory), logP31) (HCOOH) 0.77. The sample contains 9% regioisomer (logP1) (HCOOH) 0.53).1NMR((CD3)2SO): 2.45 (s, 3H), 7.52 (m, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 8,91 (s, 1H), 9.01 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In 1,4-dioxane; for 12h;Inert atmosphere; Reflux; | Copper iodide (15.6mg, 0.0824mmol), trans-N,N'-dimethyl-cyclohexyl-l,2- diamine (28.3mg, 0.2472mmol) and potassium phosphate (437.3mg, 2.0604mmol) were added to 1,4-dioxane (20mL) degassed with argon for 30 minutes. The reaction mixture was purged with argon for a further 20 minutes followed by the addition of 7- chloro-3,4-dihydro-2H-isoquinolin- 1 -one (I- Id: 150mg, 0.82417mmol) and 3-bromo- pyridine (88.9mL, 0.9065mmol). The reaction mixture was heated to reflux at 1 10C for 12 hours. The reaction was monitored by TLC (10% methanol in CHC13). The reaction mixture was filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (10% methanol in CHC13) afforded 90mg of the product (42.2% yield).]H NMR (DMSO-D6, 300 MHz): 6 8.90-8.24 (d, 2H), 8.1-7.0 (m, 5H), 4.20- 3.84 (m, 2H), 3.3-3.2 (m, 2H)LCMS purity: 90.81%, m/z = 259.0 (M+l)HPLC: 94.25% | |
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere; | General procedure: Preparation of 7-Chloro-2-pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one (1A) Copper iodide (15.6 mg, 0.0824 mmol), trans-N,N'-dimethyl-cyclohexyl-1,2-diamine (28.3 mg, 0.2472 mmol) and potassium phosphate (437.3 mg, 2.0604 mmol) were added to 1,4-dioxane (20 mL) degassed with argon for 30 minutes. The reaction mixture was purged with argon for a further 20 minutes followed by the addition of <strong>[22245-95-0]7-chloro-3,4-dihydro-2H-isoquinolin-1-one</strong> (I-1d: 150 mg, 0.82417 mmol) and 3-bromo-pyridine (88.9 mL, 0.9065 mmol). The reaction mixture was heated to reflux at 110 C. for 12 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (10% methanol in CHCl3) afforded 90 mg of the product (42.2% yield). 1H NMR (DMSO-D6, 300 MHz): delta 8.90-8.24 (d, 2H), 8.1-7.0 (m, 5H), 4.20-3.84 (m, 2H), 3.3-3.2 (m, 2H) LCMS purity: 90.81%, m/z=259.0 (M+1); HPLC: 94.25% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methyl 6-bromo-2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate [0424] A 70% perchloric acid aqueous solution (12.9 mL) was added to a 1,4-dioxane solution (31 mL) of ethyl O-mesitylsulfonylacetohydroxamate (35.7 g) under an argon atmosphere under ice-cooling, and then the mixture was stirred for 30 minutes under ice-cooling. Ice water (360 mL) was added to the reaction solution, the precipitated solid was filtered off, the obtained solid was dissolved in dichloromethane (104 mL), and the solution was divided into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered off. A dichloromethane solution (104 mL) of 3-bromopyridine (10 mL) was added to the obtained filtrate under ice-cooling, the mixture was stirred at room temperature for 1 hour, and the reaction solution was evaporated to obtain a crude product N-amino-3-bromopyridinium 2,4,6-trimethylbenzenesulfonate. Methyl phenylpropiolate (7.7 mL) and potassium carbonate (28.7 g) were added to an N,N-dimethylformamide solution (104 mL) of the crude product N-amino-3-bromopyridinium 2,4,6-trimethylbenzenesulfonate at room temperature under an argon atmosphere, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 4:1) to obtain a title compound as a yellow powder (8.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1H-imidazole; palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; magnesium chloride; In tetrahydrofuran; at 90℃; for 0.5h;Microwave irradiation; | To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)2(5 mol%), Xantphos (5 mol %), MgCl2 (0.75), Et3N ( 0.75mmol), imidazole (1 mmol) followed by Co2(CO)8 (0.15mmol). The vial was sealed immediately and microwave irradiated at 90C for 30min. The reaction mixture was concentrated and diluted with ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated. The crude product obtained was purified by column chromatography to get the pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos; In toluene; at 80.0℃; for 14.0h;Sealed tube; Microwave irradiation; | To a solution of <strong>[944898-96-8]5,6-difluoro-1H-indazole</strong> (50 mg, 0.324 mmol) in toluene (1 mL) in a microwave vial were added 3-bromo pyridine (61.5 mg, 0.389 mmol), tris(dibenzylideneacetone)palladium (0) (29.7 mg, 0.032 mmol), sodium tert- butoxide (46.8 mg, 0.487 mmol) and 2-di-tert-butylphosphino-2',4'6'- triisopropylbiphenyl (13.78 mg, 0.032 mmol). The resulting mixture was sealed and heated to 80 C for 14 hours, then concentrated under reduced pressure and purified by reverse phase HPLC (CI 8 column, 10 to 100% acetonitrile/water linear gradient, both 0.05% v/v trifluoroacetic acid) to provide the title compound: LCMS m/z 231.90 [M + H]+; 1H NMR (500 MHz, CDC13) delta 9.09 (s, 1 H), 8.71 (d, J= 2.3 Hz, 1 H), 8.26 (d, J= 8.1 Hz, 1 H), 7.56 - 7.63 (m, 3 H), 6.94 (d, J= 6.9 Hz, 1 H), 2.90 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; In 1,4-dioxane; water; at 80℃; for 21h;Inert atmosphere; | Weighed out <strong>[57002-01-4](E)-(2-cyclohexylvinyl)boronic acid</strong> (3.05 g, 19.80 mmol), 3-bromopyridine (1.80 ml, 18.34 mmol) and cesium carbonate (12.05 g, 37.0 mmol). Added 1,4-Dioxane(150 ml) followed by Water (30.0 ml), then the flask was flushed with nitrogen. Tetrakis (2.25 g, 1.947 mmol) was added and the reaction was sealed and heated to 80 C for 21h. The reaction was concentrated down in vacuo. The residue was taken back up in DCM (250 mL) and washed with water (5OmL). The organic phase was concentrated and the compound was purified by flash chromatography on silica running from 100% Hex to40% EtOAc I 60% Hexane. The desired fractions were concentrated down to give the title compound (3.3568 g, 98 % yield). LC-MS m/z 188.1 (M+H), 0.61 mm (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; L-valine; potassium carbonate; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | 6 (2.4 g, 15 mmol), cuprous iodide (572 mg, 3 mmol), L-valine (690 mg, 6 mmol), potassium carbonate (4.14 g, 30 mmol) were added to a two-neck bottle, and argon gas was added to 30 mL. In DMSO, 3-bromopyridine (3.56 g, 22.5 mmol) was added at room temperature to raise the temperature to 120 C.After the completion of the reaction, the mixture was cooled to room temperature, and then added with 50 mL of ethyl acetate. The mixture was stirred for 20 min, and the residue was evaporated to dryness. A yellow solid 7 (2.92 g, 82%). |
Tags: 626-55-1 synthesis path| 626-55-1 SDS| 626-55-1 COA| 626-55-1 purity| 626-55-1 application| 626-55-1 NMR| 626-55-1 COA| 626-55-1 structure
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