Structure of 64064-56-8
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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. : | 64064-56-8 |
Formula : | C8H8ClNO2 |
M.W : | 185.61 |
SMILES Code : | O=C(OCC)C1=NC=CC(Cl)=C1 |
MDL No. : | MFCD09702465 |
InChI Key : | MXEIFGRJRCYUDJ-UHFFFAOYSA-N |
Pubchem ID : | 13015359 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 45.33 |
TPSA ? Topological Polar Surface Area: Calculated from |
39.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.21 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.04 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.85 |
Solubility | 0.261 mg/ml ; 0.00141 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.16 |
Solubility | 0.13 mg/ml ; 0.000699 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.12 |
Solubility | 0.14 mg/ml ; 0.000753 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 |
-5.53 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) |
1.76 |
* 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 |
---|---|---|
89% | Stage #1: at 100℃; for 6 h; Stage #2: at 20℃; for 20 h; |
Step-1 : Ethyl-4-chloroypicolinate: A mixture of 4-chloropicolinic acid (20 g, 127 mmol) and thionyl chloride (200 mL) was heated to 100 °C and maintained for 6 h. The reaction was cooled to RT, and the excess of thionyl chloride was removed under vacuum. To the above obtained residue was then added ethanol (200 mL) at 0 °C drop-wise and the resulting mixture was stirred at RT for 20 h.The solvent was evaporated under vacuum and the residue was taken in ethyl acetate (1000 mL), washed with water (2x500 mL), saturated sodium bicarbonate solution (2x500 mL), brine (500 mL), dried (Na2S04) and filtered. The filtrate was evaporated to yield 21.0 g (89percent) the desired product as a semi solid. XHNMR (400 MHz, DMSO) δ 8.66 (d, = 5.0 Hz, 1Η), 8.13 (d, = 2.0Hz, 1Η), 7.49 (dd, = 5.0 &2.0HZ 1Η), 4.47 (q, = 7.0 Hz, 2Η), 1.46 (t, = 7.0 Hz, 3H); GC-MS (m/z) 185, 187 [(M)+, CI35' 37]. |
85% | Stage #1: at 100℃; for 6 h; Stage #2: at 0 - 20℃; for 8 h; |
Step 1: Preparation of ethyl 4-chloropicolinate To 4-chloropicolinic acid (1.0 g, 6.35 mmol) was added SOCl2 (10 mL) at RT. The reaction mixture was heated at 100° C. for 6 h then concentrated to remove excess SOCl2. To the resulting residue was added EtOH (10 mL) dropwise at 0° C. and the reaction mixture was stirred at RT for 8 h. After completion, the reaction mixture was concentrated and diluted with EtOAc (50 mL). The organic phase was washed with water (2*25 mL), saturated sodium bicarbonate solution (2*25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated to afford ethyl 4-chloropicolinate (1.0 g, 85percent). 1H NMR (400 MHz, DMSO-d6) δ 8.71-8.72 (d, J=8.8 Hz, 1H), 8.09 (s, 1H), 7.84-7.85 (m, 1H), 4.34-4.39 (q, J=7.2 Hz, 2H), 1.33-1.36 (t, 3H). |
83.6% | Stage #1: at 100℃; for 6 h; Inert atmosphere Stage #2: at 20℃; for 25.5 h; Cooling with ice Stage #3: With sodium hydrogencarbonate In water |
(Reference Example A-1) Ethyl 4-chloropyridine-2-carboxylate A mixture of 4-chloropyridine-2-carboxylic acid (39.4g) and thionyl chloride (64 ml) was heated and stirred at 100 °C under a nitrogen atmosphere for 6 hr. The reaction mixture was allowed to cool down to room temperature. This was concentrated under reduced pressure and distilled azeotropically with toluene. The resultant residue was gradually added to ethanol while stirring in an ice bath. The reaction mixture was stirred at room temperature for 25.5 hr. The reaction mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the titled compound as a brown oil (38.8 g, 83.6 percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 1.46 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 7.49 (1H, dd, J = 2.0, 5.2 Hz), 8.15 (1H, d, J = 2.0 Hz), 8.67 (1H, d, J = 5.2 Hz). |
55.7% | for 2 h; Inert atmosphere; Reflux | To a stirred solution of 4-chloropicolinic acid (15.0 g, 95.20 mmol, 1.0 equiv) in ethanol (225.0 mL, 15.0 vol. equiv) was added sulfuric acid (34.4 mL, 619 mmol, 6.5 equiv). (0376) The resulting mixture was stirred for 2 h at reflux. The completion of reaction was monitored by TLC. The solvent was removed under reduced pressure. The residue was treated with DM water (0377) (500.0 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extract was washed with brine (200.0 mL), saturated solution of sodium bicarbonate (500.0 mL), dried over Na2S04 and concentrated under vacuum to afford titled compound (9.84 g, 55.7percent) as a light brown oily mass. MR (300 MHz, OMSO-d6) δ 8.70-8.69 (d, 1H), 8.08-8.07 (d, 1H), 7.83-7.81 (m, 1H), 4.39-4.31 (m, 2H), 1.35-1.29 (m, 3H). MS (ES+): 186.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.6% | Stage #1: at 100℃; for 6 h; Stage #2: at 0 - 20℃; for 25.5 h; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate |
(Production Example 15) Ethyl 4-chloropyridine-2-carboxylate A mixture of 4-chloropyridine-2-carboxylic acid (39.4g) and thionyl chloride (64 ml) was heated and stirred at 100 °C under a nitrogen atmosphere for 6 hr. The reaction mixture was allowed to cool down to room temperature. This was concentrated under reduced pressure and distilled azeotropically with toluene. The resultant residue was gradually added to ethanol while stirring in an ice bath. The reaction mixture was stirred at room temperature for 25.5 hr. The reaction mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the titled compound as a brown oil (38.8 g, 83.6 percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 1.46 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 7.49 (1H, dd, J = 2.0, 5.2 Hz), 8.15 (1H, d, J = 2.0 Hz), 8.67 (1H, d, J = 5.2 Hz). |
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