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Structure of 4252-78-2 * 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 70℃; for 9 h; Stage #2: at 50 - 100℃; for 5 h; Stage #3: at 105℃; for 6 h;
This embodiment provides a method for preparing graciousness kang zuo, comprises the steps of: under stirring, sequentially the formic acid 185 g (4.0 µM), 2, 4 - dichloro -2 ' - chloro acetophenone 45.1 g (0.2 µM), triethylamine 10 g (0.1 µM), RuCl2(Pph3)39. 5 G (0.01 µM) into 500 ml three flasks, heating 70 °C insulation reaction 9 h. Reaction finishes cooling to 50 °C, negative pressure steaming to without dripping the liquid, to a room temperature. Adding DMA 175 g (2.0 µM), sodium hydroxide 16 g (0.4 µM), imidazole 22 g (0.32 µM), heating up to 100 °C insulation reaction 5 h, cooled to the room temperature, dropping propyl 24 g (0.32 µM), heating up to 105 °C insulation reaction 6 h. The completion of the reaction to room temperature, add 320 ml water, filtered to obtain [...], crude product by adding 100 ml ethanol, heating reflux 1 h, to room temperature and filtered, to obtain fine graciousness kang zuo 28.7 g, yield 64.4percent, liquid phase analysis purity ≥ 98percent, melting point 50.9 - 52.0 °C.
Reference：
[1] Patent: CN108191765, 2018, A, . Location in patent: Paragraph 0023-0034
2
[ 4252-78-2 ]
[ 24155-42-8 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 7035 - 7044
[2] Polyhedron, 2013, vol. 52, p. 106 - 114
[3] Patent: CN102180835, 2016, B,
[4] Chemical Science, 2017, vol. 8, # 4, p. 2687 - 2701
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 23, p. 4288 - 4294
3
[ 79-04-9 ]
[ 541-73-1 ]
[ 4252-78-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
With aluminum (III) chloride In dichloromethane for 3 h; Reflux
A three-necked flask dichlorobenzene (147g), chloroacetyl chloride (of 113g) and dichloromethane (750ml), at room temperature was added portionwise aluminum trichloride (147g), the addition was completed the reaction was warmed to reflux for 3h. Completion of the reaction was added to ice, the layers were separated and the organic phase washed with water (500mL × 2), saturated sodium bicarbonate solution (500mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and the residue was added petroleum ether (1200mL), cooled to room temperature, set the refrigerator overnight crystallization. Filtered and dried to yield an off-white solid, compound 2 (193g, 86percent).
Reference：
[1] Journal of Chemical Sciences, 2015, vol. 127, # 12, p. 2251 - 2260
[2] Patent: CN105566309, 2016, A, . Location in patent: Paragraph 0003; 0007
[3] Chemische Berichte, 1907, vol. 40, p. 1703
[4] Tetrahedron Asymmetry, 2003, vol. 14, # 24, p. 3861 - 3866
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5368 - 5371
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5363 - 5366
[7] Patent: WO2016/92478, 2016, A1, . Location in patent: Paragraph 0120
[8] Chinese Journal of Chemistry, 2017, vol. 35, # 4, p. 483 - 496
[9] Molecules, 2017, vol. 22, # 7,
4
[ 2234-16-4 ]
[ 2274-66-0 ]
[ 4252-78-2 ]
Yield
Reaction Conditions
Operation in experiment
73%
With chloro-trimethyl-silane; potassium nitrate In dichloromethane at 60℃; for 16 h;
General procedure: In a Nalgene.(R). bottle, to acetophenone (2 mmol) in dichloromethane (10 mL), potassium nitrate (4 mmol) and chloro/bromotrimethylsilane (8 mmol) were added. The heterogeneous mixture was stirred vigorously at 60 °C (for chlorination) or room temperature (for bromination) until the reaction went to completion (monitored by 1H NMR spectroscopy). The reaction mixture was then filtered and solvent removed under reduced pressure. The chlorinated/brominated acetophenone derivatives were obtained upon purification by flash chromatography (silica gel) with hexane as eluent. The products were characterized by comparing their spectroscopic data with those of the authentic samples.
In a reaction vessel equipped with a stirrer, a thermometer, a reflux condenser, and a dropping funnel,0.4 mol of m-dichlorobenzene (2), 0.55 mol of stannous chloride,The stirring speed was controlled at 170 rpm,0.48 mol of chloroacetamide was added slowly,Dropping time control in 90min,The solution temperature was raised to 65 & lt; 0 &Reaction 5h will react into 900ml of 20percent potassium chloride solution,Lower the temperature of the solution7 [deg.] C,Precipitation of pale yellow solid,filter,Sodium carbonate solution,Mass fraction 85percent hexane solution,Molecular sieve bleaching,The solution temperature was reduced to 4 & lt; 0 &Precipitation of yellow flaky crystals, filtration,Mass fraction of 95percent methylamine solution washing,Anhydrous magnesium sulfate dehydration,Too2,4-dichlorophenyl chloromethyl ketone 83.33 g, yield 93percent.
Reference：
[1] Patent: CN105439832, 2016, A, . Location in patent: Paragraph 0014; 0015
6
[ 79-04-9 ]
[ 95-50-1 ]
[ 4252-78-2 ]
Yield
Reaction Conditions
Operation in experiment
88.5%
at 30 - 50℃;
Referring to the literature (Pericherla et al., 2012), a mixtureof m-dichlorobenzene 14.70 g (0.1 mol) and alchlor 21.40 g(0.16 mol) were added in a 250 mL three-necked bottle witha drying device and a condenser. Chloracetyl chloride 9.8mL (130 mmol) was dripped into the above slurry understirring and the reaction temperature 30 °C. After chloracetylchloride was completely dripped into the slurry, thereaction was on with stirring under 40–50 °C for 9 h. Thereaction mixture was poured into 5percent hydrochloric acid,then was filtered and washed with distilled water. Lightyellow solid 2 in yield of 88.5percent (18.62 g) was obtainedafter recrystallizing in hexane. The detected m.p. of thetarget product 2 was 52–54 °C.
General procedure: Compound 10 was prepared following apreviously published protocol. 4-Amino-4H-1,2,4-triazole (0.15 g, 1.72mmol) was added to a stirred mixture of 2,2',4'-trichloroacetophenone (0.50 g, 2.24 mmol) in i-PrOH (3 mL). After stirring for 12 h at 80 C, the reaction mixture was cooled to rt and wasevaporated to dryness under reduced pressure to give a residue, which was dissolved in CH2Cl2(2 mL) and stirred for 30 min at 0 C. The precipitated solid was filtered and washed withCH2Cl2 (1 mL) to yield compound 10 (0.50 g, 94%) as a white solid.
94%
In isopropyl alcohol;Reflux;
The synthetic pathways for the preparation of target compounds 1-9 and 24-41 are depicted in FIG. 2. We synthesized compounds 1-9 using a straightforward strategy, which involved the Grignard reactions of 2,4-difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone with different alkyl magnesium bromide in the presence of magnesium bromide ethyl etherate. Compounds 24-41 were prepared in three steps. 4-Amino-1,2,4-triazole was reacted with various 2-haloacetophenone in refluxing isopropanol to give 10-16 in excellent yields (88-96%). Compounds 10-16 were conveniently deaminated by NaNO2 in aqueous HCl at room temperature. The desired products 17-23 were precipitated after neutralization of the reaction with potassium carbonate. The precipitates were collected by filtration and washed with water to afford pure products. No further purification was required because the excess of reactants was soluble in water and removed by filtration.
72%
In isopropyl alcohol; for 4h;Reflux;
4.41 g (0.0525 mol) of 4-amino-4H-1,2,4-triazole and 11.26 g (99.28%, 0.05 mol) of 2-chloro-1-(2,4-dichlorophenyl)ethanone Place in a 250 ml three-necked flask and stir with 100 ml of isopropanol.Heating under reflux for 4 hours; the product crystallized at the reflux temperature,The reaction mixture was cooled, filtered and washed with isopropyl alcohol.After drying, the product was 11.073g (72%).Mp. 214-215C;
With potassium carbonate In acetonitrile for 4h; Reflux;
2’-1H-Imidazole-2,4-dichloroacetophenone (10)
To a solution of 2’-chloro-2,4-dichloroacetophenone (9, 1.0 g, 4.47 mmol) in acetonitrile (60 mL), was added potassium carbonate (0.74 g, 5.37 mmol) and imidazole (0.37 g, 5.37 mmol) and the mixture was refluxed for 4 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was purified by column chromatography (SiO2, 70% EtOAc in hexanes) to give 10 as a white solid (1.1 g, 96%). 1H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 8.3 Hz, 1H), 7.51 - 7.48 (m, 2H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (t, J = 1.1 Hz, 1H), 6.94 (t, J = 1.3 Hz, 1H), 5.35 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 193.70, 139.16, 138.01, 134.02, 132.50, 131.05, 130.76, 129.61, 127.92, 120.09, 55.45.
87.2%
In dichloromethane
1.1 Synthesis of 2,4-dichloro-2-imidazoleacetophenone
in1000ml of three necked flask equipped with a stirrer, thermometer, droppingfunnel added 111g of 2,4, ω- trichloro acetophenone (0.5mol) , Dichloromethane150ml and after stirring to dissolve , while stirring added drop wise 102g (1.5mol) imidazole and 500ml dichloromethane solution within about 2 hours drop wisewill be completed , After completion it wasstirred for 4-5h. Then TLC detection reaction(Ethyl acetate: petroleum ether 6.9. = 1: 4 (ν / ν)) after the completion ofthe reaction dichloromethane recovered under reduced pressure, the residue waspoured into water to that is precipitate a solid , filtrated, washed with waterto obtain crude product . Refined 110.88, 87.2% yield, M.P. 76-78°C.
84%
Stage #1: 1H-imidazole With triethylamine In methanol at 20℃;
Stage #2: 2,2',4'-trichloroacetophenone 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]+.
72%
In dichloromethane at 0 - 20℃; for 12h;
64%
In toluene at 75℃; for 2.25h;
58%
In dichloromethane at 40℃; for 2h;
38%
With triethylamine In N,N-dimethyl-formamide for 24h; Reflux;
Compound 2d.
A mixture of 1b (2.5 g, 11.0 mmol), imidazole (0.92 g,13.5 mmol), and triethylamine (1.9 mL, 13.5 mmol) in DMF (20 mL) wasrefluxed for 24 h. The reaction was monitored by TLC (MeOH/DCM, 1:9).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 2d (1.07 g, 38%).
28%
In dichloromethane at 40℃; for 2h;
In acetonitrile
16.a 1-[2-(2,4-Dichloro-phenyl)-2-isopropoxy-vinyl]-1H-imidazole
a) Analogously to Example 1a, after reacting 2,2',4'-trichloroacetophenone with imidazole there was obtained 1-(2,4-dichlorophenyl)-2-(1H-imidazol)-1-yl-ethanone.
In DMF (N,N-dimethyl-formamide)
In acetonitrile at 20℃; for 24h;
1.a Preparation 1 a) Substitution (Introduction of the Imidazole): 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanone:
Preparation 1 [0128] a) Substitution (Introduction of the Imidazole): [0129] 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanone: [0130] Trichlorinated derivative, 2-chloro-1-(2,4-dichlorophenyl)-ethanone (5.58 g), is added to 5.10 g of imidazole (75 mmole) in 25 ml of acetonitrile, and the reaction medium is stirred at ambient temperature for 24 hours. Then 50 ml of dichloromethane and 50 ml of water are added, followed by extracting, decanting, washing then re-extracting with dichloromethane. The organic phases are dried and evaporated under reduced pressure until a dry extract is obtained, which is purified by chromatography on silica eluting with a CH2Cl2/MeOH mixture 96/4 to afford 4.76 g of the expected product. [0131] NMR (CDCl3, 300 MHz, δ, ppm): 5.35 (s, 2H, N-CH2-CO); 6.95 (s) and 7.13 (s) 2H H4 and H5; 7.38 (dd, 1H, Hb); 7.51 (d, 1H, Ha); 7.56 (bs, 1H, H2); 7.58 (d, 1H, Hc)
With potassium carbonate In acetonitrile
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.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 48h;
To a solution of 4-iodo-2-hydroxy-benzaldehyde (5. 4 g, 22 MMOL) and 2-chloro-1- (2, 4-DICHLOROPHENYL) ETHANONE (11.2 g, 50.0 MMOL) in anhydrous N, N-DIMETHYLFORMAMIDE (100 mL) was added K2CO3 (12.0 g, 86.9 MMOL). The dark brown reaction mixture was stirred at 90 C for 48 h, then poured onto water (150 mL) and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with 50% hexanes in dichloromethane. The desired product was obtained as an orange solid (2.06 g, 23%). 1H-NMR (CDCI3) a 7.98 (s, 1 H), 7.70 (dd, J = 8.3, 1.3 Hz, 1 H), 7.54-7. 21 (m, 5H).
With potassium carbonate In acetonitrile for 4h; Reflux;
2’-1H-Imidazole-2,4-dichloroacetophenone (10)
General procedure: To a solution of 2’-chloro-2,4-dichloroacetophenone (9, 1.0 g, 4.47 mmol) in acetonitrile (60 mL), was added potassium carbonate (0.74 g, 5.37 mmol) and imidazole (0.37 g, 5.37 mmol) and the mixture was refluxed for 4 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was purified by column chromatography (SiO2, 70% EtOAc in hexanes) to give 10 as a white solid (1.1 g, 96%).
95%
With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 14h;
With caesium carbonate In N,N-dimethyl-formamide
81.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
100.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl) -2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
136.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
262.A A.
A. 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then the reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The ethyl acetate layer was concentrated and then purified by trituration with diethyl ether.
With caesium carbonate In N,N-dimethyl-formamide
264.A A.
A. 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then the reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The ethyl acetate layer was concentrated and then purified by trituration with diethyl ether.
With caesium carbonate In N,N-dimethyl-formamide
83.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
94.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl) -2-oxoethyl]isoindoline-1,3 -dione.
With caesium carbonate In N,N-dimethyl-formamide
95.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl) -2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
96.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
With caesium carbonate In N,N-dimethyl-formamide
97.1 1.
1. Preparation of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione 1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and the purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl) -2-oxoethyl]isoindoline-1,3-dione.
With potassium carbonate; In acetone; at 20℃; for 20h;
Example 18A Methyl 1-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1H-1,2,4-triazole-5-carboxylate 4.3 g (33.8 mmol) of <strong>[4928-88-5]methyl 1H-1,2,4-triazole-3-carboxylate</strong> were initially charged in 58 ml of acetone, and 7.9 g (35.4 mmol) of 2'-chloro-2,4-dichloracetophenone and 5.3 g (38.9 mmol) of potassium carbonate were added. The mixture was stirred at RT for 20 h. The reaction mixture was then concentrated at 20° C. on a rotary evaporator. The residue was taken up in dichloromethane and washed twice with water and once with saturated sodium chloride solution. The organic phase was separated off, dried over magnesium sulphate and concentrated at 20° C. on a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/ethanol 100:1). This gave 1.47 g (10percent of theory) of the product as a solid. LCMS (method 8): Rt=1.08 min. (m/z=314 (M+H)+) 1H-NMR (400 MHz, DMSO-d6): delta=8.27 (s, 1H), 8.00 (d, 1H), 7.85 (ss, 1H), 7.68 (dd, 1H), 6.12 (s, 2H), 3.85 (s, 3H).
EXAMPLE 74; 2-(2,4-Dichlorophenyl)-3-(hydroxymethyl)imidazo[l,2-a]pyridine-6-carboxamide; 6-Aminonicotinamide (41 mg, 0.30 mmol) and 2,4-dichlorophenacyl chloride (45 mg, 0.20 mmol) were mixed in ethanol (0.5 mL) and stirred at rt over the weekend. The mixture was then heated at 70 °C for 2 days. 0.5 M NaOH (1.2 mL) was added slowly with stirring. The precipitate that formed was collected by centrifugation and washed with water (1.5 mL) to give the intermediate compound 2-(2,4-dichlorophenyl)imidazo[l,2-a]pyridine-6- carboxamide. MS (ESI+) m/z 306, 308 [M+H]+.
With sodium tetrahydroborate In methanol at 0℃; for 1h; Inert atmosphere;
7. 2-Chloro-1-(2,4-dichlorophenyl)ethanol (16)
Sodium borohydride (2.5 g, 65 mmol) was added at 0°C to a solution of 2-chloro-1-(2,4-dichlorophenyl)ethanone (15, 15 g, 65 mmol) in 65 ml of methanol.The reaction mixture was stirred for 1 h at 0° C, then the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution and water and warmed to room temperature. The reaction mixture was extracted with dichloromethane, and the phases were separated. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to deliver 2-chloro-1-(2,4-dichlorophenyl)ethanol (16, 14.4 g, 64 mmol, 98 %)which was pure enough to be used in the next step without any further purification.1H-NMR (400 MHz, CDCl3): δ = 2.71 (d, 1H, J = 3.9 Hz), 3.52 (dd, 1H, 8.4, 11.4Hz), 3.87 (dd, 1H, J = 2.6, 11.4 Hz), 5.26 (dt, 1H, 2.6, 8.4 Hz), 7.31 (dd, 1H, J =2.1, 8.3 Hz), 7.38 (d, 1H, J = 2.1 Hz), 7.57 (d, 1H, J = 8.3 Hz). LC-MS: Rt = 1.41min; MS: m/z = 224 [M+1]+.
90%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 0.666667h;
90%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 0.666667h;
4.4. General procedure for syntheses of rac-halohydrins (rac-2a-k)
General procedure: To a solution of α-haloketone 1a-k (45 mmol) in methanol (40 mL)at 0 °C, it was slowly added 0.085 g (2.2 mmol) of sodium borohydride.The reaction system was stirred for 30 min at r.t., and after this time,the solvent was evaporated under reduced pressure. Subsequently, thereaction mixture was acidified with the addition of 10 mL of a 1 M HClsolution and extracted with EtOAc (4 × 60 ml). After combining theorganic phases, drying with anhydrous sodium sulfate, filtration andevaporation of the solvent under reduced pressure, it was possible toobtain the crude product. The latter was purified by chromatographyusing silica gel as an adsorbent and chloroform as an eluent. Thisprocedure produced halohydrins rac-2a-k with yields from 87 to 93 %.
90.1%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 6h;
1.1 Step 1:
Dissolve 2,2’,3’-dichloroacetophenone (1g, 4.47mmol) in methanol,The temperature was lowered to 0°C in an ice bath, and then sodium borohydride (0.20g, 5.37mmol) was added.The temperature was gradually raised to room temperature and reacted for 6h. The reaction was completed by TLC.5mL saturated ammonium chloride solution was added to quench the reaction, and concentrated under reduced pressure to remove methanol,The concentrated solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the concentrated reduced product 0.91g,The reaction yield was 90.1%.
89%
Stage #1: 2,2',4'-trichloroacetophenone With sodium tetrahydroborate In methanol at 0 - 20℃; for 1.5h; Inert atmosphere;
Stage #2: With water In methanol
73%
With sodium tetrahydroborate In isopropyl alcohol at 3 - 20℃; for 2h;
General procedure for reduction. Procedure for synthesis of halohydrins
General procedure: NaBH4 (0.21 g, 5.5 mmol) was added (in three portions)to a solution of the corresponding ketone (5.5 mmol) 4 or 5 in2-propanol (25 mL) at 3-5 C. The mixture was stirred at roomtemperature for 2 h. Then, the reaction mixture was poured intowater, the solution was extracted with ethyl acetate and driedover anhydrous Na2SO4. The solvent was distilled. The obtainedlight crude product was recrystallized from the appropriate solvent. 2-Chloro-1-(2,4-dichlorophenyl)ethanol (11). Yield 73%. M.p.53 C (from acetone). IR (KBr, cm 1): 3600 (w), 3200 (m), 1475(s), 1100 (m), 815 (s), 750 (m). 1H NMR (DMSO-d6, ppm): 3.32-3.8 (m, 2 H, 2CH2), 5.0-5.2 (m, 1 H, 1CH), 5.44 (d, J = 10.4 Hz, 1 H,OH), 7.20 (d, J = 1.94 Hz, 1 H, 6CH), 7.31 (d, J = 1.94 Hz, 1 H, 5CH),7.60 (s, 1 H, 3CH). 13C NMR (DMSO-d6, ppm): d = 137.20 (2C),133.20 (5C), 132.14 (6C), 130.01 (3C), 129.20 (4C), 99.12 (6C),69.14 (7C), 48.7 (8C). Anal. Calc. for C8H7Cl3O (225.5): C, 42.61; H,3.13; Found: C, 42.62; H, 3.13%
With sodium tetrahydroborate In methanol at 20℃;
With sodium tetrahydroborate In methanol Inert atmosphere;
1.99 g
With methanol; sodium tetrahydroborate at 0℃; for 0.25h;
1.1 Preparation of 2-chloro-1-(2,4-dichlorophenyl)ethanol
A 25 mL flask is charged with 2-chloro-1-(2,4-dichlorophenyl)ethanone (2 g, 8.68 mmol) and MeOH (9 mL). The flask is cooled at 0 °C with an ice bath and NaBH4 (270 mg, 2.34 mmol) is added as a solid. After 15 minutes reaction, the reaction is quenched with a saturated aqueous solution of NH4Cl (10 mL). The aqueous phase is extracted with AcOEt (2 x 5 mL) and the combined organic phases are washed with brine (10 mL), dried with Na2SO4, filteredand evaporated to give 2-chloro-1-(2,4-dichlorophenyl)ethanol (1.99 g) as a pale orange oil. 1H-NMR (400 MHz, CDCl3): δ= 7.57 (d, J= 8.3 Hz, 1H), 7.38 (d, J= 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 2.1 Hz, 1H), 5.26 (dt, J= 8.4, 2.6 Hz, 1H), 3.87 (dd, J= 11.4, 2.6 Hz, 1H), 3.52 (dd, J= 11.4, 8.4 Hz, 1H).
With aluminum isopropoxide In isopropyl alcohol at 65℃; for 5h; Green chemistry; Industrial scale;
Into a three-necked flask equipped with an electric stirrer, a thermometer and a reflux condenser, 120 g of isopropyl alcohol was added,14 g of aluminum isopropoxide and 30 g of 2,2',4'-trichloroacetophenone were heated at 65 ° C for 5 h ; Speed control in the 400 ~ 500r / min; in the vacuum for the 08.0 ~ lmpa,The temperature is below 70 ° C distilled to remove isopropanol and acetone; by adding 15% dilute nitric acid,Stirring and neutralizing aluminum isopropoxide to remove the acid water layer; liquid with 55 ~ 65 ° C hot water washing to neutral; liquid cooling,Curing to give 2,4-dichloro-α-chloromethylbenzyl alcohol,The melting point of 49. 6 ~ 50. 4 ° C;The mixture of isopropanol and acetone distilled under reduced pressure was subjected to distillation,The fractions were collected at 80-84 ° C,Can be recycled. Acid water with 25% ammonia adjusted to ρ Η = 8 ~ 9, obtained aluminum hydroxide precipitation,The filter cake was dried at 20 ° C and then calcined at 600 ° C to give Al2O3.
With methanol; sodium tetrahydroborate Inert atmosphere;
With chloro-trimethyl-silane; potassium nitrate In dichloromethane at 60℃; for 16h;
General experimental procedure for the halogenation reaction
General procedure: In a Nalgene bottle, to acetophenone (2 mmol) in dichloromethane (10 mL), potassium nitrate (4 mmol) and chloro/bromotrimethylsilane (8 mmol) were added. The heterogeneous mixture was stirred vigorously at 60 °C (for chlorination) or room temperature (for bromination) until the reaction went to completion (monitored by 1H NMR spectroscopy). The reaction mixture was then filtered and solvent removed under reduced pressure. The chlorinated/brominated acetophenone derivatives were obtained upon purification by flash chromatography (silica gel) with hexane as eluent. The products were characterized by comparing their spectroscopic data with those of the authentic samples.
Bis(diphenylphosphino)methane (<strong>[2071-20-7]dppm</strong>) (0.50 g, 1.30 mmol) was dissolved in8 ml of chloroform and then a solution of 2,20,40-trichloroacetophenone(0.29 g, 1.30 mmol) in the same solvent (5 ml) was addeddropwise to the above solution. The resulting solution was stirredfor 10 h at room temperature and then was concentrated under reducedpressure to about 2 ml. Diethyl ether (20 ml) was added andthe white solid formed was filtered off, and dried under reducedpressure. Yield: 0.60 g (77%); m.p. 185-187 C. Anal. Calc. forC33H27Cl3OP2 (%): C, 65.34; H, 4.48. Found: C, 65.55; H, 4.54.Selected IR absorption in KBr (cm1): 1683 (mCO). 1H NMR (CDCl3).dH: 4.29 (d, 2H, PCH2P, 2JPH = 14.4); 6.07 (d, 2H, PCH2CO,2JPH = 12.6); 7.20-8.45 (m, 23H, Ph). 31P NMR (CDCl3) dP: 29.03(d, PPh2, 2JPP = 64.76); 20.34 (d, PCH2CO, 2JPP = 63.56). 13C NMR(CDCl3) dC: 21.18 (br, PCH2P); 33.96 (d, PCH2, 1JPC = 58.01);126.63-139.79 (Ph); 184.90 (s, CO).
Stage #1: 2,2',4'-trichloroacetophenone With tris(triphenylphosphine)ruthenium(II) chloride; acetic acid; triethylamine at 70℃; for 9h;
Stage #2: 1H-imidazole With N,N-dimethyl acetamide; sodium hydroxide at 50 - 100℃; for 5h;
Stage #3: 3-chloroprop-1-ene at 105℃; for 6h;
3 The implementation of the example three
This embodiment provides a method for preparing graciousness kang zuo, comprises the steps of: under stirring, sequentially the formic acid 185 g (4.0 µM), 2, 4 - dichloro -2 ' - chloro acetophenone 45.1 g (0.2 µM), triethylamine 10 g (0.1 µM), RuCl2(Pph3)39. 5 G (0.01 µM) into 500 ml three flasks, heating 70 °C insulation reaction 9 h. Reaction finishes cooling to 50 °C, negative pressure steaming to without dripping the liquid, to a room temperature. Adding DMA 175 g (2.0 µM), sodium hydroxide 16 g (0.4 µM), imidazole 22 g (0.32 µM), heating up to 100 °C insulation reaction 5 h, cooled to the room temperature, dropping propyl 24 g (0.32 µM), heating up to 105 °C insulation reaction 6 h. The completion of the reaction to room temperature, add 320 ml water, filtered to obtain [...], crude product by adding 100 ml ethanol, heating reflux 1 h, to room temperature and filtered, to obtain fine graciousness kang zuo 28.7 g, yield 64.4%, liquid phase analysis purity ≥ 98%, melting point 50.9 - 52.0 °C.
General procedure: To commercially available 2-hydroxy-4-methoxybenzaldehyde(0.50 g, 3.29 mmol) and synthesised 2-bromo-3?-methoxyacetophenone (2d) (0.75 g, 3.29 mmol) in PEG-400 (5 mL),anhydrous K2CO3 (1.36 g, 9.86 mmol) was added and the ensuingreaction mixture was mechanically stirred at 100 C, the progress of thereaction was continually monitored by TLC. Upon completion, thereaction mixture was cooled down to room temperature, quenched withH2O (20 mL) and the resulting precipitate was filtered, dried (30 C)and recrystallized from a suitable solvent (either MeOH (3a-b & f-n) orEtOH (3d-e)) to yield the title compound 3a as a light grey solid
2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4-dichlorophenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
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).
21%
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).
2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
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).
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