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Structure of 51336-94-8 * Storage: {[proInfo.prStorage]}
* 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.
Stage #1: at 30 - 35℃; for 0.5 h; Stage #2: at 30 - 55℃; for 5 h;
In the equipped with a thermometer, constant pressure funnel, the reflux condensation tube (with drying tube) of 250 ml of four flasks, adding inter-fluorobenzene (0.1 µM, 14 . 7g), three aluminum chloride (0.17 µM, 22 . 7g), the mixture in the 30 - 35 °C stirring 0.5h after, instillment chlorine acetyl chloride (0.12 µM, 13 . 56g), to maintain the reaction temperature. After dropping, the elevated temperature to 50 - 55 °C, continuing to stir, until no hydrogen chloride gas generation, about reaction 5h. Which is equipped with a reaction mixture in the flask is put into the ice water bath, so that the reactant temperature to 5 °C following, dropping 3 mol/L hydrochloric acid 20 ml acid hydrolysis, control drop acceleration the mixture temperature is maintained large. After the acid mixture is poured into the beaker, adding distilled water, precipitated solid, the decompression, drying, to obtain light yellow powdery solid 16.9g, yield 89.3percent. The light yellow powdery solid n-hexane recrystallization to obtain a bright yellow crystal.
88.2%
at 20 - 45℃; for 5 h;
Anhydrous aluminum trichloride 200 g (1.494 mol) and m-difluorobenzene 150 g (1.30 mol)Placed in 1000mL three-necked flask, stirring at room temperature, slowly dropping chloroacetyl chloride 150 g (1.30 mol)After completion of the dropwise addition, stirring was continued for 30 minutes at room temperature, and the temperature was gradually raised to 45 ° C.Stirring was continued at this temperature for 4.5 hours. The reaction solution was poured into ice water as usual to precipitate a solid,Filtration; filtrate with dichloromethane 800 mL in two extraction, combined dichloromethane extract, washed to neutral,Dried over anhydrous sodium sulfate, filtered and the solvent recovered to give a solid, iltered and the solid was recovered solvent, the resulting combined solid was recrystallized from ethanol twice to give 2-chloro-2 ',4 '-difluoroacetophenone 215 g, yield 88.2percent.
84.5%
Stage #1: With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 1 h; Stage #2: at 0 - 20℃; for 2 h;
To a stirred solution of A1C13 (14.8 g, 131.4 mmol) in DCM (100 mL) was added 2-chloroacetyl chloride (23.3 g, 175.2 mmol) at 0C and stirred at RT for 1H. To the resulting reaction mixture, a solution of 1,3-difluorobenzene (GI, 10.0 g, 87.6 mmol) in DCM (20 mL) was added dropwise at 0C and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with IN HCl solution, neutralized with 2N NaOH solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10percent EtOAc/hexane to afford compound GJ (14.1 g, 84.5percent) as an off-white solid. 1H NMR (400 MHz, CDC13): _ 8.08-8.02 (m, 1H), 7.06-7.01 (m, 1H), 6.96- 6.91 (m, 1H), 4.71 (s, 2H).
75%
Stage #1: With aluminum (III) chloride In 1,2-dichloro-ethane at 25 - 30℃; for 0.5 h; Stage #2: at 0 - 30℃; for 5.5 - 8 h;
[00062] Into the solution of 1,3-difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 molar equivalent of 1,3-difluorobenzene) at 25-30° C. and stirred for 30 minutes. The reaction mixture was then cooled to 0° C. and chloroacetyl chloride (1.1 molar equivalent of 1,3-difluorobenzene), in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 20° C. After the addition was over, the reaction mixture was stirred at 25-30° C. for 5-7 hours. The reaction mixture was then diluted with DCE and poured into dil. hydrochloric acid (5percent) at 0-5° C. The mixture was then extracted with DCE. The combined organic layer was washed successively with 5percent aq. sodium bicarbonate solution and water. Evaporating DCE from the organic layer under reduced pressure gave an oil which on triturating with n-Hexane gave the title compound as white crystalline material (Yield 75percent of theory).
Reference：
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2
[ 1440-61-5 ]
[ 348-57-2 ]
[ 51336-94-8 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
Stage #1: With magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Inert atmosphere Stage #2: at 40℃; for 2 h;
Prepare a dry, clean 1000mL glass four-port bottle, equipped with a suitable mechanical stirrer, condensing tube and thermometer, check the airtightness before feeding, and add 96.5g to the reaction flask under N2 protection. 2,4-Difluorobromobenzene (0.5mol, 1.0eq),25.5 g (0.525 mol, 1.05 eq) of magnesium bar, 500 mL of tetrahydrofuran, stirring was started, the temperature of the reaction solution was raised to 30-35° C., and the reaction was stirred for 2 h. After the reaction was completed, the reaction solution was slowly added dropwise 163.6 g (1.0 mol). , 2.0 eq.) of 4-(2-chloroacetyl)morpholine (Compound 4) in tetrahydrofuran (163.6 g dissolved in 360 ml of tetrahydrofuran), the temperature controlled during the additionAt 40°C, after the addition is complete, continue incubation at 40°C for 2 hours. After the reaction was completed, the reaction system was quenched with 100 mL of saturated ammonium chloride solution. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and then 500 mL of ethyl acetate was added for extraction. The separated ethyl acetate phase was washed with 300 mL of water and the organic phase was organic. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 92.0 g of compound 5 (yield: 96.5percent).
Reference：
[1] Patent: CN107746388, 2018, A, . Location in patent: Paragraph 0028; 0030; 0032; 0033; 0034; 0036; 0038; 0040
Stage #1: 1H-imidazole With triethylamine In methanol at 20℃;
Stage #2: 2-chloro-1-(2,4-dichlorophenyl)ethanone In methanol at 65℃; for 4h;
4.5. General procedure for the synthesis of compounds 9a-9b
General procedure: Imidazole (10.36 g, 0.15 mol) was added to anhydrous methanol(40 mL) and the mixture was stirred to dissolve at room temperature.An amount of triethylamine (10.1 g, 0.1 mol) was then addeddropwise and the reaction mixture was magnetically stirred atroom temperature, then another solution containing 8a (22.3 g,0.1 mol) and anhydrous methanol (20 mL) were added. The reactionwas heated to reflux for 4 h and cooled to room temperature.Water (100 mL) and ethyl acetate (50 mL) were added to themixture. The organic phase was separated and the water phase wasextracted with ethyl acetate (2 x 50 mL). The combined organicphases were washed with water (20 mL) and saturated sodiumchloride solution (20 mL) in order, and the organic layer was driedovernight with anhydrous sodium carbonate. The solution wasmoved by filtering and the yellow crystalline precipitate was driedin the air. The solidwas purified by recrystallization from ethanol toobtain a white solid (9a). Yield 84.0% HRMS m/z: 255.0085 [M+H]+,276.9904 [M+Na]+. According to the preparation method of 9a, 8bwas used as raw material to prepare the intermediate 9b: whitesolid, Yield 92.1%, HRMS m/z: 223.0681 [M+H]+.
90.6%
With triethylamine In methanol at 65℃;
4.5 The preparation of compounds 12a-12d
The synthesis of intermediate 1-(2,4-difluorophenyl)-2-(1H-imidazole-1-yl) ethan-1-one (12b) was chosen as the example: The 2-chloroacetyl chloride (10) (6.7g, 0.06mol) was added dropwise to the mixture of 1,3-difluorobenzene (5.7g, 0.05mol) and anhydrous aluminum trichloride (10.7g, 0.08mol) at 25°C. The reaction was stirred at room temperature for 4h. Subsequently, the mixture was diluted with ice water mixture (100g) containing concentrated hydrochloric acid (10mL). The solution was extracted with dichloromethane (3×20mL). The organic layers were combined and washed with saturated salt water (30mL). The organic layer was dried with Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethanol to give 11b (93.1%) as a yellow solid. To a stirred solution of intermediate 11b (14.5g, 0.08mol) in 70mL anhydrous methanol with triethylamine (8.1g, 0.08mol), imidazole (10g, 0.15mol) was then added at 25°C. The mixture was magnetically stirred heated to reflux for 4h and then concentrated under reduced pressure to remove methanol. The residue was purified by recrystallization from ethanol to obtain 1-(2,4-difluorophenyl)-2-(1H-imidazole-1-yl) ethan-1-one (12b, 90.6%) as a white solid. HRMS m/z: found 223.0675 [M+ H]+(calcd. for C11H8N2F2O, 223.0683).
82%
With sodium hydrogencarbonate In toluene for 4h; Reflux;
58%
With triethylamine In N,N-dimethyl-formamide for 24h; Reflux;
Compound 2c
A mixture of 1a (2.5 g, 13.0 mmol), imidazole (1.06 g, 15.6mmol), and triethylamine (2.2 mL, 15.6 mmol) in DMF (20 mL) wasrefluxed for 24 h. The reaction was monitored by TLC (MeOH/DCM, 9:91).Upon completion, the reaction mixture was poured into crushed ice and extracted with ethyl acetate.The combined organic layer was washed with H2O and brine, dried over MgSO4, and concentratedto give the crude product. The product was then isolated by column chromatography on SiO2 usinga gradient of MeOH/DCM as eluent to afford compound 2c (1.67 g, 58%).
46%
In N,N-dimethyl-formamide 1) 0-5 deg C, 2 h, 2) 0-5 deg C to RT (25 deg C);
244 parts (69%)
In chloroform
1.a EXAMPLE 1
a) To a refluxing and stirred solution of 457.6 parts of 1H-imidazole in 2400 parts of trichloromethane was added dropwise a solution of 320 parts of 2-chloro-1-(2,4-difluorophenyl)ethanone in 1440 parts of trichloromethane. After stirring for 1/2 hour at reflux temperature, the reaction mixture was poured into water. The organic layer was washed with water (2x), dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 244 parts (69%) of 1-(2,4-difluorophenyl)-2-(1H-imidazol-1-yl)ethanone; mp. 125° C. (interm. 1).
In acetonitrile at 20℃; for 24h;
2.a Preparation 2 a) Substitution (Introduction of the Imidazole):1-(2,4-difluorophenyl)-2-(1H-1,2,4-imidazol-1-yl)-ethanone:
Preparation 2 [0135] a) Substitution (Introduction of the Imidazole): [0136] 1-(2,4-difluorophenyl)-2-(1H-1,2,4-imidazol-1-yl)-ethanone: [0137] 2-chloro-1-(2,4-difluorophenyl)-ethanone (0.572 g) is added to 0.612 g of imidazole (9 mmole) in 3 ml of acetonitrile and the reaction medium is stirred at ambient temperature for 24 hours. Extraction is then carried out with dichloromethane, followed by washing, drying and evaporation under reduced pressure until the crude product is obtained in the form of oil which is recrystallized from ether to afford 0.521 g of expected product; M.p.=121° C. NMR (CDCl3, 300 MHz, δ, ppm): 5.32 (m, 2H, CO-CH2-N); 6.94 (bs) and 7.15 (bs): 2H H4 and H5; 6.98 (ddd, 1H, Ha); 7.08 (ddd, 1H, Hb); 7.56 (bs, 1H, H2); 8.05 (dt, 1H, Hc)
With potassium carbonate In acetonitrile at 85℃; for 0.833333h; microwave irradiation;
87%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
87%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
82%
With potassium carbonate In toluene for 5h; Reflux;
70%
With potassium carbonate In dichloromethane at 20℃; for 24h;
70%
With potassium carbonate In dichloromethane at 20℃; for 24h;
70%
With potassium carbonate In dichloromethane at 20℃; for 24h;
70%
With potassium carbonate In dichloromethane at 20℃; for 24h;
70.4%
With potassium carbonate In acetonitrile at 20 - 80℃;
The chloroacetylated intermediate 2 could be efficiently prepared in satisfactory yield of 65.8% by the acetylation of 2,4-difluorobenzene 1 with chloroacetyl chloride, and was then N-alkylated with 1,2,4-triazole in acetonitrile in the presence of potassium carbonate to afford the triazolyl ethanone 3 in good yield of 70.4%.
69%
With Sodium hydrogenocarbonate In toluene for 4h; Heating;
62%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
60.6%
With trimethylamine In methanol for 14h; Heating / reflux;
4.1
Step 1: Preparation of 1- (2, 4-DIFLUOROPHENYL)-2- (1, 2, 4-triazol-1-yl)-ethanone 65 g of 1-CHLORO-2 , 4'-difluoroacetophenone (0.341 mol), 24.3 g of 1,2, 4-triazole (0.344 mol), 450 ml of methanol and 48 ml (0.344 mol) of trimethylamine were refluxed for 14 hours. The mixture was concentrated, mixed with water, and extracted with ethyl acetate. The formed organic layer was dried over anhydrous magnesium sulfate, and evaporated under a reduced pressure. The resulting residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (2: 1) as an eluent to obtain 46.17 g (yield 60.6 %) of the title compound (m. p. 100~102°C). 1H-NMR (CDCl3) : 6 5.56 (d, J=3. 4HZ, 2H), 6.90-7. 16 (M, 2H), 7. 95-8. 07 (m, 1H), 7.97 (s, 1H), 8. 16 (s, 1H); GC-MS m/z (relative intensity): 223 (34, M), 140 (100), 112 (70), 62 (48)
60%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
Synthesis of 1-(2,4-dif luorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (5a)
A mixture of 2-chloro-2′,4′-difluroacetophenone (9.25 g, 48.53 mmol) (2a), 1H-1,2,4-triazole (4.01 g, 58.06 mmol) and sodium bicarbonate (4.90 g, 58.33 mmol) in toluene (50 mL) was refluxed for 5 h with magnetic stirring. Subsequently, cold water (50 mL) was added and the solution extracted with toluene (3 × 40 mL). The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography using dichloromethane as the eluent. Compound 5a was obtained as a white solid; yield 60%; m.p. 101-103 °C (lit.22 103-105 °C). IR (cm-1) ν: 3045 (CArH), 2982 and 2946 (Csp3-H), 1689 (C=O), 1609 (C=N), 1592 and 1508 (CAr-CAr); 1H NMR (CDCl3) δ (ppm): 5.53 (s, 2H), 6.92 (ddd, 1H, J = 11.0, 8.4, 2.3 Hz), 6.98 (ddd, 1H, J = 9.6, 7.0, 2.3 Hz), 7.91 (s, 1H), 7.96 (td, 1H, J = 8.5, 7.0 Hz), 8.15 (s, 1H); 13C NMR (CDCl3) δ (ppm): 58.4 (d, J = 13.5 Hz, CH2), 105.0 (t, J = 26.6 Hz, CH), 113.2 (d, J = 21.7 Hz, CH), 119.0 (d, J = 11.4 Hz, CH), 133.1 (dd, J = 10.7, 3.9 Hz, CH), 145.0 (CH), 151.9 (CH), 163.2 (dd, J = 256.9, 12.7 Hz, C-F), 166.8 (dd, J = 260.3, 12.6 Hz, C-F), 187.7 (C=O); HRESIMS calcd for C10H8F2N3O [M + H]+ 224.0635, found 224.0624.
58%
With benzyl-triethyl-ammonium chloride; potassium carbonate In dichloromethane for 24.5h; Cooling with ice;
1.1 (1) 2',4'-Difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone
Dissolve 1,2,4-triazole 6.8g (0.1mol), anhydrous K2CO3 10.35g (0.075mol), TEBA 1.2g and CH2Cl2 50mL in a 150mL flask, cool in an ice water bath, stir and instill 2-chloro-2',4'-difluoroacetophenone 9.55g (0.05mol) and the mixture of CH2Cl2 20mL was dripped for about 0.5h, stirring was continued for 24h, and the mixture was filtered. The filter cake was washed several times with CH2Cl2. The organic layer was washed with water (50mL x 3), dried over anhydrous Na2SO4, and the residue was dissolved in CH2Cl2 to dissolve the residue. In ethyl acetate, concentrated HNO3 was added dropwise to precipitate a solid, which was filtered and washed several times with a small amount of ethyl acetate. After drying, it was dissolved in water and adjusted to pH 9 with 30% NaOH solution in an ice bath to precipitate a solid, which was filtered and dried. Obtained white solid 6.4g, yield 58%.
53.1%
With Sodium hydrogenocarbonate In toluene at 100℃; for 4h;
52%
With potassium carbonate In toluene for 4h; Reflux;
50%
Stage #1: 2-chloro-1-(2,4-dichlorophenyl)ethanone With N,N,N-tributyl-1-butanaminium iodide; sodium bromide In propan-2-one for 2h; Heating;
Stage #2: 1H-1,2,4-triazole With potassium carbonate In propan-2-one at 20℃; for 0.5h;
47%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
47%
With triethylamine In ethyl acetate for 6h; Reflux;
1.2; 3 Example 3
The difference between this embodiment and embodiment 1 lies in step (2):In this embodiment, the preparation method of α-(1H-1,2,4-triazol-1-yl)-2,4-difluoroacetophenone is as follows: sequentially add to a 100ml three-necked flask with a condenser 1.91g of 2-chloro-2',4'-difluoroacetophenone and 0.83g of 1,2,4-1H-triazole, add ethyl acetate to dissolve. After the dissolution is completed, 1.21 g of triethylamine is slowly added dropwise with a constant pressure dropping funnel under magnetic stirring, and the temperature is raised to reflux temperature. The reaction is completed after 6 hours. Then use the eluent of ethyl acetate: petroleum ether = 5:2 to separate through the chromatographic column, and then the separated material is detected by infrared and nuclear magnetic. It is found that the final product separated is the final product, and α-(1H-1,2,4-Triazol-1-yl)-2,4-difluoroacetophenone 1.05g, the yield was 47%.
42%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
42%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
42%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
42%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
41.7%
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
41.7%
With benzyl-triethyl-ammonium chloride; potassium carbonate In dichloromethane at 0 - 20℃; for 29h;
2.2 2. Preparation of 2- (1 H-1, 2,4-triazol-1-yl) -2 ', 4'-difluoroacetophenone
54 g (0.4 mol) of triazole, 0. 8 g of TEBA,Anhydrous potassium carbonate 82 g (0.3 mol) was added to 400 mL of CH2Cl2.; 76 g (0.4 mol) of 2-chloro-2',4'-difluoroacetophenone was dissolved in 60 mL of CH2Cl2 under ice-cooling bath conditions, drop it into the 400 mL suspension, about 2 hours drop finished,After completion of the reaction at 0-5 ° C for 5 hours at room temperature for 24 hours.Then filter, filter cake washed with CH2CI2 several times, collect the filtrate, the filtrate washed 3 times, each 200 mL,Anhydrous Na2S04 dry, steamed out CH2C12. The residue was dissolved in 200 mL of anhydrous ethyl acetate,Stirring concentrated nitric acid to the yellow solid is no longer precipitated; filter cake with a small amount of ethyl acetate wash several times,Dried, dissolved in 200 mL of water, with 30% NaOH solution (w / w) adjusted pH value of 9, precipitation of solid,Filtered and dried to give the crude product which was recrystallized from n-hexane: ethyl acetate (v / v) 1: 1 to give 76 g of compound,Yield 41.7%
27%
With potassium carbonate In acetonitrile at 20℃; for 5h;
In dichloromethane
With potassium carbonate In chloroform Heating;
With Sodium hydrogenocarbonate In toluene for 4h; Reflux;
In toluene Heating / reflux;
1.2 Step 2: Preparation of 2-(1H,2,4-Triazol-1-yl)-2',4'-difluoro Acetophenone
The product obtained in Step-1 was reacted with 1,2,4-triazole (1.2 molar equivalent) in the presence of sodium bicarbonate as base and toluene as solvent under refluxing condition. After the reaction was over, the reaction mixture was poured into crushed ice and extracted with toluene. The combined organic layer was then washed with water and concentrated under reduced pressure to give brown semisolid compound which was recrystallized from ethyl acetate-hexane mixture to give light yellow solid compound which was then used as such in the next step.
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 8h;
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
25.9 g
With potassium carbonate In acetonitrile at 60℃;
1.2. 1-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4)
General procedure: A suspension of potassium carbonate (27.6 g, 0.20 mmol), 1H-1,2,4-triazole (9.8 g, 0.14 mol) and compound 3 (26.6 g, 0.14 mol) was stirred in acetonitrile (30 mL) at 60 °C. After the reaction was completed (monitored by TLC, eluent, ethyl acetate/methanol, 15/1, V/V), the solvent was removed and the residue was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. After concentrating the filtrate, the crude product was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (15/1, V/V) to give compound 4 (25.9 g) as white solid. Yield: 83.1%; mp: 105-107 °C. (literature mp: 103-105 °C) [36].
With potassium carbonate In acetonitrile at 20 - 80℃;
With potassium carbonate In acetonitrile at 20 - 80℃;
With Sodium hydrogenocarbonate In toluene for 5h; Reflux;
Stage #1: 1H-1,2,4-triazole With sodium hydroxide In lithium hydroxide monohydrate
Stage #2: 2-chloro-1-(2,4-dichlorophenyl)ethanone In acetonitrile for 8h; Reflux;
4.1 RRN 34General procedure for the synthesis of the alkyl-triazoles
General procedure: The triazoles were converted to their sodium salts by treatment with an aqueous solution of sodium hydroxide followed by precipitation, according to the previous literature [26]. The reaction proceeded according to the procedure described by Papadopoulou etal. [27] After dried, the sodium salt of the respective triazole was solubilized in acetonitrile and added to an equimolar solution (0.5M) of 2-Chloro-2′,4′-difluoroacetophenone in acetonitrile for a nucleophilic substitution, which occurred under refluxing conditions (8h). The resulting suspension was filtered, and the liquid phase was evaporated. The resulting solid was purified using automated flash column chromatography.
With benzyl-triethyl-ammonium chloride; potassium carbonate In dichloromethane at 0 - 20℃; for 17h;
1.2 (2) Preparation of 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (Intermediate 3)
2-chloro-2',4'-difluoroacetophenone and triazole, benzyltriethylammonium chloride (TEBA) and potassium carbonate in CH2Cl2. At 0-5 deg.C, react for 5 hours, followed by a reaction at room temperature for 12 hours, to form 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (3).
With benzyl-triethyl-ammonium chloride; potassium carbonate In dichloromethane at 0 - 20℃; for 17h;
With benzyl-triethyl-ammonium chloride; potassium carbonate In dichloromethane at 0 - 20℃; for 17h;
1.2 (2) Preparation of 2- (1H-1,2,4-triazol-1-yl) -2 ', 4'-difluoroacetophenone (Intermediate 3)
2-Chloro-2 ', 4'-difluoroacetophenone with triazole, triethylbenzylammonium chloride (TEBA) and potassium carbonate in CH2Cl2The reaction was carried out at 0-5 ° C for 5 hours and then at room temperature for 12 hours to give 2- (1H-1,2,4-triazol-1-yl) -2 ', 4'-difluorophenylethylKetone (3).
With potassium carbonate In acetonitrile at 0 - 25℃;
With Sodium hydrogenocarbonate In toluene for 24h; Reflux;
3.1.2. General Procedure for the Synthesis of 1-(2,4-Disubstituted phenyl)-2-(1H-1,2,4-triazol-1-yl)Ethanone (3a-e)
General procedure: A flask equipped with a reflux condenser was charged with a mixture of 2-chloro-1-(2,4-disubstituted phenyl) ethanone (2a-e) (40 mmol) and 1,2,4-triazole (40 mmol, 3.31 g) which refluxed in 40 mL toluene in the presence of sodium bicarbonate (48 mmol, 4.04 g) for 24 h. Then the reactionmixture was poured into crushed ice and extracted with ethyl acetate (2 50 mL). The combinedorganic layers were washed with water and brine, dried over anhydrous sodium sulfate andconcentrated in a vacuum. The compounds 3a-e crystallized from diethyl ether.
With potassium carbonate In acetonitrile at 20 - 60℃;
With potassium carbonate In acetonitrile at 85℃; for 0.833333h; Microwave irradiation;
With triethylamine In methanol at 65℃;
4.5 The preparation of compounds 12a-12d
General procedure: The synthesis of intermediate 1-(2,4-difluorophenyl)-2-(1H-imidazole-1-yl) ethan-1-one (12b) was chosen as the example: The 2-chloroacetyl chloride (10) (6.7g, 0.06mol) was added dropwise to the mixture of 1,3-difluorobenzene (5.7g, 0.05mol) and anhydrous aluminum trichloride (10.7g, 0.08mol) at 25°C. The reaction was stirred at room temperature for 4h. Subsequently, the mixture was diluted with ice water mixture (100g) containing concentrated hydrochloric acid (10mL). The solution was extracted with dichloromethane (3×20mL). The organic layers were combined and washed with saturated salt water (30mL). The organic layer was dried with Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethanol to give 11b (93.1%) as a yellow solid. To a stirred solution of intermediate 11b (14.5g, 0.08mol) in 70mL anhydrous methanol with triethylamine (8.1g, 0.08mol), imidazole (10g, 0.15mol) was then added at 25°C. The mixture was magnetically stirred heated to reflux for 4h and then concentrated under reduced pressure to remove methanol. The residue was purified by recrystallization from ethanol to obtain 1-(2,4-difluorophenyl)-2-(1H-imidazole-1-yl) ethan-1-one (12b, 90.6%) as a white solid.
ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluoro-2-methylbutyrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In hexane; water; ethyl acetate;
REFERENCE EXAMPLE 7 To 40 ml of a solution of lithium diisopropylamide in dried diethyl ether prepared from 4.3 g of diisopropylamine and 26.0 ml of a 1.64N n-hexane solution of n-butyllithium was dropwise added 10 ml of a dried diethyl ether solution containing 5.1 g of <strong>[349-43-9]ethyl 2-fluoropropionate</strong> at -70° to -60° C. The mixture was stirred at the same temperature for 15 minutes. Thereto was dropwise added 60 ml of a dried diethyl ether solution containing 6.2 g of 2-chloro-2',4'-difluoroacetophenone at -70° to -60° C. Then, the temperature of the mixture was elevated to 20° C. in 5 hours. The reaction mixture obtained was introduced into a mixed solvent consisting of 100 ml of ethyl acetate and 50 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=2/1) to obtain 3.9 g of oily ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluoro-2-methylbutyrate (a mixture of diastereomers). IR (neat) cm-1: 2985, 1760, 1740, 1505, 1140
EXAMPLE 1a 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl-2-hexane to obtain 198 g of the title compound. STR94
With sodium acetate; sodium iodide; In N,N-dimethyl-formamide;
EXAMPLE 1A 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of NaI, and 3L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1L. Pour the residue into 6L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl-2-hexane to obtain 198 g of the title compound. STR100
With sodium acetate; In N,N-dimethyl-formamide;
EXAMPLE 1A 2-Acetyloxy-1(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl2 -hexane to obtain 198 g of the title compound. STR35
With sodium acetate; In N,N-dimethyl-formamide;
EXAMPLE 1A 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1L. Pour the residue into 6L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl-2-hexane to obtain 198 g of the title compound. STR103
With sodium acetate; In N,N-dimethyl-formamide;
EXAMPLE 1a 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl-2-hexane to obtain 198 g of the title compound. STR106
With sodium acetate; In N,N-dimethyl-formamide;
Example 1a 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20 C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2 SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2 Cl-2-hexane to obtain 198 g of the title compound. STR101
With sodium acetate; In acetic acid;
(i) 2-Acetoxy-2',4'-difluoroacetophenone A solution of 2-chloro-2',4'-difluoroacetophenone (19.0 g) and anhydrous sodium acetate (16.4 g) in acetic acid (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with sodium bicarbonate solution and dried (Na2 SO4). Evaporation of the solvent gave an oil which was triturated with hexane. The resulting solid was filtered off, washed with hexane and dried to give the title compound, (16.2 g), m.p. 54-56.
With sodium acetate; In N,N-dimethyl-formamide;
EXAMPLE 1a 2-Acetyloxy-1-(2,4-difluorophenyl)ethanone Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20C for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluding with CH2Cl2-hexane to obtain 198 g of the title compound.
1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloroethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; ammonium chloride; In tetrahydrofuran; hexane;
(1) Synthesis of 1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloroethanol STR113 After <strong>[58249-61-9]6-cyanobenzothiazole</strong> (1.60 g) was dissolved in tetrahydrofuran (80 ml), and the solution was cooled to -98 C. in a nitrogen atmosphere, a 1.6M solution (5.9 ml) of n-butyllithium in hexane was added dropwise over 10 minutes, and the resultant mixture was stirred for 5 minutes. A solution of 2-chloro-2',4'-difluoroacetophenone (2.85 g) in tetrahydrofuran (20 ml) was added dropwise to this mixture. After the liquid reaction mixture was heated to -10 C., an aqueous solution of ammonium chloride was added thereto. After the mixture was heated to room temperature, an organic layer was taken out, and the solvent was distilled out under reduced pressure. A water layer was extracted with ethyl acetate and the extract was then put together with the residue of the organic layer. This organic layer was washed with water and then with saturated saline, dried over magnesium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography on silica gel (solvent: hexane/ethyl acetate=20/1, next, hexane/ethyl acetate=5/1), thereby obtaining the intended compound (1.49 g).
With potassium carbonate; In acetone; at 20℃; for 20h;
Example 41A Methyl 1-[2-(2,4-difluorophenyl)-2-oxoethyl]-1H-1,2,4-triazole-5-carboxylate 5.0 g (39.34 mmol) of <strong>[4928-88-5]methyl 1H-1,2,4-triazole-3-carboxylate</strong> were initially charged in 96 ml of acetone, and 7.87 g (41.3 mmol) of 2-chloro-1-(2,4-difluorophenyl)ethanone and 6.25 g (45.2 mmol) of potassium carbonate were added. The reaction mixture was stirred at RT for 20 h and then concentrated at 30° C. on a rotary evaporator. The residue was taken up in 600 ml of dichloromethane and 400 ml of water and washed twice with water and once with saturated sodium chloride solution. The organic phase was separated off, dried over magnesium sulphate and freed from the solvent. The crude product was chromatographed on a reversed phase, column type: Daisco C18, 10 mum Bio (DAN 300*100 nm). The mobile phase was a gradient of acetonitrile and water. 0.97 g (9percent of theory) of the product was obtained as a solid. LCMS (method 8): Rt=0.81 min. (m/z=282 (M+H)+) 1H-NMR (400 MHz, DMSO-d6): delta=8.26 (s, 1H), 8.04 (q, 1H), 7.57 (m, 1H), 7.33 (dt, 1H), 6.05 (s, 2H), 3.82 (s, 3H).
With potassium carbonate In dichloromethane at 20℃; for 24h;
65%
With potassium carbonate In acetonitrile
1 Example 1: Preparation of 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone (abbreviated as Compound 1)
Triazole (6.9 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were added to a 250 mL round bottom flask, and an appropriate amount of acetonitrile was used as a solvent, and 2',4'-difluoro-2-chlorobenzene was added with stirring. Ketone (19.0 g, 0.1 mol). After the completion of the reaction, the solvent was evaporated to dryness, and then evaporated, and then evaporated and evaporated. After rotary distillation and recrystallization, 14.5 g of a pale yellow solid was obtained, yield: 65%.Melting point: 108 to 110 ° C (commercial product 107 to 111 ° C).
With potassium carbonate; In tetrahydrofuran; at 20℃; for 7h;
First, 43.7 g of <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> is introduced into 200 mL of tetrahydrofuran (THF), the resultant mixture is agitated, and 40.4 g of 2-chloro-2,4-difluoroacetophenone is further introduced thereto. Next, 36.3g of potassium carbonate is introduced to the reaction mixture and the resultant mixture is agitated for 7 hours at room temperature. After the completion of the reaction, the reaction mixture is filtered, washed with 100 mL of tetrahydrofuran (THF), andconcentrated at room temperature. Then, 437 mL of purified water is introduced so that the crystals are slurried, followed by filtering. The filtered crystals are reslurried in 175 mL of isopropanol and filtered again. The crystals are washed with 44 mL of isopropanol and dried with hot air at 50C to obtain 63.8 g of the title compound as a white solid (yield 87%, purity 99.2%, HPLC, detected at a wavelength of 256 nm, 18C 4.6 X 250 mm, mobile phase 60% ACN, flow rate 1 mL/min). [96] 1H-NMR (200MHz, CDCl3) delta (ppm) : 8.11~8.03(1H), 7.11-6.96(2H), 5.51(2H).
87%
With potassium carbonate; In tetrahydrofuran; at 20℃; for 7h;
EXAMPLE 1Preparation of 2-(3,5-dibromo-1H-1,2,4-triazol-1-yl)-1-(2,4-difluorophenyl)ethan-1-oneFirst, 43.7 g of <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> is introduced into 200 mL of tetrahydrofuran (THF), the resultant mixture is agitated, and 40.4 g of 2-chloro-2,4-difluoroacetophenone is further introduced thereto. Next, 36.3 g of potassium carbonate is introduced to the reaction mixture and the resultant mixture is agitated for 7 hours at room temperature. After the completion of the reaction, the reaction mixture is filtered, washed with 100 mL of tetrahydrofuran (THF), and concentrated at room temperature. Then, 437 mL of purified water is introduced so that the crystals are slurried, followed by filtering. The filtered crystals are reslurried in 175 mL of isopropanol and filtered again. The crystals are washed with 44 mL of isopropanol and dried with hot air at 50 C. to obtain 63.8 g of the title compound as a white solid (yield 87%, purity 99.2%, HPLC, detected at a wavelength of 256 nm, 18C 4.6×250 mm, mobile phase 60% ACN, flow rate 1 mL/min).1H-NMR (200 MHz, CDCl3) delta (ppm): 8.118.03(1H), 7.11-6.96(2H), 5.51(2H).
3-(2-(2,4-difluorophenyl)-2-oxoethyl)-6-propylthieno[2,3-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-(n-propyl)thieno[2,3-d]pyrimidin-4(3H)-one With potassium carbonate at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 2-chloro-1-(2,4-dichlorophenyl)ethanone at 20℃; for 12h; Inert atmosphere;
1-(2,4-difluorophenyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
General procedure: The triazoles were converted to their sodium salts by treatment with an aqueous solution of sodium hydroxide followed by precipitation, according to the previous literature [26]. The reaction proceeded according to the procedure described by Papadopoulou etal. [27] After dried, the sodium salt of the respective triazole was solubilized in acetonitrile and added to an equimolar solution (0.5M) of 2-Chloro-2?,4?-difluoroacetophenone in acetonitrile for a nucleophilic substitution, which occurred under refluxing conditions (8h). The resulting suspension was filtered, and the liquid phase was evaporated. The resulting solid was purified using automated flash column chromatography.
Stage #1: 3H-1,2,4-triazole With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In dichloromethane for 0.166667h;
Stage #2: 2-chloro-1-(2,4-dichlorophenyl)ethanone In dichloromethane at 20℃; for 6h; Cooling with ice;
1.2 (2) 2 ', 4' - difluoro -2 - (1H - 1,2, 4 - triazole -1 - yl) acetophenone synthesis (d2)
In the equipped with a thermometer, constant pressure funnel, the reflux condensation tube (with drying tube) of 250 ml of four flasks, adding 1, 2, 4 - triazole (0.13 µM, 8 . 97g), catalyst TEBA (0.2 µM, 0 . 5g), K2CO3(0.1 µM, 13 . 8g), CH2Cl2(50 ml), stirring 10min. The ice under the condition α - chloro - 2, 4 - difluoro have drip acetophenone (0.1 µM, 19 . 1g) of CH2Cl2(50 ml), after dropping, the removal of the ice bath, the room temperature room temperature reaction 6h, then filtering the residue, pressure reducing and recovering the solvent, to obtain the crude product. The crude product is poured into ice water (500 ml) in, by adding 1 mol/L hydrochloric acid (120 ml) the crude product is dissolved completely, separation and the removal of the insoluble oil object, the water layer NaHCO3(8g) and to pH6 in, and then to the water layer by adding ethyl acetate (50 ml) extraction of the organic matter, and steaming and to obtain white solid 15.1g, yield 67.3%. White solid using ethyl acetate followed by recrystallization to obtain white crystal.
In N,N-dimethyl-formamide; at 70 - 75℃; for 12h;Inert atmosphere;
Prepare a dry, clean 500mL glass four-port bottle, equipped with a suitable mechanical stirrer, condenser tube and thermometer, and check the airtightness before adding the material.95 g of 2'-chloro-2,4-difluoroacetophenone (compound 5) (0.5 mol, 1 eq), 69 g was added to the reaction flask under N2 protection.Sodium 1,2,4-triazolyl (Compound 6) (0.75 mol, 1.5 eq) and 200 mL of DMF were stirred and the temperature of the reaction solution was raised to 70-75 C. The reaction was stirred for 12 h. After the reaction was completed, the reaction system was cooled to At room temperature, 400 ml of water was added, and then 600 ml of ethyl acetate was added for extraction. The separated ethyl acetate phase was washed with 300 ml of water and the organic phase was separated. The solvent was distilled off under reduced pressure and 300 ml of n-heptane was added for recrystallization to give a white solid. Powdery Compound 1 84.8 g (yield: 76.0%).
2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4-difluorophenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With Sodium hydrogenocarbonate In acetonitrile for 24h; Reflux;
3.3. Synthesis of N-Phenacylbenzimidazoles 4,5a-f, 4,5h-j
General procedure: The mixture of benzimidazole 1 or 2 (4 mmol), MeCN (160 mL), phenacyl halide3 (4 mmol), andNaHCO3(20 mmol, 1.68 g) was stirred magnetically at reflux. Thereaction was monitored by TLC (CHCl3/MeOH 95/5 v/v) typically after 16, 20, and24 h. If necessary, additional portions of phenacyl halide (1-4 mmol) were added after16.5 and 20.5 h. In most cases, full conversion of benzimidazole 1 or 2 was observed afterca 24 h. The mixture was cooled, filtered through a short pad of celite, washed with MeCN(410 mL), evaporated to dryness. The solid residue was transferred to a Schott funneland washed with the respective solvent (5-72-10 mL, see Supporting Information S2).The oily residue was purified by column chromatography (silica gel,CHCl3as eluent). Iffull conversion of benzimidazole 1 or 2 was not observed after 24 h, further portions ofsubstrate 3 were added, the reaction was continued and worked-up as described above.Traces of isomeric 2-(5,7-dibromo-1H-benzimidazol-1yl)-1-arylethanones formed inN-alkylations of 4,6-dibromobenzimidazole 2 with phenacyl halides 3a-j were removedby column chromatography (silica gel, chloroform as eluent) or by crystallization (MeOHor EtOH).
22%
With potassium carbonate In acetonitrile for 3h;
4.1.2. Synthesis of 4e-i and 5e-i
General procedure: To a stirred suspension of 5,6-dibromobenzimidazole 1 or 4,6-dibromobenzimidazole2 (1 mmol, 0.276 g) in MeCN (20 mL) K2CO3 (8 mmol, 1.106 g) followed by 3e-j (2mmol) was added. The reaction was carried out at room temperature (20-22 °C) for 3h for3e-i and 96 h for 3j. After this time the solid products were filtered, washed out withMeCN (25 mL), evaporated. The residue was purified twice by column chromatography(silica gel/CHCl3, eluent CHCl3 followed by silica gel/toluene, eluent toluene/EtOAc gradient,50:0 to 50:15). Analytical sample was crystallized (EtOH).
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