Structure of 156150-67-3
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CAS No. : | 156150-67-3 |
Formula : | C6H3ClFI |
M.W : | 256.44 |
SMILES Code : | IC1=CC=C(F)C(Cl)=C1 |
MDL No. : | MFCD00042210 |
InChI Key : | OMASDGWBVAVFQZ-UHFFFAOYSA-N |
Pubchem ID : | 2724605 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 44.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.3 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.5 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.22 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.89 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.43 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.0 |
Solubility | 0.0255 mg/ml ; 0.0000995 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.98 |
Solubility | 0.271 mg/ml ; 0.00106 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.25 |
Solubility | 0.0146 mg/ml ; 0.0000568 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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 |
-5.52 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
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 |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.27 |
* 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 |
---|---|---|
25% | With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 18h; | EXAMPLE 42-(2-Chloro-4-iodorhohenylaminoV5.5-dimethyl-8-oxo-5,6J.8-tetrahvdro-4H-thienor2,3- clazepine-S-carboxylic acid ethyl ester; Caesium carbonate (2.77 g, 8.51 mmol) and 2-chloro-4-iodo-l-fluorobenzene (2.18 g, 8.51 mmol) were added to a solution of Intermediate 6 (2.0 g, 7.09 mmol) in DMF (20 mL) and heated at 650C for 18 h. Brine (100 mL) was added to the reaction and the mixture extracted with DCM (3 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residual DMF was azeotroped with heptane. The crude product was purified by chromatography (silica, 0-30% EtOAc in DCM) to give the title compound as a cream solid (916 mg, 25%). deltaeta (DMSO-d6) 10.60 (IH, s), 8.01 (IH, t, J 5.0 Hz), 7.95 (IH, d, J2.0 Hz), 7.78 (IH, dd, J 8.6, 2.0 Hz), 7.54 (IH, d, J 8.6 Hz), 4.32 (2H, q, J 7.1 Hz), 2.91 (2H, s), 2.85 (2H, d, J 5.2 Hz), 1.33 (3H, t, J 7.1 Hz), 0.99 (6H, s). LCMS (ES+) RT 3.81 minutes, 519 (M+H)+. |
25% | With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 18h; | INTERMEDIATE 4; 2-(2-ChloiO-4-iodophenylamino)-5,5-dimethyl-8-oxo-5,6.7.8-tetrahydro-4H-thieno["2,3- c"|azepine-3-carboxylic acid ethyl ester Caesium carbonate (2.77 g, 8.51 mmol) and 2-chloro-4-iodo-l-fluorobenzene(2.18 g, 8.51 mmol) were added to a solution of 2-amino-5,5-dimethyl-8-oxo-5, 6,7,8- tetrahydro-4i7-thieno[2,3-c]azepine-3-carboxylic acid ethyl ester (WO 2007/141504, Intermediate 20) (2.0 g, 7.09 mmol) in DMF (20 mL) and heated at 650C for 18 h. Brine (100 mL) was added to the reaction and the mixture extracted with DCM (3 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residual DMF was azeotroped with heptane. The crude product was purified by chromatography (silica, 0-30% EtOAc in DCM) to give the title compound as a cream solid (916 mg, 25%). deltaH (DMSO-d6) 10.60 (IH, s), 8.01 (IH, t, J 5.0 Hz), 7.95 (IH, d, J <n="32"/>2.0 Hz), 7.78 (IH, dd, J8.6, 2.0 Hz), 7.54 (IH, d, J8.6 Hz), 4.32 (2H, q, J7.1 Hz), 2.91 (2H, s), 2.85 (2H, d, J5.2 Hz), 1.33 (3H, t, J7.1 Hz), 0.99 (6H, s). LCMS (ES+) RT 3.81 minutes, 519 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(l) iodide;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 20℃; for 21h; | To the stannane (0.39 g, 0.95 mmol) in DMF (10 ml) was added the 2-chloro-4-fluoroiodobenzene (0.73 g, 2.86 mmol), Cul (0.19 g, 1.05 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.095 mmol). The reaction was stirred at RT under N2 for 21 h. The reaction mixture was added to Et2O and the heterogeneous solution filtered through a bed of celite, washing with EtOAc. The filtrate was washed with water and brine and dried (MgSO4). Filtration and evaporation of the solvent in vacuo afforded a residue that was preadsorbed on silica gel. Purification by silica gel chromatography (4% EtOAc/hexane) yielded the arylacrylate (0.19 g, 78%), which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 60℃; for 5h; | Add bis (triphenylphosphine) palladium (II) dichloride (64 mg, 0. 091 mmol), copper (I) iodide (35 mg, 0. 18 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1. 8 mmol) to a solution of 2-chloro-1-fluoro- 4-iodobenzene (560 mg, 2. 2 mmol) in triethylamine (3. 8 mL, 27 mmol) and heat at 60 C for 5 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 50 : 50 to 100 : 0 dichloromethane : hexanes, followed by a second silica gel chromatography, eluting with 100 : 0 to 90 : 10 hexanes : ethyl acetate, to give the title compound as a white solid (340 mg, 70%). 1H NMR (300 MHz, CDCl3) 8 7. 11-7. 19 (t, J = 8. 6 Hz, 1H), 7. 38-7. 46 (m, 1H), 7. 58- 7. 64 (m, 1H), 7. 77-7. 81 (t, J = 2. 0 Hz, 1H), 8. 52-8. 55 (d, J = 2. 3 Hz, 1H), 8. 60-8. 63 (d, J = 1. 7 Hz, 1H) ; MS (APCI) : m/z = 266 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 60℃; for 5h; | Add bis (triphenylphosphine) palladium (II) dichloride (110 mg, 0. 15 mmol), copper (I) iodide (57 mg, 0. 30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3. 0 mmol) to a solution of 2-chloro-1-fluoro- 4-iodobenzene (0. 46 mL, 3. 6 mmol) in triethylamine (6. 3 mL, 45. 0 mmol-) and heat at 60 C for 5 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100 : 0 to 80 : 20 dichloromethane : ethyl acetate, followed by a second silica gel chromatography, eluting with 67 : 33 to 60 : 40 hexanes : ethyl acetate, to give the title compound as a white solid (730 mg, 93%). 1H NMR (300 MHz, Cd13) 8 3. 88 (s, 3H), 7. 11-7. 18 (t, J = 8. 7 Hz, 1H), 7. 28-7. 32 (m, 1H), 7. 39-7. 46 (m, 1H), 7. 57-7. 63 (m, 1H), 8. 27-8. 30 (d, J = 2. 8 Hz, 1H), 8. 34-8. 37 (d, J = 1. 5 Hz, 1H) ; MS (APCI) : m/z = 262 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With tetrabutyl ammonium fluoride; triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at -78 - 70℃; | Stir 5-trimethylsilanylethynyl-nicotinonitrile (300 mg, 1. 5 mmol), (prepared essentially as described in PREPARATION 3), <strong>[156150-67-3]2-chloro-1-fluoro-4-iodobenzene</strong> (390 mg, 1. 5 mmol), bis (triphenylphosphine) palladium (II) dichloride (50 mg, 0. 08 mmol) and copper (I) iodide (20 mg, 0. 15 mmol) in triethylamine (15 mL) under nitrogen and cool to - 78C. Add a 1 M solution of tetrabutylammonium fluoride (1. 5 mL) in tetrahydrofuran and warm to room temperature and then heat at 70 C until complete by thin layer chromatography. Concentrate and purify the residue by silica gel chromatography, eluting with hexanes : ethyl acetate, and then recrystallize from hexanes : ethyl acetate to give the title compound (120 mg, 31%). 1H NMR (400 MHz, CDCl3) 6 7. 18 (t, J = 8. 8 Hz, 1H), 7. 46-7. 42 (m, 1H), 7. 62 (dd, J = 6. 8 Hz, 2. 0 Hz, 1H), 8. 06 (t, J = 2. 2 Hz, 1H), 8. 82 (d, J = 1. 8 Hz, 1H), 8. 91 (d, J = 2. 2 Hz, 1H) ; HRMS calcd for C14H7ClFN2 257. 0282. Found 257. 0266 ; Anal. Calcd for C14H6ClFN2 : C, 65. 52 ; H, 2. 37 ; N, 10. 91. Found : C, 65. 59 ; H, 2. 48 ; N, 10. 67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; ethylene glycol;copper(l) iodide; for 46h;Heating / reflux; | To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-l-fluoro-4-iodobenzene(96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol),9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol) , and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 4 : 1) . The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3 (S)- (3- chloro-4-fluorophenylamino)pyrrolidine-l-carboxylic acid tert- butyl ester. 1H-NMR(CDCl3) deltappm: 1.47(9H,s), 1.78-1.96 (lH,m) , 2.10-2.28 (IH,m) , 2.10-2.28 (lH,m) , EPO <DP n="69"/>3.11-3.30 (IH,m), 3.30-3.56 (2H,m) , 3.57-3.79 (2H,m) , 3.85- 4.03(lH,m), 6.38-6.47 (IH,m) , 6.60 (IH, dd, J=6. OHz, J=2.9Hz) , 6.90- 7.00 (IH,m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.8% | With cesium acetate;palladium diacetate; tris(para-trifluoromethyl)phenyl phosphine; In N,N-dimethyl-formamide; at 125℃; for 18.5h;Product distribution / selectivity; | Example 22 : 5-([l ,2,4] triazolo [1 ,5-a] pyridin-6-yl)-4-(3-chloro-4-fluorophenyl)-2,2- dimethylfuran-3(2H)-one; [00195] Cesium acetate (167 mg, 0.000872 mol) was added to a round bottom flask and dried under vacuum at 125 C for 2 hours. Palladium acetate (0.98 mg, 0.0000044 mol), tris(4-trifluoromethylphenyl)phosphine (8.1 mg, 0.000017 mol), and N,N- dimethylformamide (1.7 mL, 0.022 mol) were added to the dried cesium acetate and the mixture stirred for 30 min. 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2,2-dimethylfuran-3(2H)- one (100.0 mg, 0.0004362 mol) and 2-chloro-l-fluoro-4-iodobenzene (112 mg, 0.000436 mol) in N,N-dimethylformamide (1.7 mL, 0.022 mol) were added and the mixture stirred at 125 0C <n="60"/>for 18 hr. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a yellow oil. The yellow oil was purified on HPLC eluting with acetonitrile: water (0.1% TFA) to give 20.0 mg (12.8%) of the title compound as a yellow solid.1H NMR (300 MHz, Methanol-^) delta 9.19 (s, IH), 8.49 (s, IH), 7.75 (m, 3H), 7.29 (m, 2H), 1.59 (s, 6H). MS (ESP+) m/z 358.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | A mixture of compound IV (0.314 g, 1 mmol), copper(l)tris(triphenyl- phosphine)bromide (372 mg, 0.4 mmol), Cs2CO3 (977 mg, 3 mmol), and toluene (15 mL) was heated under argon at 110 0C for 5 min. The aryl iodide (2 mmol) was added via syringe and the mixture was stirred at 110 0C for 1-2 days. After cooling, the mixture was filtered through a small pad of silica gel, concentrated and purified by chromatography, furnishing the di-arylated compound as the minor product and the mono-arylated as the major product. The subsequent hydrolysis was carried out in accordance with the procedure described in Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.5% | With sodium azide;copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; dimethyl sulfoxide; at 20 - 65℃; | Intermediate 5: Ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1 H-1 ,2,3-triazole-4- carboxylate; To a mixture of <strong>[156150-67-3]2-chloro-1-fluoro-4-iodobenzene</strong> (0.5 g, 1.950 mmol) and ethyl 2- butynoate (0.227 ml, 1.950 mmol) in water/DMSO (0.22ml/2ml) at room temperature was added L-proline (0.045 g, 0.390 mmol), sodium carbonate (0.041 g, 0.390 mmol), sodium azide (0.152 g, 2.340 mmol), sodium l-ascorbate (0.039 g, 0.195 mmol) and copper(ll) sulfate pentahydrate (0.024 g, 0.097 mmol) (in this order) and the mixture was heated at 65 0C overnight. On cooling to room temperature, the mixture was quenched with aqueous ammonia (1 ml) and EtOAc (20ml) and water (20 ml) were added. The two phases were separated, and the aqueous phase was extracted with EtOAc (3 x 30 ml). All organic phases were combined and washed with water/brine (50ml) repeatedly. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to afford a crude product that was purified by MDAP to afford the title compound (6.5%); MH+=284. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130℃; for 1h;microwave irradiation; | A solution of L-1 (1.0 g, 8.4 mmol), Cul (960 mg, 5.4 mmol), K2CO3 (2.78 g, 20.2 mmol), N,N'-dimethyl-l,2-diaminocyclohexane (0.130 mL, 0.84 mmol), and L-2 (2.8 g, 11 mmol) in 13 mL of DMF is warmed at 130C in a microwave reactor. After 1 hour, the reaction is diluted with saturated aqueous NH4C1 (50 mL) and NaHCO3 is added and the mixture is stirred for 30 minutes. EtOAc (200 mL) is added and the mixture is stirred overnight at room temperature. The mixture is extracted with EtOAc (3 x 50 mL). The combined organic layers are washed with saturated aqueous NH4CI (3 x 40 mL), dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in 15 mL methanol and stirred at 80C for 30 minutes and allowed to cool for 1 hour. The material is collected by filtration, washed with hexanes, and dried to provide L-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 13h; | A round bottom flask is charged with 2-sulfanyl-N-(2,2,2-trifluoroethyl)acetamide (example 14, Step 3, 7.69 g), cesium carbonate (19.7 g), dimethylformamide (100 ml) then the suspension is stirred for 30 min at rt. A solution of <strong>[156150-67-3]3-chloro-4-fluoroiodobenzene</strong> (7.69 g) in dimethylformamide (50 ml) was added and the mixture is stirred at room temperature for 12 hours then 1 hour at 70C. The mixture was diluted with ethyl acetate (100 ml) then washed with water (5*100 ml), 2N hydrochloric acid solution, brine, then dried over sodium sulphate. The solvent was removed under reduced pressure to dryness to afford the crude as yellow solid (13 g). The residue was purified by flash column chromatography of the residue (ethyl acetate / heptanes) afforded the title product as a yellow solid (900 mg). lU NMR (400Mz, CDC13): delta 3.70 (s, 2H), 4.40 (m, 2H), 6.90 (d, 2H), 6.95 (br s, 1H), 7.48 (d, 2H), 7.76 (d, 2H). LCMS (Method E) RT 1.03 min, [M+H]+ 408/410. |
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