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Structure of 403-43-0
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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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Faisal Aziz ; Kanamata Reddy ; Virneliz Fernandez Vega ; Raja Dey ; Katherine A. Hicks ; Sumitha Rao , et al.
Abstract: The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, rebamipide, as a putative inhibitor of Sts phosphatase activity. Rebamipide, and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC50 values from low to submicromolar. SAR analysis indicates that the quinolinone, the acid, and the amide moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the protein. Although rebamipide has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the phosphatase activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.
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Purchased from AmBeed: 2251-65-2 ; 90098-04-7 ; 4876-14-6 ; 90098-08-1 ; 874-60-2 ; 4876-10-2 ; 7158-32-9 ; 5271-67-0 ; 118-45-6 ; 73-22-3 ; 56-41-7 ; 34893-92-0 ; 403-43-0 ; 58757-38-3 ; 76903-88-3 ; 52-90-4 ; 6068-72-0 ; 4122-68-3 ; 2243-83-6 ; 38818-50-7 ; 16331-45-6 ; 36823-88-8 ; 90098-06-9 ; 90098-05-8 ; 3024-72-4 ; 618-46-2 ; 63024-43-1 ; 22980-09-2 ; 681806-75-7 ; 39544-74-6
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CAS No. : | 403-43-0 |
Formula : | C7H4ClFO |
M.W : | 158.56 |
SMILES Code : | O=C(Cl)C1=CC=C(F)C=C1 |
MDL No. : | MFCD00000684 |
InChI Key : | CZKLEJHVLCMVQR-UHFFFAOYSA-N |
Pubchem ID : | 67879 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.58 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.82 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.62 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.48 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.12 |
Solubility | 0.12 mg/ml ; 0.000754 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.07 |
Solubility | 0.134 mg/ml ; 0.000842 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.23 |
Solubility | 0.0938 mg/ml ; 0.000592 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 |
-5.1 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) |
1.08 |
* 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 |
---|---|---|
64% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate; In neat (no solvent); at 100℃; for 1h;Inert atmosphere; Microwave irradiation; | General procedure: The reaction methods used for all the reactions shown in Tables2-4 are the same except for cholesterol, 1e where 1.0 mL of 1,4-dioxane was added. An oven dry clean microwave vial is loadedwith 1.0 mmol of NaOtBu (100.0 mg), 0.0025 mmol of PdCl2(dtbpf)(2.0 mg), capped with air-tight silicon septa and flushed withargon. Then 0.5 mmol of aroyl chloride was added as limiting reagentvia micro syringe, and tertiary alcohol (1.0 mL) was added via drysyringe. The resulting reaction mixture was then microwaved(CEM Explorer 24, 300 W) at 100 C for 60 min. Crude reaction productin reaction tube was diluted with dichloromethane and transferredinto a separating funnel. Water was then added to the funneland, after standard extraction, excess alcohol was completely misciblewith water. The bottom organic layer was collected in a smallErlenmeyer flask over anhydrous Na2SO4. The dichloromethanelayer was filtered through sintered funnel and filtrate, collectedin a round bottom flask, and completely dried by rotary evaporator and under reduced pressure in vacuo. In case of cholesterol 1e,0.5 mmol of aroyl chloride, 1.0 mmol of cholesterol, and 1.0 mLof 1,4-dioxane were used. The desired ester product was confirmedby 1H NMR, 13C NMR, and 19F NMR. |
816 g | With triethylamine; In toluene; at 45 - 60℃; | The 445.0g t-butanol was added dropwise a toluene solution of the intermediate step 1, tert-butyl alcohol after the completion of the dropwise addition, the body again based 759.0g of triethylamine was added dropwise, 45-60 deg.] C after the reaction, the reaction embodies After adding 3000 g of water, stirring for 10 minutes, thelayers wereallowed to stand, the organic phase was retained, and the toluene solvent was evaporated to give 816 g of Intermediate 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine; In dichloromethane; | Step 1. N-methoxy-N-methyl-4-fluorobenzamide. To a 0 C. solution of 4-fluorobenzoyl chloride (11.9 g, 75.0 mmol) in CH2 Cl2 (150 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.00 g, 82.0 mmol) and a solution of pyridine (13.0 g, 164 mmol) in CH2 Cl2 (25 mL). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature and then was washed with 0.5N aqueous HCl (3*100 mL), saturated aqueous NaHCO3, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-4-fluorobenzamide (13.3 g, 97%) as an oil. |
96% | With pyridine; In chloroform; at 0 - 22℃; for 1h; | 4-Fluorobenzoyl chloride (15g, 94.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.1g, 104mmol) were dissolved in CHCl3 (200mL) and stirred at room temperature. The solution was cooled to 0C and pyridine (17.3mL, 230mmol) was added. The mixture was warmed and stirred at room temperature for 1h and then poured into aq. sat. NaCl solution (300mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100mL). The combined organic layers were washed with water (3×50mL), dried (anhyd. Na2SO4) and then evaporated. The crude 4-fluoro-N-methoxy-N-methylbenzamide 7a was purified via distillation under vacuum to afford a colourless liquid (96%), bp=120C at 0.3 mmHg (lit. b.p. 70C at 0.1mmHg [13]); numax 583, 905, 918, 1262, 1375, 1508, 1582, 1630, 2972, 3274cm-1; deltaH 3.34 (3H, s, CH3), 3.52 (3H, s, OCH3), 7.08 (2H, m, Ar-H), 7.73 (2H, m, Ar-H). |
93% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 10℃; for 1h; | To a solution of N,O-dimethylhydroxylamine hydrochloride (1.39 g, 14.3 mmol) and N,N- diisopropylethylamine (3.40 mg, 28.5 mmol) in dichloromethane was added slowly a solution of 4-fluorobenzoyl chloride (2.26 g, 14.3 mmol) in dichloromethane at 0-5C over 20 minutes. The resulting mixture was stirred at 5-l0C for 40 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with water (80 mL), brine (80 ml), dried over sodium sulfate and concentrated under reduced pressure to afford 4-fluoro-N-methoxy-N- methylbenzamide (2.44 g, 93%) as a pale-yellow solid, which was used in next step without further purification. LCMS: (ES+): m/z 184.0 [M+H] +. tR = 2.36 min; 1 H NMR (400 MHz, CDCI3): d 3.36 (s, 3H), 3.54 (s, 3H), 7.09 (t, J = 8.4 Hz, 2H), 7.72-7.76 (m, 2H). |
88% | With triethylamine; In dichloromethane; at 5℃; for 0.5h; | In A VOLUMETRIC flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0C. 4- Fluorobenzoyl chloride (34. 59 G, 218. 2 MMOL) WAS ADDED FOLLOWED BY THE SLOW addition OF TRIETHYLAMINE (48. 13 G, 475. 6 MMOL). THE REACTION WAS STIRRED FOR 30 min at 5 C and allowed to reach room temperature. It was washed with 5% aqueous citric acid (180 ML) and with 5% aqueous NaHCO3 (180 ML). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 20. 23 G OF THE DESIRED COMPOUND (YIELD : 88%). |
With pyridine; In dichloromethane; at 20℃; for 20h; | To N,O-dimethylhydroxylamine hydrochloride (27.7 g, 284 mmol) in DCM (660 mL) was added pyridine (45.8 mL, 569 mmol) followed by 4-fluorobenzoyl chloride (31.0 mL, 258 mmol). The resulting suspension was stirred at room temperature for 20 hours, then was filtered to remove a white solid precipitate. The solid was washed with DCM and the filtrate was washed with 1 N aqueous HCl (2×), then water. The organic phase was dried (Na2SO4), filtered, and concentrated, yielding the crude title compound which was used without further purification | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere; | A solution of methoxymethylamine hydrochloride (0.634 g, 6.37 mmol) and Et3N (0.860 mL, 6.12 mmol) in CH2Cl2 (3.75 mL) at 0 oC was treated dropwise via syringe with 4-fluorobenzoyl chloride (0.370 mL, 3.07 mmol) over 30 min. The reaction mixture was allowed to stir at rt for 2 h, poured into H2O and extracted with CH2Cl2 (3 x20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. Further drying under high vacuum gave crude 4-fluoro-N-methoxy-N-methylbenzamide (0.672 g, 2.63 mmol, quant.) which was used without further purification | |
With triethylamine; In dichloromethane; at 0℃; for 0.5h; | To a mixture containing O,N-dimethylhydroxylamine hydrochloride (6.0 g) and triethylamine (4.05 g) in DCM (50 mL) at 0 C. was added 4-fluorobenzoyl chloride (6.0 g) over 30 minutes. The ice-bath was removed and after stirring for an additional 30 minutes, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL*3). The organic extract was washed with brine and dried (MgSO4). Removal of the solvent in vacuo provided 4-fluoro-N-methoxy-N-methyl-benzamide, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | a 4-Fluoro-N-methoxy-N-methyl-benzamide To a solution of commercially-available 4-fluorobenzoyl chloride (9.1 g, 57.4 mmol) and N,O-dimethylhydroxylamine (6.2 g, 63.1 mmol) in CH2Cl2 (200 mL) is added triethylamine (20.0 mL, 143.5 mmol) dropwise. After stirring 1.5 h at room temperature, the reaction mixture is diluted with EtOAc and washed with aqueous saturated NaHCO3. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure to give the crude amide 75a, which is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
aluminium trichloride; In toluene; | REFERENCE EXAMPLE 2 (Synthesis of starting material for Reference Example 1) STR529 Into a toluene suspension (200 ml) of aluminum chloride (26 g), a toluene solution (50 ml) of p-fluorobenzoyl chloride (16 g) was dropwise added at a room temperature. Subsequently, the mixture was stirred for 20 hours at a room temperature, and then carefully poured into ice-water. Toluene (200 ml) was added thereto, and then the organic layer was separated, and washed successively with aqueous 2N hydrochloric acid solution, water and aqueous saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-fluoro-4'-methylbenzophenone (16 g). melting point: 97-98° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; | (a) 4-Fluoro-N-methoxy-N-methylbenzamide --To a mixture containing methoxymethylamine hydrochloride (44 g, 0.45 mol) and triethylamine (138 mL, 0.99 mol) in CH2 Cl2 (500 mL) at 0 C. was added over 30 min, 4-fluorobenzoyl chloride (50 mL, 0.41 mol). The resulting mixture was allowed to warm to rt and stirring was continued for 30 min, at which time the mixture was poured into H2 O and extracted with Et2 O. The Organic extract was washed with saturated aqueous NaCl and dried (MgSO4). Removal of the solvent in vacuo afforded the title compound (80 g, 100%), which was used without further purification: 1 H NMR (CDCl3): delta7.72 (dd, 2H); 7.06 (apparent t, 2H); 3.52 (s, 3H); 3.43 (s, 3H). |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h; | (4-Fluorophenyl)-N-methoxy-N-methylcarboxamide (1-32).1 A solution of methoxymethylamine hydrochloride (0.634 g, 6.37 mmol) and Et3N (0.860 mL, 6.12 mmol) in CH2CI2 (3.75 mL) at 0 C was treated dropwise via syringe with 4-fluorobenzoyl chloride (0.370 mL, 3.07 mmol) over 30 min and the resulting solution was allowed to stir at rt for 2 h. The reaction mixture was poured into H2O and extracted with CH2CI2 (3 x 20 mL). The organic extracts were washed with brine, dried (MgS04), and the solvent removed under reduced pressure. Further drying under high vacuum gave crude 1-32 (0.672 g, 2.63 mmol, quant.) which was used without further purification: NMR (CDCb, 400 MHz) delta 7.74 (m, 2 H), 7.08 (m, 2 H), 3.53 (s, 3 H), 3.36 (s, 3 H); HRMS (HESI) m/z calcd for C9H11NO2F (M+H) 184.0768, found 184.0768. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; | 64-1) 1-[2-(4-Fluorobenzoylamino)ethyl]-4-(t-butoxycarbonyl)piperazine The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (1.33 g) obtained in Example 58 and 4-fluorobenzoyl chloride (1.1 g) were dissolved in tetrahydrofuran (20 ml), then triethylamine (1.6 ml) was added thereto, and the mixture was stirred overnight at room temperature. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.42 g, 70 percent) was obtained as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyridine; In dichloromethane; tert-butyl alcohol; | (a) t-Butyl 4-fluorobenzoate t-Butanol (6.6 ml) and pyridine (5.62 ml) were dissolved in dry dichloromethane (40 ml) and cooled in a dry ice/acetone bath to -50C. A solution of 4-fluorobenzoic acid chloride (10.0 g) in dry dichloromethane (20 ml) was added slowly to the alcohol solution. The solution was kept under nitrogen throughout, and allowed to warm slowly to room temperature. It was then heated at reflux for 1d. More t-butanol (1 ml) and pyridine (1 ml) were added and reflux continued for two days more. After cooling the reaction mixture was washed successively with 2 M hydrochloric acid (40 ml), 10% sodium hydrogen carbonate solution (40 ml) and saturated aqueous sodium sulphate solution. The organic layer was dried, filtered and evaporated to leave an oil (10.62 g). This contained the title compound and some 4-fluorobenzoic anhydride. The two components were separated by column chromatography (100 g silica/ 30% dichloromethane/70% petroleum ether) to leave the title compound (8.48 g, 69%) 1H NMR (CDCl3) delta 8.05, 7.05 (4H, m, aryl- H) and 1.60 (9H, S, C H 3). Infra Red (Thin Film) Vmax2970, 1715, 1610, 1510, 1290, 1155, 1120, 850, and 770 cmmin1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | EXAMPLE 6 To a suspension of <strong>[214147-48-5]1-acetyl-4-aminopiperidine hydrochloride</strong> (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzoyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 10:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (738 mg) was obtained. NMR (DMSO-d6, delta): 1.40 (2H, m), 1.81 (2H, distorted t, J=12.4 Hz), 2.01 (3H, s), 2.68 (1H, br t, J=11.4 Hz), 3.13 (1H, br t, J=11.6 Hz), 3.83 (1H, br t, J=13.9 Hz), 4.01 (1H, m), 4.33 (1H, br d, J=13.7 Hz), 7.29 (2H, t, J=8.9 Hz), 7.92 (2H, dd, J=5.5, 8.8 Hz), 8.31 (1H, d, J=7.7 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | 2-Chloro-6-fluoro phenol (1, 30 g, 0.2054 mol) was dissolved in DCM, triethylamine (TEA, 45.73 g, 0.4519 mol) was added and the reaction mixture was cooled to 0 °C. A solution of 4-fluorobenzoyl chloride (2a, 33.9 g, 0.2157 mol) in DCM was added slowly to the above mixture and internal temperature was maintained to 0-10 °C. Finally the reaction mixture was stirred at ambient temperaturefor 3 h. Then the reaction mass was diluted with DCM (200 mL),washed with 10percent sodium hydroxide solution (3 x 30 mL), water (3 30 mL), brine (2 x 60 mL), and again with water (3 x 30 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated to achieve compound 3a as white solid. Yield: 94percent; m.p.: 52.6-54.1 °C; IR (KBr) numax (cm-1): 1738 (ester,C]O); 1H NMR (400 MHz) (DMSO-d6) d (ppm): 7.42-7.53 (m, 4H,Ar-H), 8.25-8.28 (m, 3H, Ar-H); MS (EI): m/z (75percent) M 268.5;Anal. Calcd. for C13H7ClF2O2 (268.5): C, 58.12; H, 2.63; Cl, 13.20; F,14.14. Found: C, 58.22; H, 2.43; Cl, 13.30; F, 14.29percent. |
92% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | General procedure: 2-Chloro-6-fluoro phenol (1, 0.20 mol) was dissolved indichloro methane (DCM) and triethylamine (TEA, 0.45 mol) wasadded to it. Then the reaction mixture was cooled to 0 C. Further,a solution of substituted benzoyl chloride 2a?d (0.21 mol) in DCMwas slowly added to the reaction mixture and stirred for 3 h andthe completion of the reaction was monitored by TLC using 4:1n-hexane: ethyl acetate solvent mixture. Then the reaction masswas diluted with DCM (100 ml), washed with 10percent sodium hydroxidesolution (3 40 ml), followed by water (3 30 ml). Theorganic layer was dried over sodium sulphate and the solidobtained after evaporation of the solvent was recrystallized fromethanol to give compounds 3a?d. [21] Compound (3a) is taken asa representative example to explain physical and characterizationdata. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With palladium diacetate; In chloroform; at 60℃; for 2h;Inert atmosphere; | General procedure: After the reaction of arylboronic acid (1 mmol) with tributyltin methoxide (0.321 g, 1 mmol) at 100 C for 1 h under solvent-free conditions, chloroform (4 mL) was added to the reaction mixture at room temperature. Either Pd(OAc)2 (0.0022 g, 0.01 mmol) or PdCl2 (0.0017 g, 0.01 mmol) and tri(2-furyl)phosphine (0.0046 g,0.02 mmol) were added under an argon gas stream, followed by addition of aroyl chloride (1 mmol) at room temperature. The resulting mixture was heated in a heating block with stirring at 60 C for 2 h. The reaction mixture was filtered through a Celite pad, and the solvent was removed under reduced pressure. After addition of THF (5 mL) and 3 M NaOH (1 mL) to the residue, the mixture was stirred for 0.5 h at room temperature and then diluted with H2O (4 mL). The aqueous phase was extracted with EtOAc (35 mL) and organic layers were washed with brine (5 mL) dried over Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel to give pure diaryl ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(l) cyanide; lithium chloride; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; | General procedure: Into a 25 mL round-bottomed flask were placed CuCN (0.02 g,10 mol%) and LiCl (0.02 g, 20 mol%). Benzylic zinc mesylate (I,5.0 mL, 0.5 M in THF, 2.5 mmol) was added into the flask underan argon atmosphere. Next, 4-bromobenzoyl chloride (0.44 g,2.0 mmol) was slowly added via a syringe while being stirred at0 C. The resulting mixture was at 0 C for 2 h, quenched with3.0 M HCl solution, then extracted with Et2O (3 × 10 mL),washed with sat. NaHCO3, Na2S2O3 solution and brine, and thendried over anhydrous MgSO4. Purification by column chromatographyon silica gel (EtOAc-heptane, 2:98) afforded 0.38 g of 1-(4-bromophenyl)-2-phenylethanone (1b) in 70% isolatedyield as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.1 mg | Methyl 3-amino-4-f uorobenzoate (21.0 mg, 0.124 mmol) and 4-fluorobenzoyl chloride (0.124 mmol) in toluene (2 ml) were heated at 110 °C for 1.5 h. Lawesson's reagent (40 mg, 0.100 mmol) was added and the mixture stirred at 110 °C overnight. Solvent was evaporated and residue purified by flash chromatography using 5-10percent EtOAc in hexanes as eluent. Yield: 9.1 mg |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In toluene; at 100℃; for 2h;Schlenk technique; | General procedure: An oven-dried Schlenk flask, equipped with a magnetic stir bar, septum and a condenser was charged with acyl chloride (1.0 mmol), arylboronic acid (1.0 mmol), NaOH (4 mmol) and 5.0 mL of toluene. The flask was immersed and stirred in an oil bath at 100 °C. Upon complete consumption of starting materials as determined by GC analysis, the water (10.0 mL) was added. The reaction mixture was extracted with diethyl ether (3 × 5.0 mL). The combined organic layer was collected, dried over anhydrous Na2SO4 and concentrated in vacuum to afford product which was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9:1 or 8:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.3 g | With triethylamine; In tetrahydrofuran; at 10 - 35℃; for 16h; | A) N-(2-chloro-6-methylpyridin-3-yl)-4-fluorobenzamide (1166) To a mixture of 850 <strong>[39745-40-9]2-chloro-6-methylpyridine-3-amine</strong> (10 g), 851 4-fluorobenzoyl chloride (11 g) and 38 THF (100 ml) was added 121 triethylamine (21.3 g), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 29 water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the 852 title compound (16.3 g). 1H NMR (400 MHz, DMSO-d6) delta 2.51 (3H, s), 7.34-7.46 (3H, m), 7.91 (1H, d, J = 8.0 Hz), 8.08 (2H, dd, J = 8.8, 5.6 Hz), 10.19 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With dmap; triethylamine; In dichloromethane; at 0℃; for 10h;Reflux; | In a 50 mL three-necked flask with magnetic stirring, 4.8 mmol of <strong>[120068-37-3]fipronil</strong> was added [Chemical name:5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole-3-carboxamide],10 ml of dry dichloromethane (DCM),After the bath is kept below 0C, 0.5 mmol of 4-dimethylaminopyridine (DMAP) and 6.5 mmol of triethylamine are added.Add 5 ml of the acid chloride in dichloromethane, add the ice bath, and slowly raise the temperature to reflux.React for 10 hours and cool to room temperatureWash twice with 1% dilute hydrochloric acid, wash twice, dry organic phase over anhydrous sodium sulfate, and dissolve.Column chromatography with petroleum ether and ethyl acetate (5:1 by volume) gives structural formulae such asWhite solid shown in I-33N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylsulfinyl-1H-pyrazol-5-yl-4-fluorobenzamide1.88 g,The yield was 70.2% based on <strong>[120068-37-3]fipronil</strong>. |
Tags: 403-43-0 synthesis path| 403-43-0 SDS| 403-43-0 COA| 403-43-0 purity| 403-43-0 application| 403-43-0 NMR| 403-43-0 COA| 403-43-0 structure
A1483303 [91742-47-1]
4-Fluorobenzoyl chloride-1-13C
Reason: Stable Isotope
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