Structure of 313545-34-5
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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. : | 313545-34-5 |
Formula : | C7H5BF4O2 |
M.W : | 207.92 |
SMILES Code : | OB(O)C1=C(F)C=CC=C1C(F)(F)F |
MDL No. : | MFCD07781239 |
InChI Key : | TXBRJTKFAYXKMV-UHFFFAOYSA-N |
Pubchem ID : | 16217168 |
GHS Pictogram: |
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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 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 41.23 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.8 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.29 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.45 |
Solubility | 0.73 mg/ml ; 0.00351 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.28 |
Solubility | 1.09 mg/ml ; 0.00526 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.46 |
Solubility | 0.721 mg/ml ; 0.00347 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 |
-6.28 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) |
2.0 |
* 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 |
---|---|---|
30% | With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,2-dimethoxyethane; at 95℃; for 18.0h; | A solution of 5-bromo-2-[2-(4,4-difluoro-cyclohexyl)-vinyl]-1 H- benzimidazole (0.030 g, 0.088 mmol, prepared as in STEP F above), 2-fluoro- 6-thfluoromethylphenyl boronic acid (0.040 g, 0.19 mmol), 1 ,1-bis(di-t-butyl- phosphinoferrocene palladium chloride (0.012 g, 0.018 mmol) in dimethoxyethane (2 ml_) and 2M sodium carbonate (1.0 ml_, 2 mmol) was stirred at 95C for 18 h. The resulting solution was cooled to room temperature and poured into a solution of ethyl acetate and water (1 :1 , 50 ml_). The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica using ethyl acetate/hexanes 3:7 as eluent to yield 2-[2-(4,4-difluoro-cyclohexyl)-vinyl]-5-(2- fluoro-6-thfluoromethyl-phenyl)-1 H-benzimidazole.1H-NMR (400 MHz, DMSO d6) delta (ppm) 7.56-7.64 (m, 2H) 7.44-7.52 (m, 2H) 7.32-7.38 (m, 1 H) 7.14-7.18 (m, 1 H) 6.68-6.78 (m, 1 H) 6.47-6.56 (m, 1 H) 2.32-2.40 (m, 1 H) 2.10-2.20 (m, 2H) 1.80-1.96 (m, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22Hi8F6N2: 407.1 (M + H), Found 407.3 and 2- [2-(4-fluoro-cyclohex-3-enyl)-vinyl]-5-(2-thfluoromethyl-phenyl)-1 H- benzimidazole (0.50 g, 30%). 1H-NMR (400 MHz, CDCI3) delta (ppm): 7.70-7.76 (m, 1 H) 7.40-7.56 (m, 4H) 7.38-7.40 (m, 1 H) 7.16-7.22 (m, 1 H) 6.74-6.82 (m, 1 H) 6.48-6.56 (m, 1 H) 5.14-5.23 (m, 1 H) 2.44-2.56 (m, 1 H) 2.16-2.30 (m, 3H) 1.90-2.04 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22Hi8F4N2: 387.2 (M + H), Found 387.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 278 5-amino-N-(5-((2S,5R,6R)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)thiazole-4-carboxamide 278 Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with <strong>[313545-34-5](2-fluoro-6-(trifluoromethyl)phenyl)boronic acid</strong> gave 278. 1H NMR (400 MHz, DMSO-d6) delta 9.19 (s, 1H), 7.85-7.69 (m, 4H), 7.47 (s, 2H), 5.03-4.74 (m, 2H), 4.00-3.86 (m, 2H), 3.74 (s, 3H), 2.13 (ddt, J=14.4, 6.1, 2.8 Hz, 1H), 2.01-1.61 (m, 3H). LCMS (ES+) m/z 517 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 331 5-amino-N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)thiazole-4-carboxamide 331 Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with <strong>[313545-34-5](2-fluoro-6-(trifluoromethyl)phenyl)boronic acid</strong> gave 331. 1H NMR (400 MHz, DMSO-d6) delta 9.18 (s, 1H), 7.81-7.68 (m, 3H), 7.42 (s, 2H), 4.78-4.68 (m, 1H), 4.45-4.26 (m, 1H), 4.14-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.88-1.76 (m, 1H), 1.76-1.65 (m, 2H). LCMS (ES+) m/z 517 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 279 5-amino-N-(5-((2S,5R,6R)-5-amino-6-methoxyoxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)thiazole-4-carboxamide 279 Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with <strong>[313545-34-5](2-fluoro-6-(trifluoromethyl)phenyl)boronic acid</strong> gave 279. 1H NMR (400 MHz, DMSO-d6) delta 9.41 (s, 1H), 7.90 (s, 1H), 7.84-7.68 (m, 3H), 7.47 (s, 2H), 5.03 (t, J=5.2 Hz, 1H), 3.71-3.52 (m, 5H), 3.29-3.13 (m, 2H), 2.72 (s, 3H), 2.48-2.40 (m, 1H), 1.63-1.47 (m, 5H). LCMS (ES+) m/z 529 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 4.0h; | A mixture of tert-butyl 4- (( (trifluoromethyl) sulfonyl) oxy) - 5, 6-dihydropyridine- 1 (2H) -carboxylate (2, 1.20 g, 3.62 mmol) , and 6- fluoro- (2-trifluoromethyl) phenyl boronic acid (0.528 g, 2.53 mmol), Pd(PPh3)4 (0.292 g, 0.253 mmol), and 2 M Na2C03 (20 mL) in DME (30 mL) was heated to 80 C for 4 h. The mixture cooled to ambient temperature, was diluted with EtOAc (50 mL) , and filtered through a Celite pad. The organic filtrate was washed with saturated sodium bicarbonate solution (2 chi 30 mL) , H2O (30 ml) , and concentrated to under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 0% to 10% EtOAc in hexanes) to provide tert-butyl 4- (2-fluoro-6- (trifluoromethyl) phenyl) -5, 6-dihydropyridine-l (2H) -carboxylate (21) as a clear oil (0.479 g, 39%) : XH NMR (300 MHz, DMSO-d6) delta 7.66-7.51 (m, 3H) , 5.68 (s, 1H) , 4.04-3.82 (m, 2H) , 3.67-3.39 (m, 2H) , 2.39-2.02 (m, 2H) , 1.43 (s, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With [Rh(OH)(cod)]2; In 1,4-dioxane; water; at 80 - 100℃; for 2.0h; | General procedure: To a solution of 34 15 (260mg, 0.598mmol) in 117 dioxane/114 H2O (10/1) (3 ml) were added 118 2-cyanophenylboronic acid (172mg, 1.17mmol) and 119 hydroxy(1,5-cyclooctadiene)rhodium (I) dimer (27.3mg, 0.060mmol), and the mixture was stirred at 80C for 2h. The reaction mixture was diluted with AcOEt, and successively washed with sat. KHSO4 aq., sat. NaHCO3 aq., and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent A: hexane/AcOEt (1/1), eluent B: MeOH; A/B=95/5 to 90/10) to give the 120 title compound as a pale yellow solid (321mg, quant.). |
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