Structure of 171919-36-1
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CAS No. : | 171919-36-1 |
Formula : | C9H8N2O |
M.W : | 160.17 |
SMILES Code : | O=CC1=CN(C)C2=NC=CC=C21 |
MDL No. : | MFCD11054209 |
InChI Key : | IZPRBMBNUDLUMD-UHFFFAOYSA-N |
Pubchem ID : | 10441960 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
34.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.51 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.73 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.39 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.67 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.17 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.78 |
Solubility | 2.65 mg/ml ; 0.0165 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.04 |
Solubility | 14.6 mg/ml ; 0.0909 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.41 |
Solubility | 0.623 mg/ml ; 0.00389 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 |
-6.76 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 |
1.0 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) |
1.33 |
* 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 |
---|---|---|
74% | b) 1-Methyl-lH-pyrrolo [2, 3-b] pyridine-3-carbaldehyde; POC13 (1.2 g, 7.9 mmol) was added dropwise with stirring to 10 mL of DMF at 0C. After stirring 10 min a solution of 1-methyl-lH-pyrrolo [2, 3-b] pyridine (0.95 g, 7. 2 mmol) in 5 mL of DMF was added during 1 min. The reaction mixture was stirred for lh at 0C and a further 30 min at 60C. It was poured into water which was made alkaline with NaHC03 (aq) and extracted 3 times with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated. The crude product (0.85 g, 74%) was sufficiently pure to be used in the subsequent step below. 'H NMR (300 MHz, CDC13) No. 9. 97 (s, 1H), 8.55 (m, 1H), 8.44 (m, 1H), 7.84 (s, 1H), 7.27 (m, 1H), 3.97 (s, 3H). | |
9. 7-[2-(4-CYCLOBUTYLPIPERAZIN-l-YL)-2-OXOETHYL]-9-METHYL- 6,7,8,9-TETRAHYDRO-5H-PYRIDO[4',3':4,5]PYRROLO[2,3-B]PYRIDINE (SCHEME 7); Compound 9; Step 1. 1 -Methyl- 1 H-pyrro Io [2,3 -b]pyridine-3-carbaldehyde; <n="63"/>POCl3 (1.48 mL, 9.65 mmol) is added dropwise to a 0 0C solution of DMF (5 mL). The mixture is stirred 0.5 h at 0 0C. In a separate flask, 1 -methyl- IH- pyrrolo[2,3-b]pyridine (Journal of the American Chemical Society (2005) 127(22):8050-57; 1.04 g, 7.87 mmol) is dissolved in DMF (10 mL) and added dropwise to the first solution at 0 0C. The mixture is allowed to warm to rt and stirred overnight. The mixture is diluted with water (100 mL) and basified with IO N NaOH. The mixture is extracted with DCM (3 x 50 mL). The combined organic extracts are washed with water (3 x 100 mL) and brine (100 mL), dried over Na2SO4, and evaporated to yield the title compound. MS (+VE) m/z 161.12 (M+ +1). | ||
General procedure: POCl3 (5.87 ml, 63.0 mmol) was added dropwise to DMF (45 ml) at 0 C, and the mixture was stirred for 20 min at same temperature. A solution of 6-fluoro-1-methylindole (6.71 g, 45.0 mmol) in DMF (45 ml) was added slowly to the mixture at 0 C. After being stirred at room temperature for 1.5 h, the reaction mixture was poured into ice, and the resulting mixture was neutralized with 1 N NaOH and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated to dryness. The residue was purified by column chromatography on silica gel with EtOAc as eluent to give the title compound (4.18 g, 52%) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydrogencarbonate; trichlorophosphate; In ethyl acetate; N,N-dimethyl-formamide; | (Step 2) Synthesis of 1-methyl-1H-pyrrolo(2,3-b)pyridine-3-carbaldehyde Phosphoryl chloride (5.15 ml, 55.3 mmol) was added dropwise to DMF (70 ml) under stirring at 0ØC. After the reaction mixture was stirred at 0ØC for 10 minutes, a solution of 1-methyl-1H-pyrrolo(2,3-b)pyridine (4.87 g, 36.8 mmol) in DMF (5 ml) was added dropwise at the same temperature. After completion of the dropwise addition, the reaction mixture was stirred at 0ØC for 4 hours and at 60ØC for 3.5 hours. The reaction mixture was poured in ice water - a saturated aqueous solution of sodium bicarbonate to neutralize the mixture therewith, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 1-methyl-1H-pyrrolo(2,3-b)pyridine-3-carbaldehyde (4.87 g, 83%) was obtained as a yellow solid. 1H-NMR (CDCl3) delta: 3.98 (s, 3H), 7.28 (dd, J=7.8,4.7Hz, 1H), 7.85 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 8.55 (d, J=7.8Hz, 1H), 9.97 (s, 1H). MS (ESI) m/z 160 (M+-H). |
47% | b) 1-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde According to the procedure of Preparation 40 (b), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 5.3 mmole) for the 1,3-dimethylindole, the title compound (0.4 g, 47%) was prepared as a white solid: MS (ES) m/e 161 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | c) (1S, 35)-N-(6-Fluoro-4-methylquinolin-2-yl)-lV-l (1-methyl-lH-pyrrolo [2, 3-b] pyridin- 3-yl) methyl] cyclopentane-1, 3-diamine; (1S, 3S)-N-(6-Fluoro-4-methylquinolin-2-yl)cyclopentane-1, 3-diamine (76 mg, 0.29 mmol ; see Ex 6b) and 1-methyl-lH-pyrrolo [2, 3-b] pyridine-3-carbaldehyde (47 mg, 29 mmo; from step b above) were dissolved in 2 mL of methanol and allowed to react overnight. Sodium borohydride (50 mg, 1.3 mmol) was added and the reaction mixture was stirred for 15 min after which 5 mL of 2M HC1 was added and after an additional 5 min the mixture was made alkaline by addition of 2M NaOH. The mixture was extracted three times with EtOAc and the combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated. The crude product was chromatographed on a pre-packed SiO2-column (Isolute, 5 g) eluted with DCM: MeOH: Et3N 100: 5: 1 to give 78 mg (65%) of the title compound after freeze-drying from dioxane. 'H NMR (400 MHz, CDCl3) 8 8.30 (m, 1H), 7.93 (m, 1H), 7.60 (dd, 1H), 7.32 (dd, 1H), 7.24 (m, 1H), 7.07, (s, 1H), 7.01 (dd, 1H), 6.48 (s, 1H), 4.93 (m, 1H), 4.42 (m, 1H), 3.89 (s, 2H), 3.81 (s, 3H), 3.37 (m, 1H), 2.45 (s, 3H), 2.35-2. 20 (m, 2H), 2.15-1. 95 (m, 2H), 1.80 (m, 1H), 1.50 (m, 1H). 3C NMR (101 MHz, CDC13) additional signals due to C-F coupling 8 159.9, 157.5, 156.9, 148.9, 145.6, 145.3, 143.8, 129.0, 128.9, 128.0, 127.9, 124.7, 124.6, 120.7, 119.4, 119.1, 116. 0, 113. 0, 112. 7,108. 5,108. 3,58. 3,52. 6,44. 2,41. 6,33. 3,32. 7,31. 9,19. 7. LC-MS [M+H] +404. 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | c) 1-Methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine According to the procedure of Preparation 40 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; at 70℃; | Step 2. l-Methyl-3-[(E)-2-nitrovinyl]-lH-pyrrolo[2,3-b]pyridine; To a solution of l-methyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.18 g, 7.34 mmol) in nitromethane (20 mL) is added NH4OAc (200 mg, 2.59 mmol). The mixture is stirred overnight at 70 0C. The solution is cooled to rt and concentrated under reduced pressure. The residue is dissolved in EtOAc (50 mL) and extracted with saturated aqueous NaHCO3 (2 x 50 mL). The organic extract is dried over Na2SO4, and evaporated to yield the title compound. MS (+VE) m/z 204.18 (M+ +1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A mixture of 6-fluoro-1-methylindole-3-carbaldehyde (13a) (500 mg, 2.82 mmol) and methyl 4-amino-3-hydroxyphenylacetate (11a) (767 mg, 4.23 mmol) in EtOH (15 ml) was stirred for 22 h, and iodobenzene diacetate (1.09 g, 3.38 mmol) was added portionwise to the mixture. After being stirred for 1 h, the mixture was concentrated, and the residue was purified column chromatography with n-hexane-AcOEt (1:1, v/v) as eluent to give methyl [2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl]acetate (889 mg, 93%) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With water; iodine; oxygen; sodium carbonate; In 1,4-dioxane; at 100℃; under 760.051 Torr; for 36h;Schlenk technique; Sealed tube; | General procedure: Under air, a 20 mL of Schlenk tube equipped with a stir bar was charged with indole 1 (0.2 mmol, 1 equiv),TMEDA (75 muL, 0.5 mmol, 2.5 equiv), Na2CO3 (42.4 mg, 0.4mmol, 2.0 equiv), 1,4-dioxane (0.5 mL) and H2O (100 muL). Then I2 (101.5 mg, 0.4 mmol, 2.0 equiv) was added and the tube was sealed with a rubber plug and charged with O2. The reaction mixture was stirred at 100 C for 36 h in oil bath. After cooling to room temperature, the resultant mixture was evaporated with EtOAc (20 mL) under reduced pressure and the residue was purified by flash column chromatography on a silica gel to give the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: Titanium tetrachloride (1.90 g, 10 mmol) was slowly added to100 mL of anhydrous THF at 0 C, followed by addition of 5 mmol of the aldehyde (1) and stirred for 10 min, then ethyl 2-(3-bromopyridin-2-yl)acetate (2) (1.47 g, 6 mmol) was added. Subsequently, a solution of pyridine (3.16 g, 40 mmol) in 25 mL of anhydrous THF was added dropwise during a period of 30-60 min at 0 C. The reaction mixture was then stirred for 1 h at room temperature and refluxed for 24 h. After that the mixture was poured on to crashed ice and extracted with ethyl acetate (4 30 mL). The combined extracts were successively washed with brine, saturated sodium hydrogen carbonate and brine, and then dried over anhydrous MgSO4. The organic phase was filtrated and the solvent was removed in vacuo, the residue was purified by column chromatography (silica gel) using PE/EA (5:1) / DCM/MeOH (50:1) to provide 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5% | To a solution of tert-butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [118 mg (0.2 mmol)] in THF (5 ml) with <strong>[171919-36-1]1-methylpyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> [96 mg (0.6 mmol)] was added at -38 C. 1M LiN(TMSi)2 [600 ul (0.6 mmol)]. The reaction was stirred at -38 C. for 60 min and then at room temperature for 30 min longer. The reaction was quenched with sat NH4Cl (10 ml), extracted with EtOAc (20 ml), dried (MgSO4) and the solvent removed. The residue was treated with 2 ml of 4NHCl in dioxane for 1 h, rotary evaporated to dryness and chromatographed via reverse phase chromatography. Yield=3 mg (3.5%) as TFA salt via prep chrom. MS (m/z): 426 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 C). The reaction was stirred at 0 C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92% yields along with the by-product aldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In tetrahydrofuran; at 0℃; for 1h; | General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 C). The reaction was stirred at 0 C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92% yields along with the by-product aldehyde. |
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