Structure of 1158786-59-4
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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. : | 1158786-59-4 |
Formula : | C6H7BrN2O |
M.W : | 203.04 |
SMILES Code : | NC1=NC(Br)=CC(OC)=C1 |
MDL No. : | MFCD20040422 |
InChI Key : | FHWXKDVDUIKUFF-UHFFFAOYSA-N |
Pubchem ID : | 71464228 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.83 |
TPSA ? Topological Polar Surface Area: Calculated from |
48.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.71 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.44 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.72 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.31 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.34 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.42 |
Solubility | 0.769 mg/ml ; 0.00379 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.12 |
Solubility | 1.54 mg/ml ; 0.00761 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.65 |
Solubility | 0.453 mg/ml ; 0.00223 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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.47 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 |
0.0 |
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) |
2.21 |
* 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; at 140℃; for 4h; | A solution of 2.00 g <strong>[117873-72-0]2,6-dibromo-4-methoxy-pyridine</strong> in 80 g liquid ammonia under was heated in an autoclave to 140 C. for 4 h. The reaction was cooled to room, evaporated and the residue was purified by silica column chromatography to yield 0.457 g of the title compound as white solid. MS (ISP) M+H+=203.2 205.5; 118b) 6-Bromo-4-methoxy-pyridin-2-ylamineA solution of 2.00 g <strong>[117873-72-0]2,6-dibromo-4-methoxy-pyridine</strong> in 80 g liquid ammonia under was heated in an autoclave to 140 C. for 4 h. The reaction was cooled to room, evaporated and the residue was purified by silica column chromatography to yield 0.457 g of the title compound as white solid. MS (ISP) M+H+=203.2 205.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; at 130℃; under 52505.3 Torr; for 20.0h; | To a solution of 0.124 g <strong>[1158786-59-4]6-bromo-4-methoxy-pyridin-2-ylamine</strong> in 5 ml methanol was added 0.093 g triethylamine and 0.020 g PdCl2dppf.CH2Cl2 and the mixture was stirred under an atmosphere of 70 bar of carbon monoxide at 130 C. for 20 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with heptane: ethyl acetate mixtures to yield the title compound as reddish solid MS (ISP) M+H+=183.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 220℃; for 0.1h;Microwave irradiation; | To a solution of 0.40 g <strong>[1158786-59-4]6-bromo-4-methoxy-pyridin-2-ylamine</strong> in 8.0 ml dimethylformamide was added 0.265 g copper(I) cyanide and the mixture was heated to 220 C. under microwave irradiation for 6 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and washed with water and brine, dried over magnesium sulfate dihydrate and purified by chromatography on silica gel with heptane : ethyl acetate to yield 0.086 g of the title compound as greenish solid MS (ISP) M+H+=183.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 120 - 140℃; for 3.0h;Microwave irradiation; | 6-Bromo-4-methoxy-iyridi n-2-ylami neA solution of 6-bromo-4-chloro-pyridin-2-ylamine (200 mg, 0.964 mmol) and sodium methanolate (0.5 M in MeOH, 12.5 ml, 6.25 mmol) was subjected to microwave irradiation at 120C for2 h, then at 140C for 1 h. Et20 and water were added, the layers were separated and the aqueous layer was extracted with Et20 (x2). The combined organic extracts were dried (Na2504), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5pm, 3OxlOOmm, gradient: 0-0.5 mm 5% CH3CN in H20, Flow:5mL/min; 0.5-18.5 mm 5 to 100% CH3CN in H20, Flow: 4OmL/min; 18.5-20 mm 100% CH3CN, Flow: 4OmL/min, CH3CN and H20 containing 0.1% TFA). The pure fractions were combined, neutralized with a sat. aq. solution of Na2CO3 and extracted with CH2CI2 (x2). The combined organic extracts were dried (Na2504), filtered and concentrated to give the title compound as white solid. R, TLC (EtOAc) = 0.75; MS (UPLC-MS): 203.0/205.0 [M+H]+; tR (HPLC conditions g): 0.76 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To an ice cold solution of (2S,4R)- 1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.1 mmole) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.15 mL, 1.1 equiv) was added drop-wise with stirring. The stirring was continued for 3 hours at the same temperature. Then <strong>[1158786-59-4]6-bromo-4-methoxypyridin-2-amine</strong> (239 mg, 1.0 equiv) was added, followed by 0.50 mL (3 equiv) Hunig's base. The cooling bath was removed and the reaction mixture was stirred at room temperature for overnight. The solvent was co-evaporated with 5 mL of MeOH, and the residue was purified by ISCO (eluted with ethyl acetate in hexane, gradient) to obtain 436 mg (97%) of tert-butyl-(2S,4R)-2-((6-bromo-4-methoxypyridine-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate as clear oil. | |
Step 1: ferf-Butyl (2S,4R)-2-((6-bromo-4-methoxypyridin-2-yl)carbamoyl)-4- fluoropyrrolidine-l-carboxylate (211) [0698] To an ice-cold solution of (2S,4R)~l-(/m-butoxycarbonyl)-4-fluoropyrro]idine-2- carboxylic acid (1 equiv) in DCM (10 vol) was added l-chloro-N,N,2-trimethyl-l-propenylamine ( 1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature, and then <strong>[1158786-59-4]6-bromo-4-methoxypyridin-2-amine</strong> (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM. The organic layer was washed successively with an aqueous solution of NaHCCb, water and brine, then dried over Na SC and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (DCM/EtOAc) to give compound 211. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | With pyridine; trichlorophosphate; In dichloromethane; at 0 - 20℃; for 2.0h;Inert atmosphere; | To a mixture of compound 91- 1 (40 mg, 0.17 mmol) and compound 113-1 (6-Bromo-4-methoxy-pyridin-2-ylamine, 34 mg, 0.17 mmol) in DCM (5 mL) was added pyridine (67 mg, 0.85 mmol) followed by phosphoryl chloride (39 mg, 0.26 mmol) at 0 C, and the mixture was stirred at room temperature under N2 atmosphere for 2 hrs. The mixture was poured into ice water and extracted with DCM twice. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (PE: EtOAc= 30: 1 to 13: 1) to give compound 113-2 (63 mg, yield 87.2%) as a light oil. LC/MS (ESI) m/z: 426/428 (M+H)+. |