Structure of 785777-87-9
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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. : | 785777-87-9 |
Formula : | C5H2BrF3N2 |
M.W : | 226.98 |
SMILES Code : | BrC1=NC=CC(=N1)C(F)(F)F |
MDL No. : | MFCD09802248 |
InChI Key : | RHCZXIKKGYOYQZ-UHFFFAOYSA-N |
Pubchem ID : | 11436086 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 34.73 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.78 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.8 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.41 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.65 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.3 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.94 |
Solubility | 0.261 mg/ml ; 0.00115 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.32 |
Solubility | 1.08 mg/ml ; 0.00475 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.4 |
Solubility | 0.0908 mg/ml ; 0.0004 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 |
-6.16 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 |
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) |
1.83 |
* 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 |
---|---|---|
29.8% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Reflux; | A mixture of 4,5 Bis(diphenyl- phosphino)-9,9-dimethylxanthene[xanthopos](8.6 mg, 0.01488 mmol) and Tris(dibenzylideneacetone)di- palladium(0)[Pd2(dba)3](6.81 mg, 0.00744 mmol) in dry l ,4-dioxane(5 ml)was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. 5-Bromo pyrimidine (19.7 mg, 0.1247 mmol), 3-(l ,4-Dioxa-8-aza- spiro[4.5]dec-8-yl)-4-methyl-phenylamine (30.96 mg, 0.1247 mmol) and dry cesium carbonate (100 mg,0.31 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated under vacuum. Further purification by silica gel chromatography using 5-10% ethyl acetate/hexane as eluent [3-(l ,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-phenyl]-(4- trifluoromethyl-pyrimidin-2-yl)-amine [30] as a pale yellow solid [Yield:4.05 mg, 29.8%] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 85℃; for 3h;Inert atmosphere; | General procedure: To a solution of 2-ethynylquinoline 9 (50 mg, 0.33 mmol) in triethylamine (0.4 mL) was added PdCl2(PPh3)2 (12 mg, 0.02 mmol), copper(I) iodide 98% (6 mg, 0.03 mmol) and 2- bromo-3-trifluoromethylpyridine (110 mg, 0.5 mmol). After the reaction was stirred at 85 C for 3 h, it was allowed to cool to room temperature and filtered through a pad of Celite by the aid of EtOAc. The filtrate was treated with water and extracted with EtOAc (3 x 10 mL). The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 2-((3-(trifluoromethyl)pyridin-2-yl)ethynyl) quinoline 6a (48 mg, 49%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine; In acetonitrile; at 20 - 100℃;Inert atmosphere; | [0607] Synthesis of methyl 4-(trifluoromethyl) pyrimidine-2-carboxylate: [0608] To a stirred solution of 2-bromo-4-(trifluoromethyl) pyrimidine (800 mg, 3.52 mmol) in MeOH: CH3CN (4: 1, 5 mL) under argon atmosphere was added Pd(dppf)2Cl2 (503 mg, 0.70 mmol), triethyl amine (1.0 mL, 7.04 mmol) at RT; heated to 100 C and stirred for 16 h under CO pressure. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ Hexanes to afford methyl 4-(trifluoromethyl) pyrimidine-2-carboxylate (300 mg, 41%) as Light pink solid. [0609] 1H-NMR (CDCI3, 500 MHz): delta 9.20 (d, 1H), 7.82 (d, 1H), 4.10 (s, 3H); LC-MS: 96.04%; 207 (M++l); (column; X-bridge C-18, (50 3.0 mm, 3.5 mu); RT 2.48 min. 0.05% TFA (aq.): ACN; 0.8 mL/min); TLC: 50% EtOAc/ Hexanes (R 0.3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N,N-dimethyl-aniline; phosphorus(V) oxybromide; In toluene; at 20 - 100℃;Inert atmosphere; | [0604] Synthesis of 2-bromo-4-(trifluoromethyl) pyrimidine:[0605] To a stirred solution of 6-(trifluoromethyl)-l, 2-dihydropyrimidin-2-ol (2 g, 12.19 mmol) in toluene (40 mL) under argon atmosphere were added phosphorous oxybromide (5.24 g, 18.20 mmol), N, N-dimethyl aniline (156 mg, 1.20 mmol) at RT; heated to 100 C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with hexanes (2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulphate, and concentrated in vacuo to obtain 2- bromo-4-(trifluoromethyl) pyrimidine (800 mg, 29%) as light yellow oil. [0606] 1H-NMR (CDCls, 500 MHz): delta 8.82 (d, 1H), 7.64 (d, 1H); TLC: 10% EtOAc/ Hexanes (R 0.8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
230 mg | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 17h; | To a stirred solution of (1 S*,2S*,3S*)-methyl-2-(4-bromophenyl)-1 - f(1 S*,2S*,3S*)-Methyl-1-fluoro-2-phenyl-3-(4-(4-(trifluoromethyl)pyrimidin-2- yl)phenyl)cyclopropanecarboxylate luoro-3-phenylcyclopropane carboxylate (470 mg, 1 .47 mmol) in dioxane (1 0 mL) was added bis-pinacolato diboron (412 mg, 1 .62 mmol), Pd(dppf)CI2 (120 mg, 0.15mmol) and potassium acetate (720 mg, 7.35 mmol). The mixture was degassed with nitrogen and heated to 100 C for 2 h. The reaction mixture was diluted with H20 (20 ml_) and extracted into DCM (2 x 20 ml_). The organic phase was concentrated and the crude used in the next step. [00199] A solution of (1 S*,2S* 3S*)-methyl-1 -fluoro-2-phenyl-3-(4-(4 4 5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (538 mg, 1 .47 mmol), Pd(dppf)2CI2 (169 mg, 0.1 5 mmol), <strong>[785777-87-9]2-bromo-4-(trifluoromethyl)pyrimidine</strong> (367 mg, 1 .62 mmol), and 2 M Na2C03 (aq) (2.2 ml_, 4.41 mmol) in dioxane (1 5 ml_) was stirred at 100 C for 17 h. The reaction mixture was diluted with water and extracted into DCM. The organic phase was passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution /'- hex to 30% EtOAc in /-hex) afforded the target compound (230 mg, 41 %). LCMS (ES+) 417 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With ammonium peroxydisulfate; silver nitrate; In water; acetonitrile; at 60℃; for 2h; | General procedure: Toa vial was added pyrimidine (0.42-0.65 mmol, 1.0 equiv.) (if solid), carboxylic acid (3.0 equiv.) (if solid), silver nitrate (4.0 equiv.) and ammonium persulfate (5.0equiv.). Acetonitrile (5 mL) and water(5 mL) were then added (followed by the pyrimidine and/or carboxylic acid if liquids) and the vial was capped and heated to 60 C for 2 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was quenched by the addition of concentrated ammonium hydroxide (0.8 mL) and water (3.2 mL), diluted with brine and filtered through Celite. The filtrate was then extracted with DCM (3 x10 mL) and the organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto silica and purified by flash chromatography (0-50% EtOAc in heptane) to afford the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Arctigenin (50mg, 0.134mmol) dissolved in 2ml of dry N,N-dimethylformamide (DMF) was added potassium carbonate (37mg, 0.268mmol) and stirred for 10min at room temperature. To this was added <strong>[785777-87-9]2-bromo-4-trifluoromethylpyrimidine</strong> (37mg, 0.161mmol) and was stirred at 120C for 8h. 10mL of ice water was added after cooling to room temperature and solids precipitated. It was filtered and the filter cake was washed with 5% potassium bisulfate solution. After recrystallization from methanol and dried in vacuo, it gave a 64mg white solid, yield 92%. |
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