Structure of 189882-33-5
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CAS No. : | 189882-33-5 |
Formula : | C8H5N3 |
M.W : | 143.15 |
SMILES Code : | N#CC1=NC2=C(C=C1)C=CN2 |
MDL No. : | MFCD06659673 |
InChI Key : | GAFBPZMOMITHLG-UHFFFAOYSA-N |
Pubchem ID : | 10534776 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.81 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.47 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.36 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.43 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.35 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.99 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.27 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.19 |
Solubility | 0.925 mg/ml ; 0.00646 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.06 |
Solubility | 1.23 mg/ml ; 0.00862 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.97 |
Solubility | 0.153 mg/ml ; 0.00107 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) |
Yes |
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 |
-6.21 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 |
1.0 |
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) |
1.64 |
* 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 |
---|---|---|
60% | With triethylamine; In acetonitrile; for 72h;Reflux; | To a mixture of lH-pyrrolo[2,3- bjpyridine 7-oxide(3.0 g, 22.4 mmol) in MeCN were added TEA (5.6 g, 56 mmol) and TMSCN (13.2 g, 134 mmol) in five portions. The reaction mixture was stirred at reflux for 3 d then concentrated under reduced pressure. The residue was purified by column chromatography to give the desired compound (1.9 g, 60% yield) as yellow solid. LC-MS: m/z 144 (M+H)+. |
41 mg | With triethylamine; In acetonitrile; at 85℃; for 2h; | To a solution of the compound [96-1] obtained in the process (1) (360 mg) in acetonitrile (5 mL) were added triethylamine (0.75 mL) and trimethylsilyl cyanide (0.33 mL) at room temperature, and then the reaction mixture was stirred at 85C for 2 hours. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (41 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 8.08 (1H, d, J = 8.1 Hz), 7.71 (1H, dd, J = 3.5, 2.6 Hz), 7.52 (1H, d, J = 8.1 Hz), 6.65 (1H, dd, J = 3.7, 2.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: Phenyl(1H-pyrrolo[2,3-b]pyridin-6-yl)methanone In a round-bottomed flask under argon, 25.2 ml of 1M phenylmagnesium bromide in tetrahydrofuran are dissolved in 7 ml of anhydrous tetrahydrofuran. In another round-bottomed flask under argon, 0.6 g of <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> and 1.07 ml of trimethylsilyl chloride are dissolved in 7 ml of tetrahydrofuran. That solution is then pipetted onto the magnesium solution at ambient temperature. After stirring for one night, the mixture is hydrolyzed with 20 ml of 2N ammonium chloride solution. The pH is then adjusted to 1 using 10% hydrochloric acid and the solution obtained is stirred for 2 hours at ambient temperature. The pH of the solution is adjusted to 9 using concentrated ammonium hydroxide solution and the aqueous phase is extracted twice with 20 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. After purification by chromatography on silica gel (pure dichloromethane and then dichloromethane/methanol:99/1), the title compound is obtained in the form of a yellow solid. Melting point: 174 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of lH-Pyitauolo[2,3-b]pyridine-6-carbonitrile (500 mg, 3.49 mmol) in THF (80 mL) was added Titanium (IV) isopropoxide (2.05 mL, 6.98 mmol) followed by EtMgBr (4.66 mL, 13.97 mmol) dropwise. The mixture was stirred at room temperature for 3 h. The dark color reaction mixture was quenched with 10 mL of H2O and stirred efficiently for 30 min. The resulting yellow suspension was filtered through a plug of celite, washed the celite cake with EtOAc followed by 10% MeOH/CH2Cl2. Solvents were removed and the resulting brown oil was suspended in Toluene (2x10 mL) to removed residual water. After evaporation of the solvent the crude amine products were obtained as a brownish solid. To a mixture of these crude amines and DIEA (801 uL, 4.60 mmol) in DCM (15 mL) was added BoC2O (810 mg, 3.71 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with DCM and washed with water, followed by Brine. Dried over MgSO4, filtered and concentrated down to provide crude material which was purified by silica gel chromatography (5% to 50% EtOAc in hexane) to give 80 mg of [1-(lH-Pyrrolo[2,3-&]pyridin-6-yl)-cyclopropyl]- carbamic acid tert-butyl ester (m/z 274.40 [M + I]+) and 230 mg of [1-(1H-Pyrrolo[2,3- b]pyridin-6-yl)-propyl]-carbamic acid tert-butyl ester m/z 276.41 [M + I]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: Cyclopropyl(1H-pyrrolo[2,3-b]pyridin-6-yl)methanone In a round-bottomed flask under an argon atmosphere, 3 g (21 mmol) of <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> are dissolved in 35 ml of anhydrous tetrahydrofuran. 5.35 ml (42 mmol) of trimethylsilyl chloride and 126 ml (126 mmol) of phenylmagnesium bromide (1M in tetrahydrofuran) are then added. The reaction mixture is stirred for 1 night at ambient temperature. It is then hydrolyzed with 100 ml of 2M ammonium chloride solution. The pH is then acidified to 1 using 10% hydrochloric acid and the mixture is stirred for 2 hours at ambient temperature. The pH of that solution is then brought to 9 using concentrated ammonium hydroxide solution. The aqueous phase is extracted twice with 100 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (petroleum ether/ethyl acetate: 9/1 then 8/2) to yield the title product in the form of a beige solid. Melting point: 159 C. MS: m/z=187 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: 6-(1-Cyclohexylvinyl)-1H-pyrrolo[2,3-b]pyridine Under an argon atmosphere, 1.5 g (10.48 mmol) of <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> are dissolved in 20 ml of anhydrous tetrahydrofuran. 2.66 ml (20.96 mmol) of trimethysilyl chloride are then added. That mixture is then added to 31 ml (62.87 mmol) of cyclohexylmagnesium chloride dissolved in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at ambient temperature. It is then hydrolyzed with 50 ml of 2M ammonium chloride. After acidification to pH 1 using 6M hydrochloric acid, the mixture is stirred for 2 hours at ambient temperature. It is then rendered basic to pH 8 using aqueous ammonium hydroxide solution and extracted 3 times with 20 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated. The crude product is purified by chromatography on silica gel (petroleum ether/ethyl acetate: 9/1, 8/2 then 7/3) to yield the title product in the form of a yellowish solid. Melting point: 160 C. MS: m/z=229 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Steps 1-3BzCI 1A7-azaindoline was sequentially treated with mCPBA (J. Org. Chem. 1980, 45, 4045), TMSCN/benzoyl chloride (Synthesis, 1992, 661) and LiOH (J. Agric. Food Chem. 1997, 45, 2345) to provide 6-cyano-7-azaindole 1A. The formation of compound 1 A is also described in the literature by alternate approaches (Synthesis 2008, 201 and Synthesis, 2008, 707). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Step 41A 1 BA solution of 1A (45 mg, 0.3 mmol) in THF (5 ml_) and DMF (1 ml_) was treated with NaHMDS (1 M/THF, 1.5mL) and stirred at RT for 30 min. NaI (45rng, 0.3 mmol) and 4-(chloromethyl)-1 -tritylimidazole (0.3g, 0.9mmol) were then added. The reaction was stirred overnight at RT and then concentrated. Chromatography (20-50% EtOAc/hex) provided 1 B (72 mg, 50%) and recovered starting material 1A (23 mg, 50%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 7-hydroxy-lH-pyrrolo[2,3-]pyridine (1.15 g, 8.57 mmol) in dry CH3CN (30 ml) was added isopropyl iodide (2.6 ml, 25.71 mmol) at RT. The mixture was stirred at 45 0C for about 40 h, before more isopropyl iodide was added (2.6 ml, 25.71 mmol). The mixture was further heated at 55 0C overnight. The solution was evaporated to dryness in vacuo. The residue was dissolved in sat. aq. NH4Cl (40 ml) and a solution, of potassium cyanide (1.12 g, 17.14 mmol) in water (10 ml) was added slowly at RT. The mixture was stirred at 45 0C overnight, then cooled to 4 0C in an ice bath, and sat. aq. NaHCO3 (30 ml) was added slowly. The mixture was stirred vigorously for Ih, then the precipitates were collected by filtration. The wet cake was rinsed with cold water and dried in vacuo to yield the title compound as an off-white solid. (HR-MS: 144.0568). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 140℃; for 4h;Inert atmosphere; | Acid-4: 3-Chloro-1 H-pyrrolo[2,3-b]pyridine-6-carboxylic acid; a) 1 H-Pyrrolo[2,3-b]pyridine-6-carbonitrile; To a mixture of 6-bromo-1 H-pyrrolo[2,3-b]pyridine (Synthesis, 1992, 661 , example 3b) (788 mg, 4 mmol), zinccyanide (329 mg, 2.80 mmol) and zinc dust (26.2 mg, 0.4 mmol) in dry DMF (12 ml) was added (dppf)PdCI2xCH2Cl2 adduct catalyst (163 mg, 0.2 mmol) under nitrogen. The mixture was heated at 140 C for 4 h. The reaction mixture was diluted with ethyl acetate and washed with aq. Saturated bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. 1.04 g dark yellow oil. The crude product was chromatographed over silica gel (cyclohexane/ethyl acetate 3:1) to provide the title compound as a white solid.TLC Rf=0.35 (2: 1 cyclohexane:ethyl acetate);LC-MS: 0.81 min. (100% purity, ESI+ 144), API-ES+ 144;1H-NMR (400 MHz, CDCI3): delta 11.05 (s, 1 H, NH), 8.08 (d, 1 H), 7.71 (dd, 1 H), 7.52 (d, 1 H), 6.66 (m, 1 H). | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; zinc; In N,N-dimethyl-formamide; at 140℃; for 5h;Inert atmosphere; | A mixture of 6-bromo-1H-pyrrolo[2,3-b]pyridine (4.00 g, 20.30 mmol, 1.00 eq), Zn (132.75 mg, 2.03 mmol, 0.10 eq), Zn(CN)2(1.67 g, 14.21 mmol, 902.05 uL, 0.70 eq) and Pd(dppf)Cl2.CH2Cl2 (828.95 mg, 1.02 mmol, 0.05 eq) in DMF (10.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 140C for 5 h under N2 atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with aq. saturated bicarbonate solution (100 mL) and brine (100 mL*2), dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (SiO2, PE/EtOAc=10:1 to 3:1) to afford the title compound (1.50 g, 8.91 mmol, 43.88% yield, 85% purity) as a white solid. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; zinc; In N,N-dimethyl-formamide; at 140℃; for 5h;Inert atmosphere; | A mixture of 6-bromo-lH-pyrrolo[2,3-b]pyridine (10 g, 50.75 mmol, 1 eq), Zn (331.88 mg, 5.08 mmol, 0.1 eq), Zn(CN)2 (4.17 g, 35.53 mmol, 2.26 mL, 0.7 eq) and Pd(dppf)Cl2.CH2Cl2 (2.07 g, 2.54 mmol, 0.05 eq) in DMF (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at l40C for 5 h under N2 atmosphere. It was diluted with water (500mL) and EtOAc (300mL), and then filtered to remove the solid, the solid was washed with EtOAc (200mLx2). The combined organic layers were washed with brine (500 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, PE/EtOAc = 5/1 to 2/1) to afford the title compound (5.3 g, 89% purity) as a green solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydroxide; In ethanol; at 90℃; for 18h; | <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> (120mg, 0.84mmol) was dissolved in ethanol (10ml). 6N Sodium hydroxide (1.4ml, 8.4mmol) was added, and the mixture was stirred for 18 hours at 90. The mixture was distilled under reduced pressure, and then 1N hydrochloric acid solution was added. The resulting solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (100mg, 74%). [945] NMR:1H-NMR(400HMz, DMS)-d 6); delta 12.08(brs, 1H),8.11(d, 1H), 7.83(d, 1H), 7.70(d, 1H), 6.58(d, 1H) |
b) 1 H-Pyrrolo[2,3-b]pyridine-6-carboxylic acid; A suspension of 1 H-pyrrolo[2,3-b]pyridine-6-carbonitrile (690 mg, 4.82 mmol) in NaOH 2M (12 ml) was stirred at 100 C for 6 h. The reaction mixture was washed with diethyl ether and the aq. phase was set slightly acidic (pH 6-7) with cone. HCI. The solid formed was filtered off and dried to provide the title compound.LC-MS: RtH8= 0.51 min. (100% purity, ESI+ 163);1H-NMR (400 MHz, DMSO-D6): delta 12.78 (s, 1 H), 12.01 (s, 1 H), 8.08 (d, 1 H), 7.80 (m, 1 H), 7.73 (s, broad, unresolved, 1 H), 6.56 (s, broad, 1 H). | ||
176 g | With sodium hydroxide; In ethanol; at 80℃; | With 5 liters three bottles,Under mechanical agitation,123 g of <strong>[189882-33-5]6-cyano-7-azaindole</strong> was added to 1.7 liters of ethanol,At room temperature,Add the concentration of 5N sodium hydroxide solution 1.2 liters,The temperature was kept at 80 C overnight,Thin layer chromatography TLC detection,To the raw material reaction completely,The reaction was stopped. Post-processing:After naturally dropping to room temperature, the reaction solution was poured into 5 liters of ice water and the pH was adjusted to 3 to 4 with hydrochloric acid to precipitate solidBody products, filtration, drying,be made of7-azaindole 6-carboxylic acid176 g.Sampling detection,High Pressure LiquidThe purity was 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | To a solution of the compound [96-2] obtained in the process (2) (40 mg) in N,N-dimethylformamide (2 mL) were added potassium carbonate (82 mg) and 2,6-dimethylbenzyl chloride (69 mg) at room temperature, and then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (67 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.98 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 8.1 Hz), 7.22 (1H, dd, J = 8.2, 7.0 Hz), 7.12 (2H, d, J = 7.6 Hz), 6.96 (1H, d, J = 3.4 Hz), 6.46 (1H, d, J = 3.7 Hz), 5.49 (2H, s), 2.27 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a mixture of AICI3 (2.2 g, 16.8 mmol) in anhydrous DCM (50 mL) at 0C was added acetyl chloride (2.1 g, 33.5 mmol). The mixture was stirred at r.t. for 1 hr, followed by addition of a solution of lH-pyrrolo[2,3-b]pyridine-6- carbonitrile (800 mg, 5.6 mmol) in anhydrous DCM (20 mL). The resulting mixture was stirred at r.t. for 2 hr then poured into ice -water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (500 mg, 50% yield). LC-MS: m/z 186 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[592] To a solution of <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> (WO2011128455) (150 mg, 1.05 mmol) in THF (5.2 mL) at 0 C, was added NaH (60% in mineral oil, 46 mg, 1.15 mmol), and the reaction mixture was stirred for 30 minutes, warming to RT. chloromethyl methyl ether (MOM-Cl) (80 uL, 1.05 mmol) was added, and the reaction mixture was stirred at RT for 1 h, then quenched with sat. NaHCO3 (0.1 mL) and concentrated under reduced pressure. The residue was diluted with water (10 mL), extracted with DCM (3 x 10 mL), and the collected organics were washed with (1:1) water/NaHCO3 (2 x 10 mL) and brine (2 x 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (189 mg, 0.93 mmol, 87% yield) as a dark brown solid, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a solution of <strong>[189882-33-5]1H-pyrrolo[2,3-b]pyridine-6-carbonitrile</strong> (1.50 g, 10.48 mmol, 1.00 eq) in DCM (3.00 mL) was added NBS (2.24 g, 12.57 mmol, 1.20 eq) at 0C . The mixture was stirred at 20C for 16 h. It was concentrated. The residue was washed with PE (50 mL) and filtered to afford the title compound (3.00 g, 6.76 mmol, 64.46% yield, 50% purity) as a yellow solid. It was used for next step directly^ | |
With N-Bromosuccinimide; In dichloromethane; at 0 - 15℃; for 1h; | To a solution of lH-pyrrolo[2,3-b]pyridine-6-carbonitrile (4 g, 25.15 mmol, 1 eq) in DCM (40 mL) was added NBS (5.37 g, 30.18 mmol, 1.2 eq) at 0 C. The mixture was stirred at 15 C for 1 h. It was concentrated and the residue was washed with PE (500 mL) and the solid was filtered to afford the title compound (5 g, crude) as a yellow solid. |
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