Structure of 4591-55-3
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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. : | 4591-55-3 |
Formula : | C9H9NO4 |
M.W : | 195.17 |
SMILES Code : | O=C(C1=CC(C(OC)=O)=CN=C1)OC |
MDL No. : | MFCD00518827 |
InChI Key : | HDTNLHHNQYBOHJ-UHFFFAOYSA-N |
Pubchem ID : | 78339 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.8 |
TPSA ? Topological Polar Surface Area: Calculated from |
65.49 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.29 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.46 |
Solubility | 6.83 mg/ml ; 0.035 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.51 |
Solubility | 6.06 mg/ml ; 0.0311 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.18 |
Solubility | 1.28 mg/ml ; 0.00658 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 |
No |
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 |
-7.09 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) |
1.6 |
* 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 |
---|---|---|
With ammonia; | 3,5-pyridine-dicarboxamide is made from the action of NH3 on dimethyl- pyridine-3,5-dicarboxylate. This diamide is quaternarized with dimetyl sulfate and treated with a solution of cyanogen bromide in acetonitile in the presence of imidazole. The result is the imidazolium salt of N,N'-dicyano-1-methyl-pyridinium-3,5dicarboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sulfuric acid; for 18h;Reflux; | 2,6-Pyridine dicarboxylic acid (5.00 g, 29.92 mmol) was dissolved in MeOH (100 ml) and concentrated sulfuric acid (2 ml) was slowly added thereto and refluxed for 18 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the mixture was extracted with sodium bicarbonate and dichloromethane. The dichloromethane layer was washed with a saturated sodium chloride aqueous solution to obtain 5.5 g (94%) of compound l1 |
89% | With thionyl chloride; at 0℃; for 4h;Inert atmosphere; Reflux; | To a precooled (0 C) solution of pyridine-3,5-dicarboxylic acid (10.0 g, 59.8 mmol) in MeOH (100 mL) under N2 atmosphere was slowly added thionyl chloride (13 mL, 180 mmol). The resulting mixture was allowed to warm to room temperature then heated to reflux and stirred for 4 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The resulting white solid was taken up in H2O and the aqueous solution was cooled (0 C) then neutralized with 10 M aq. NaOH (white ppt formed). The heterogenous mixture was diluted with EtOAc and the bisphasic solution was stirred for 5 min. The layers were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the product as a white solid (10.4 g, 89% yield).1H NMR (500 MHz, Chloroform-d) d 9.35 (d, J = 2.1 Hz, 2H), 8.85 (t, J = 2.1 Hz, 1H), 3.98 (s, 6H); 13C NMR (126 MHz, CDCl3) d 165.05, 154.37, 138.19, 126.15, 52.85; IR (ATR) vmax 3074, 2966, 1713, 1445, 1312, 1256, 1108, 979, 745 cm-1; AMM (ESI) m/z 196.0600 [calc for C9H10NO4 (M+H)+ 196.0610]. |
82.0% | With sulfuric acid; at 50 - 65℃; | 4) To a mixture of pyridine-3,5-dicarboxylic acid (110 g, 0.66 mol) and methanol (660 mL) was added dropwise conc. sulfuric acid (226.0 g, 2.30 mol) at 50 C. or lower. Thereafter, the mixture was heated to 55-65 C. and stirred for 7 hr. The reaction mixture was allowed to cool to 40-50 C., and water (220 mL) was added. Furthermore, 5% aqueous ammonia (about 1.10 L) was added dropwise at 40-50 C. to adjust the mixture to pH 8.0-8.5. After stirring at 40-50 C. for 30 min, the mixture was cooled to 0-10 C. and stirred for 1 hr. The precipitated crystals were collected by filtration, washed successively with methanol-water (1:3, 165 mL) and water (440 mL), and dried under reduced pressure at 50 C. to give dimethyl pyridine-3,5-dicarbonate as a white crystalline powder (105.0 g, yield 82.0%). 1H-NMR (300 MHz, CDCl3) delta 4.00 (s, 6H), 8.87 (s, 1H), 9.37 (s, 2H). Anal. Calcd for C9H9NO4: C, 55.39; H, 4.65; N, 7.18; O, 32.79. Found: C, 55.42; H, 4.65; N, 7.16. |
With sulfuric acid; In methanol; at 120℃; for 2h;Microwave irradiation; | A: Pyridine-3,5-dicarboxylic acid dimethyl ester 3,5-Pyridinedicarboxylic acid (1.5 g, 63 mmol) and conc. H2SO4 (0.9 mL) in MeOH (15 mL) are heated in a microwave oven at 120 C. for 2 h. The solvent is evaporated to give a residue which is partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 196 [M+H]+ TLC, Rf (ethyl acetate/hexane 1:1)=0.56. | |
3,5-Pyridinedicarboxylic acid (1.5 g, 63 mmol) and conc. H2SO4 (0.9 mL) in MeOH (15 mL) are heated in a microwave oven at 120 C. for 2 h. The solvent is evaporated to give a residue with is partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 196 [M+H]+ TLC, Rf (ethyl acetate/hexane 1:1)=0.56. | ||
With thionyl chloride; at 10 - 35℃;Reflux; | Reference Example 1dimethyl pyridine-3,5-dicarboxylate Pyridine-3,5-dicarboxylic acid (25.5 g) was suspended in methanol (184 ml), and thionyl chloride (33.8 ml) was added dropwise at room temperature. The reaction mixture was stirred with heating under reflux for 3 hr, and the mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (27.9 g) as a powder.1H-NMR (CDCl3) delta 4.00 (6H, s), 8.88(1H, t), 9.37(2H, d) | |
Reference Example 33 dimethyl pyridine-3,5-dicarboxylate [Show Image] Pyridine-3,5-dicarboxylic acid (100 g) was suspended in methanol (1000 ml), and thionyl chloride (130 ml) was added dropwise at room temperature. The reaction mixture was stirred with heating to reflux for 3 hr. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 8 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (117 g) as a powder. 1H-NMR (CDCl3) delta 4.00 (6H, s), 8.88 (1H, t), 9.37 (2H, d). | ||
With thionyl chloride; at 60℃; for 12h; | Dimethyl pyridine-3,5-dicarboxylateTo a solution of pyridine-3,5-dicarboxylic acid (85.0 g, 508.62 mmol) in MeOH (1 L) was added SOCl2 (61.80 g, 519.46 mmol) dropwise. The reaction mixture was stirred and heated to 60 C for 12 hr. The reaction mixture was concentrated under vacuum to afford the title compound (120.00 g, crude) as a white solid. | |
3,5-Pyridinedicarboxylic acid (1.5g, 63 mmol) and cone. H2SO4 (0.9 mL) in MeOH (15 mL) are heated in a microwave oven at 120C for 2 h. The solvent is evaporated to give a residue with is partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 196 [M+H]+ TLC, Rf (ethyl acetate/hexane 1 :1 ) = 0.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With methanol; sodium tetrahydroborate; calcium chloride; at 50℃; for 5h; | Compound ll (3.00 g, 17.95 mmol) was added to a solution of Sodium borohydride (0.81 g, 21.54 mmol) and calcium chloride (3.16 g, 21.54 mmol) were placed in methanol (200 mL), followed by stirring at 50 C for 5 hours. After the reaction was completed, the solvent was completely removed under reduced pressure, and a saturated aqueous solution of potassium carbonate (100 ml) was added thereto. The mixture was stirred at 100 C for 1 hour and slowly cooled to room temperature. Filtered, and then purified by column chromatography (methanol: dichloromethane = 0.5: 9.5) to obtain 0.5 g (20%) of compound 12 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In methanol; at 20℃; for 16h; | A solution of potassium hydroxide (1.30 g, 23.2 mmol.) in MeOH (25 mL) was added carefully to a solution of <strong>[4591-55-3]pyridine-3,5-dicarboxylic acid dimethyl ester</strong> (4.53 g, 23.2 mmol.) in MeOH (50 mL). The reaction mixture was stirred at room temperature for 16 h. Diethyl ether (600 mL) was added, the reaction was filtered, and the precipitate was suspended in MeOH (20 mL). Concentrated HCl (75 mL) was added followed by ditheyl ether (120 mL). Filtration of the resulting mixture yielded the ester/acid as the hydrochloride salt (3.23 g, 14.9 mmol., 64%) which was used without further purification. The ester/acid (1.0 g, 4.61 mmol.) was suspended in toluene and thionyl chloride (1.33 mL, 18.44 mmol.) was added. The reaction was heated to reflux for 4 h, then concentrated without heating the reaction flask above 50 C. The crude acid chloride was dried in vacuo and used directly in the next step. Lithium tri-tertbutoxyaluminum hydride (1M, 3.58 mL, 3.58 mmol.) was added to a solution of acid chloride (841 mg, 3.58 mmol.) in THF (10 mL) at -78 C. The reaction was allowed to warm to room temperature, was stirred for 16 h, and was quenched with 1N HCl. The resulting solution was concentrated, was partitioned between ethyl acetate and saturated sodium bicarbonate was extracted with ethyl acetate (3×). The combined organic extracts were dried with MgSO4 and concentrated. The crude alcohol was purified by column chromatography (70% ethyl acetate/hexane) to yield pure product (200 mg, 1.20 mmol., 26%). 1H NMR (DMSO-d6): delta=8.97 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 5.48 (t, J=6 Hz, 1H), 4.62 (d, J=6 Hz, 3H), 3.89 (s, 3H). Calculated mass=165.1, [M+H]+=168. HPLC (method D) rt=3.4 min ( 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; | Step 2: Dimethyl pyridine-3,5-dicarboxylate 1 -oxide; Dimethyl pyridine-3,5-dicarboxyIate hydrochloride was treated with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM and the organic layer concentrated to afford the free base, dimethyl pyridine-355-dicarboxylate5 as a white solid. This solid (5.Og, 25.6 mmol) was dissolved in DCM (150 mL) and the solution cooled to 0 0C and treated with urea hydrogen peroxide (5.06 g, 53.8 mmol) followed by trifluoroacetic anhydride (7.2 mL, 51.2 mmol). The reaction mixture was stirred at room temperature overnight and was then treated with additional urea hydrogen peroxide (2.0 g, 21.3 mmol) and trifluoroacetic anhydride (3.1 mL, 22 mmol). The mixture was stirred at room temperature for an additional 3 hours and was then quenched by addition of aqueous sodium dithionite and stirred for 15 minutes. The mixture was then poured into 1 N aqueous HCl and extracted with DCM. The combined organic extracts were dried, filtered and concentrated. The residue was purified by SCG (0-5% MeOH/DCM) to give the title compound as a light yellow solid. 1H TSlMR (400 MHz, d6-DMSO, ppm): delta 8.73 (m, 2H)3 8.08 (m, IH), and 3.92 (s, 6H). ES MS: m/z = 212 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With urea hydrogen peroxide adduct; trifluoroacetic anhydride; In dichloromethane; at 20℃; | Step 2: Dimethyl pyridine-3,5-dicarboxylate 1 -oxide; Dimethyl pyridine-3,5-dicarboxyIate hydrochloride was treated with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM and the organic layer concentrated to afford the free base, dimethyl pyridine-355-dicarboxylate5 as a white solid. This solid (5.Og, 25.6 mmol) was dissolved in DCM (150 mL) and the solution cooled to 0 0C and treated with urea hydrogen peroxide (5.06 g, 53.8 mmol) followed by trifluoroacetic anhydride (7.2 mL, 51.2 mmol). The reaction mixture was stirred at room temperature overnight and was then treated with additional urea hydrogen peroxide (2.0 g, 21.3 mmol) and trifluoroacetic anhydride (3.1 mL, 22 mmol). The mixture was stirred at room temperature for an additional 3 hours and was then quenched by addition of aqueous sodium dithionite and stirred for 15 minutes. The mixture was then poured into 1 N aqueous HCl and extracted with DCM. The combined organic extracts were dried, filtered and concentrated. The residue was purified by SCG (0-5% MeOH/DCM) to give the title compound as a light yellow solid. 1H TSlMR (400 MHz, d6-DMSO, ppm): delta 8.73 (m, 2H)3 8.08 (m, IH), and 3.92 (s, 6H). ES MS: m/z = 212 (M+l). |
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