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CAS No. : | 18063-02-0 |
Formula : | C7H3ClF2O |
M.W : | 176.55 |
SMILES Code : | O=C(Cl)C1=C(F)C=CC=C1F |
MDL No. : | MFCD00000659 |
InChI Key : | QRHUZEVERIHEPT-UHFFFAOYSA-N |
Pubchem ID : | 87438 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8(3) |
UN#: | 2920 |
Packing Group: | Ⅱ |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.7 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.18 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.71 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.89 |
Solubility | 0.227 mg/ml ; 0.00128 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.58 |
Solubility | 0.468 mg/ml ; 0.00265 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.52 |
Solubility | 0.0536 mg/ml ; 0.000303 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 |
-5.55 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 |
2.0 |
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) |
1.28 |
* 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 triethylamine; In tetrahydrofuran; | EXAMPLE 1 STR6 At 0 to 5 C., 2,6-difluorobenzoyl chloride (1.77 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), tetrahydrofuran (30 ml) and triethylamine (1.1 g). The reaction mixture was stirred at 30 to 40 C. for 5 hours, and then tetrahydrofuran was evaporated. The solid residue was washed with water and recrystallized from ethanol to give the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide (2.8 g). mp. 256-257 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In tetrahydrofuran; pyridine; at 20.0℃; for 3.0h; | 2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 ml_ of 1 :1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; at 20℃; for 1.5h; | Step C: Methyl 3-[(2,6-difluorophenyl)carbonyl]amino}-4-fluorobenzoate; To a solution of <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (5.5 g, 33 mmol) in DCM (100 ml_) was added TEA (6.8 ml_, 49 mmol) and 2,6-difluorobenzoyl chloride (4.3 ml_, 34 mmol). After 90 min at rt, the reaction mixture was washed with H2O and concentrated to a brown oil. The product was purified by column chromatography (eluting with 30-60percent EtOAc /hexanes) to generate the desired product in 52percent yield (5.37 g, 17 mmol). MS (ESI) m/z = 310 [M+Hf . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 20℃;Cooling with ice; Inert atmosphere; | 1/-/-Pyrazol-4-amine (for a preparation see intermediate 1 ; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System 1): MH+= 224, tRET = 2.08 min. | |
Intermediate 6: 2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide.1H-Pyrazol-4-amine (for a preparation see intermediate 5; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System1): MH+= 224, tRET = 2.08 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; In dichloromethane; at 20℃; | To a (0 C) cooled and stirred solution of 2,6-difluorobenzoyl chloride (357 2.83 mmol) in DCM (5 mL) was added <strong>[156118-16-0]6-bromo-4-methylpyridin-3-amine</strong> (583 mg, 3.12 mmol) followed by the addition of pyridine (344 mu, 4.25 mmol). The resulting mixture was then stirred at room temperature overnight. Water (5 mL) was added to the above mixture and then extracted with DCM (3x10 mL). The combined organic layers were washed with 10% aq.HCl (10 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum to afford 650mg (70%) of the title compound as a white solid. XHNMR (400 MHz, DMSO- d6) delta 10.56 (s, 1H, D20 exchangeable), 8.41 (s, 1H), 7.66 (s, 1H), 7.65-7.58 (m, 1H), 7.27 (t, = 7.0Hz, 2Eta), 2.27 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH)+, Br79' 81]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With pyridine; In dichloromethane; at 0 - 20℃; | To a (0 C) cooled and stirred solution of 2,6-difluorobenzoyl chloride (500mg, 2.83 mmol) in DCM (10 mL) was added 4-bromo-3-methylaniline (632 mg, 3.40 mmol) followed by the addition of pyridine (275 mu, 3.40 mmol). The resulting mixture was warmed to room temperature and stirred overnight. Water (10 mL) was then added to the above mixture and extracted with DCM (3x20 mL). The combined organic layers were washed with 10% aq.HCl (lOmL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum to afford 250mg (28%) of the title compound as a white solid. XHNMR (400 MHz, DMSO-ife) delta 11.44 (s, 1H, D20 exchangeable), 8.53 (s, 1H), 7.63 (s, 1H), 7.61-7.54 (m, 1H), 7.21 (t, = 7.0Hz, 2Eta), 2.41 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH) + Br79' 81] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With 3-dimethylaminoacrolein; In pyridine; dichloromethane; at 20℃; for 0.5h; | Part II- Synthesis of 2,6-Difluoro-N-[1,8]naphthyridin-2-ylbenzamide; [1,8]-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was dissolved in dichloromethane(2 mL) and pyridine (0.10 mL, 1.2 mmol). 2,6-Difluorobenzoyl chloride (0.068 mL, 0.76mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture was diluted with ethyl acetate and washed with water followed bybrine. The resulting organic solution was purified by column chromatography (EtOAc/hexanes) to give 2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide. Yield 35 mg (21 %).LCMS (ESI): calc. C1sH9FzN30 = 285; obs. M+H = 286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | To a suspension of 2-am ino-N-benzyloxy-acetam ide 2,2,2-trifluoroacetic acid(Intermediate Ab, 59 mg, 0.2 mmol) and <strong>[118289-17-1]2-bromopyridine-4-carboxaldehyde</strong> (37 mg, 0.2 mmol)in acetonitrile (1 mL) was added N,N-diisopropylethylamine (33.0 iL, 0.2 mmol). The whitesuspension was heated for 2 h at 50 °G. The mixture was cooled on an ice-water bath to < 5 00 and N,N-diisopropylethylamine (33.0 iL, 0.2 mmcl) was added. Subsequently a solution of 2,6- difluorobenzoyl chloride (30 iL, 0.24 mmol) in acetonitrile (0.1 mL) was added dropwise keeping the temperature below 5 00. The temperature of the reaction mixture was allowed to come to room temperature. The mixture was partially diluted with ethyl acetate (5 mL) and water (3 mL)was added slowly. The resulting phases were separated and the water layer was extracted with ethyl acetate (3 mL). The combined organic layers were washed with water (5 mL), 5percent NaHCO3- solution (5 mL), water (5 mL) and brine (5 mL), filtered over an PE filter filled with Na2504 and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate = 100/0 to 0/100 v/vpercent) to afford the title compound(63 mg, 64percent) as a white solid. |
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