Structure of 387-46-2
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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. : | 387-46-2 |
Formula : | C7H6O3 |
M.W : | 138.12 |
SMILES Code : | O=CC1=C(O)C=CC=C1O |
MDL No. : | MFCD08061915 |
Boiling Point : | No data available |
InChI Key : | DGXAGETVRDOQFP-UHFFFAOYSA-N |
Pubchem ID : | 10285801 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 35.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
57.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.02 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.9 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.85 |
Solubility | 1.95 mg/ml ; 0.0141 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.04 |
Solubility | 1.27 mg/ml ; 0.00921 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.17 |
Solubility | 9.4 mg/ml ; 0.0681 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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.27 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) |
1.0 |
* 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 |
---|---|---|
88% | [0179] A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K2C03 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(l-isopropyI-lH-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, leq.) at rt. The mixture was heated at 50 C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(l- isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid. NMR (400 MHz, CDC13) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J = 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H). LRMS (M+rf") m/z 338.1 | |
37% | [0178] A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) and Cs2C03 (7.5 g, 21.3 mmol, 3 eq.) in DMF (180 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (1.93 g, 7.1 mmol, leq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6- ((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (920 mg, 37%) as a pale yellow oil. NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8,7 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J = 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H). LRMS (M+H+) m/z 338.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; | Example 8: Synthesis of Compound (I) by Mitsunobu couplingInto a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H2O. The resulting solution was extracted with 3x500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1 :50-l :3) as eluent to yield the crude product. The crude product was re- crystallized from i-propanol/H2O in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 C. MS (ES, m/z): 338.1 [M+1]. 1H NMR (300 MHz, DMSO-d6) delta 11.72(s, 1H), 10.21(s, 1H), 8.76(d, J=3.6Hz, 1H), 8.24(d, J=2.7Hz, lH),7.55(m, 3H), 6.55(m,3H) ,5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1Hz, 6H). 1H NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J= 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H). |
37% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 22℃;Inert atmosphere; | Example 8 Synthesis of Compound (I) by Mitsunobu Coupling Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H2O. The resulting solution was extracted with 3*500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:50-1:3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H2O in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 C. MS (ES, m/z): 338.1 [M+1]. 1H NMR (300 MHz, DMSO-d6) delta 11.72 (s, 1H), 10.21 (s, 1H), 8.76 (d, J=3.6 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.55 (m, 3H), 6.55 (m, 3H), 5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1 Hz, 6H). 1H NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In 1-methyl-pyrrolidin-2-one; at 40 - 50℃; | A suitably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH- pyrazol-5-yl)pyridine dihydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (4 equivalent), l-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy- benzaldehyde (1 to 1.05 equiv.). The reaction mixture was heated slowly to 40 C to 50 C and stirred until the reaction was complete. Water was then added and the reaction mixture was cooled and maintained at 17 C to 25 C. When the water addition was complete, the reaction mixture was stirred at 17 C to 25 C and slowly cooled to 0C to 5C and the resulting solids were collected by filtration. The solids were washed with a 0 C to 5 C 2: 1 water/NMP solution, followed by 0 C to 5 C water. The solids were filtered and dried to give 2-hydroxy-6- ((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I or a mixture of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I Form I and NMP solvates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | A mixture of 2,6-dihydroxybenzaldehyde (leq) and <strong>[55876-84-1]methyl 5-(bromomethyl)picolinate</strong> (leq) was dissolved in anhydrous N,N-Dimethylformamide (DMF). Anhydrous potassium carbonate (K2CO3) (l .2eq) was added to this mixture and the reaction was stirred at room temperature for 4 hours. The solvent was then evaporated and the reaction mixture extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 6: 1 to obtain pure product as white powder with a yield of 54%. IR (Diamond, cm-1): 2954, 1731, 1679, 1644, 1618, 1574, 1458, 1440, 1392, 1357, 1289, 1249, 1 177, 1 144, 1 122; 1H-NMR (400 MHz, DMSO-d6): 5 1 1.74 (s, 1H), 10.37 (s, 1 H), 8.86 (s, 1 H), 8.12 (m, 2H), 7.54 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.32 Hz, 1H), 6.56 (d, ./ = 8.4 Hz, 1H), 5.40 (s, 2H), 3.89 (s, 3H); 13C-NMR (100 MHz, DMSO-d6): d 193.83, 162.42, 160.69, 148.72, 147.01 , 138.64, 136.32, 135.91, 135.78, 124.64, 109.79, 103.37, 67.31, 52.39. MS (ESI) m/z found 310.08 (M+Na)+, Calculated 301.2940 [M]+. The purity of the compound was checked by HPLC and was found to be 99% pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | A mixture of 2,6-dihydroxybenzaldehyde (leq) and <strong>[116986-09-5]methyl 3-(bromomethyl)picolinate</strong> (leq) was dissolved in anhydrous N,N-Dimethylformamide (DMF). Anhydrous potassium carbonate (K2CO3) ( 1 2eq) was added to this mixture and the reaction was stirred at room temperature for 4 hours. The solvent was then evaporated and the reaction mixture extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 6: 1 to obtain pure product as pale yellow powder with a yield of 54%. IR (Diamond, cm-1): 3092, 2923, 2851, 1774, 1712, 1632, 1599, 1566, 1515, 1478, 1366, 1276, 1231 , 1 180, 1 136, 1072; 1H-NMR (400 MHz, DMSO-d6): d 1 1.72 (s, 1H), 10.32 (s, 1 H), 8.65 (dd, .7= 4.64, 1.52 Hz, 1H), 8.22 (m, 1 H), 7.66 (dd, J= 7.88, 4.64 Hz, 1 H), 7.54 (t, J= 8.4 Hz, 1H), 6.66 (d, T = 8 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.51 (s, 2H), 3.84 (s, 3H), 13C-NMR (100 MHz, DMSO-d6): d 193.59, 166.09, 162.46, 160.68, 148.53, 146.54, 138.72, 136.83, 132.78, 126.44, 1 10.74, 109.79, 103.26, 67.04, 52.35. MS (ESI) m/z found 310.08 (M+Na)+, Calculated 301.2940 [M]+. The purity of the compound was checked by HPLC and was found to be 100% pure. |
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