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CAS No. : | 21900-54-9 | MDL No. : | MFCD00084954 |
Formula : | C7H3Cl2FO | Boiling Point : | 213.7°C at 760 mmHg |
Linear Structure Formula : | - | InChI Key : | N/A |
M.W : | 193.00 g/mol | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride | ||
With thionyl chloride; N,N-dimethyl-formamide for 2h; Heating; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating; |
With thionyl chloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 18h; | 8 REFERENCE EXAMPLE 8(2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone REFERENCE EXAMPLE 8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml).. Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature.. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating / reflux; | 1.C Step C. 2-Chloro-4-fluorobenzoyl chloride Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61g, 78 mmol) in dichloromethane (85 ML) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents).. After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo.. The crude acid chloride was used as such in the next step. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating / reflux; | 16.B Step B. (2-Chloro-4-fluoro-phenyl)-(11H-5-oxa-4,10-diazadibenzo[a,d]cyclohepten-10-yl)-methanone Under anhydrous conditions a mixture of 2-chloro-4-fluorobenzoic acid (0.37 g, 2.12 mmol) and oxalyl chloride (0.303 mL, 2.3 mmol) in 10 mL of dichloromethane containing a catalytic amount of dimethylformamide was stirred at room temperature until gas evolution ceased. The crude acid chloride solution was then added portionwise to a stirred solution of 6H-pyrido[2,3-b][1,5]benzoxazepine of Step A (0.45 g, 2.12 mmol) and triethylamine (0.35 mL, 2.5 mmol) in 15 mL of dichloromethane. The reaction mixture was stirred overnight at ambient temperature, washed with water and dried over sodium sulfate. Evaporation of the solvent provided the crude title compound as a gummy solid which was used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 5.1 (broad, 2H, CH2N), 6.9-7.5 (m, 8H), 7.92 (d, 1H), 8.22 (m, 1H) MS (EI, m/z): 354 [M]+, 319, 198, 157 | |
With oxalyl dichloride In dichloromethane at 20℃; for 18h; | 8 EXAMPLE 8; (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g). | |
With thionyl chloride Reflux; | ||
With pyridine; 1,3,5-trichloro-2,4,6-triazine In dichloromethane at 50℃; for 0.25h; Microwave irradiation; | 8 Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using AlCl3): General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for 5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 °C. Then the reaction mixture was poured onto the ice and filter from Celite. The filtrate was washed with water followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give crude product, which is purified by column chromatography (98:2 heptane/ethyl acetate) to give the pure white color product 6a (269.5 mg, 91% yield). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 0.5h; Inert atmosphere; | 6.1. General synthetic procedure for the isocoumarin derivatives 3(a-d) General procedure: 2-Chloro-4-fluorobenzoic acid, 2-chloro-6-fluorobenzoic acid, 3-chloro-4-fluorobenzoic acid and 4-chloro-2-fluorobenzoic acid 1(a-d) (5 g, 28.7 mmol) were converted into their respective acid chlorides 2(a-d) by reaction with thionyl chloride (4.09 g, 2.49 mL and 34 mmol) in the presence of a drop of DMF under reflux for 30 min. Completion of the reaction was indicated by the stoppage of gas evolution. Removal of excess of thionyl chloride was carried out under reduced pressure to afford dihalobenzoyl chlorides 2(a-d). Mixtures of homophthalic acid (1.3 g, 7.2 mmol) and dihalobenzoyl chlorides 2(a-d) (5.516 g, 28.7 mmol) were heated at 200 °C under reflux for 4 h. The mixtures were dissolved in ethyl acetate and aqueous solution of sodium carbonate was added in order to remove the unreacted homophthalic acid. Organic layer was separated and the aqueous layer was extracted with 2× 25 mL ethyl acetate. The combined organic layers were concentrated and chromatographed on silica gel using pet ether (40-80 °C fraction) as eluent which gave 3-(dihalophenyl)isocoumarins 3(a-d) as solids, which were further purified by recrystallization from methanol. | |
With thionyl chloride Reflux; | ||
With thionyl chloride at 90℃; for 1h; | 8 Preparation of 2-Chloro-N-(2-chloro-4-{fl-(4-methoxybenzyl)-lH-pyrazolof4,3- b]pyridin-S-yl]amino}phenyl)-4-fluorobenzamide[01 19] Into a vessel containing 10 mL of SO2CI2 was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride. Into 6 mL of a 5: 1 vohvol mixture of dichloromethane (D CM): pyridine was dissolved 50 mg of 2-chloro-7V4-[l-(4-methoxybenzyl)-lH-pyrazolo [4,3-&]pyridin-3-yl] benzene- 1 ,4-diamine (0.13 mmol) at RT. Into this solution was added, dropwise, 50 mg of the crude 2-chloro-4-fluoro-benzoyl chloride previously prepared. The reaction mixture thus provided was stirred overnight at ambient temperature (RT) then the reaction mixture was washed with HQ (aq) and extracted with DCM. The combined organics were washed sequentially with water and brine, dried over Na2S04, filtered, then concentrated under reduced pressure yielding 48 mg of Exp-8-g3 (calculated yield 68.5 %). The crude material was used directly in the next step without purification. The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 536, 538 (M+H)+ | |
With thionyl chloride In 1-methyl-pyrrolidin-2-one; toluene at 75℃; for 1h; | ||
With sulfuryl dichloride at 90℃; for 1h; | 8 EXAMPLE 8: 3-[(3-Chloro-4-[(2-chloro-4-fluorophenyl)carbonyl]amino} iyl)amino] - ΙΗ-pyr azolo [4,3-b] pyridin-4-ium trifluoroacetate Preparation of 2-Chloro-N-(2-chloro-4-ifl-(4-methoxybenzyl)-lH-pyrazolo[4,3- b]pyridin-3-yl]aminojphenyl)-4-fluorobenzam,ide Into a vessel containing 10 mL of SO2CI2 was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride | |
With 1-methyl-pyrrolidin-2-one; thionyl chloride In toluene at 78 - 85℃; for 4h; Large scale; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 8 General procedure for the preparation of acid chlorides 32-42 General procedure: Under inert atmosphere, a mixture of carboxylic acid 21-31 ( Scheme 1 ) (1 equiv), thionyl chloride (1.5 equiv) and DMF (3-5 drops) in dichloromethane was stirred at rt until the complete consumption of the carboxylic acid (1H NMR control). The pale yellow solution was concentrated in vacuo to give the crude acid chloride 32-42 ( Scheme 1 ) as a yellow pale solid in quantitative yield | |
With thionyl chloride for 3h; Reflux; | 37-1 2-chloro-4-flu oro-N ,N -dimethylbenzamide The reaction mixture of 2-chloro-4-fluorobenzoic acid (5 g, 28.6 mmol, 1.0 eq) in thionyl5 chloride (10 mL, 137 mmol, 4.7 eq) was refluxed for 3 h. Then the mixture was cooled tort andthe solvent was evaporated under reduced pressure to give 2-chloro-4-fluorobenzoyl chloride.The crude chloride was dissolved in THF ( 5 mL ), then treated with triethylamine ( 16 mL, 115mmol, 4.0 eq) and dimethylamine (42 mL, 84 mmol, 2M in THF, 2.9 eq) at ambient temperature.The reaction mixture was stirred at ambient temperature for 17h. The mixture was diluted with10 ethyl acetate (90 mL), washed with water (10 mL x 3), dried over anhydrous Na2S04, filteredand concentrated. The crude product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc = 3/1, VN) to afford 2-chloro-4-fluoro-N,N-dimethylbenzamide. LRMSm/z (M+H) 202.0 found, 202.0 required. | |
With thionyl chloride In dichloromethane at 20 - 38℃; for 2.5h; | 59-4 2-Chloro-4-fluorobenzoyl chloride Reference example 59-4 2-Chloro-4-fluorobenzoyl chloride To a mixture of 2-chloro-4-fluorobenzoic acid (159 mg) in dichloromethane (2.0 mL) were added thionyl chloride (332 uL) and a catalytic amount of N-methylpyrrolidone at room temperature, and the mixture was stirred at room temperature for an hour, followed by stirring at 38 °C for 1.5 hours. The solvent was removed under reduced pressure to give 2-chloro-4-fluorobenzoyl chloride (175 mg). | |
With thionyl chloride In toluene for 3h; Reflux; | 4.2.13. Synthesis of 2-chloro-N-(4-chloro-3-(8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-4-fluorobenzamide (TPB12) Thionyl chloride (0.356 g; 3 mmol) was added to a mixture of 2-chloro-4-fluorobenzoic acid (0.175 g, 1 mmol) in toluene and themixture was heated at reflux for 3 h. The reaction was cooled to roomtemperature and the solvent was removed under reduced pressure. Theresultant acid chloride was dropwised to a mixture of Compound 4 (0.279 g, 1 mmol) and DIPEA (0.258 g, 2 mmol) in dichloromethane(15 ml) at room temperature. The solution was stirred for overnight,then concentrated in vacuo. The residue was purified by silica gelcolumn (DCM/MeOH = 20/1) to afford TPB12 (0.280 g, yield: 65%);purity: 99%; mp: 237.5-239.2 °C; 1H-NMR (d6-DMSO): δ = 10.95 (s,1H), 8.19-8.13 (m, 1H), 8.11 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 8.9,2.6 Hz, 1H), 7.81-7.73 (m, 2H), 7.73-7.68 (m, 1H), 7.63 (dd, J = 9.0,2.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H); 13CNMR(d6-DMSO): δ = 164.99 (s), 164.12 (s), 161.63 (s), 148.00 (s),146.14 (s), 138.78 (s), 133.54 (d, J = 3.5 Hz), 131.92 (d, J = 11.0 Hz),131.36 (d, J = 9.6 Hz), 131.12 (s), 127.92 (d, J = 3.8 Hz), 125.89 (s),124.18 (s), 123.84 (d, J = 12.4 Hz), 120.63 (s), 117.81 (s), 117.56 (s),115.22 (s), 114.94 (d, J = 14.1 Hz); HR-ESI-MS for C19H9ON4Cl3F([M-H]+) Calcd: 432.9826; Found: 432.9838. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With aluminium trichloride for 1h; Heating; | |
Stage #1: 2-chloro-4-fluorobenzoyl chloride With aluminum (III) chloride In dichloromethane at 30℃; for 0.0833333h; Microwave irradiation; Stage #2: benzene In dichloromethane at 70℃; for 0.25h; Microwave irradiation; | 8 Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using AlCl3): General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for 5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 °C. Then the reaction mixture was poured onto the ice and filter from Celite. The filtrate was washed with water followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give crude product, which is purified by column chromatography (98:2 heptane/ethyl acetate) to give the pure white color product 6a (269.5 mg, 91% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate In <i>N</i>-methyl-acetamide | 1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH) MS (EI, m/z): 353/355 [M]+, 196 |
62% | With potassium carbonate In <i>N</i>-methyl-acetamide | 1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2 m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH); MS (EI, m/z): 353/355 [M]+, 196. |
62% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 1.25h; | 1.D Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 ML) under nitrogen was added potassium carbonate (19.76 g, 143 mmol).. The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 ML).. After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane.. The organic extracts were dried over magnesium sulfate and evaporated to dryness.. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g).. The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2 m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH) MS (EI, m/z): 353/355 [M]+, 196 |
With potassium carbonate In <i>N</i>-methyl-acetamide | 1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2H), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H) MS (EI, m/z): 353/355 [M]+, 196 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In hexane; dichloromethane | 8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 8 REFERENCE EXAMPLE 8; (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml).. After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate.. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane.. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred.. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112 °C. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 8 The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropylamine In dichloromethane | 37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone EXAMPLE 37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluding several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 37 EXAMPLE 37; {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone EXAMPLE 37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath.. The reaction mixture was allowed to stir at room temperature overnight.. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate.. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluding several additional volumes of dichloromethane.. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157 °C; MS, m/z: 510 (M)+. | |
With diisopropylamine In dichloromethane at 0 - 20℃; | 37 EXAMPLE 37; {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluting several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
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78% | Stage #1: 2-fluoro-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine; 2-chloro-4-fluorobenzoyl chloride In 1,4-dioxane for 2h; Heating / reflux; Stage #2: With ammonia In methanol; dichloromethane | 43 Example 43. 2-Chloro-4-fluoro-N- (2-fluoro-3- (1-methyl-piperidinylamino)-phenyl)- benzamide Mix 2-fluoro-N-(l-methyl-piperidin-4-yl)-benzene-1, 3-diamine (Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg) in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g of the title compound (78% yield): mass spectrum (ion spray) : 7nez = 380 (M+1) ; 1H NMR (CDC13) : 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd, lH), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H). Dissolve the benzamide in methanol, add 0.28 mL of 1 N HCl in ether and evaporate to give its mono-hydrochloric acid salt. |
Yield | Reaction Conditions | Operation in experiment |
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100% | Stage #1: 1-methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine; 2-chloro-4-fluorobenzoyl chloride In 1,4-dioxane for 3h; Heating / reflux; Stage #2: With ammonia In methanol | 48 Example48. 2-Chloro-4-fluoro-N-(3-fluoro-5-(methyl-(1-metllyl-piperidin-4-yl)-amino)- phenyl)-benzamide; Combine 5-fluoro-N-methyl-N- (l-methyl-piperidin-4-yl)-benzene-1, 3-diamine (Preparation 29,0. 036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-doxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495 ; Calc. m/z 394.1497 ; 1H NMR (CDCI3) of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1 H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1 H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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85% | In 1,4-dioxane at 20℃; | 13 Preparation 13. 2-Chloro-4-fluoro-N- (4-fluoro-3- nitrophenyl) benzamide; Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray) : m/z = 313.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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72% | Stage #1: 3-(1-methylpiperidin-4-ylsulfanyl)phenylamine With pyridine In dichloromethane at 0℃; Stage #2: 2-chloro-4-fluorobenzoyl chloride In dichloromethane at 20℃; for 2h; | 171 Combine pyridine (0.110 mL, 1.36 MMOL), 3- (1-METHYL-PIPERIDIN-4-YLSULFANYL)- PHENYLAMINE (preparation 76,151 mg, 0.679 mmol) in dichloromethane (6.5 mL) at 0°C. Stir and add 2-CH] ORO-4-FLUOROBENZOYL CHLORIDE (0.105 mL, 0.815 mmol). Allow to warm to ambient temperature and stir. After 2HR., dilute with dichloromethane (10 mL) and wash with sodium hydroxide (1N, 3x10 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with DICHLOROMETHANE/AMMONIA (2.0 N in methanol) [20/1] to give the title compound as free base (184 MG, 72%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride (1.0 M). Triturate the resulting gum with ether to give the title compound as the hydrogen chloride SALT. H NMR (free base, CDCI3) : 8. 37 (bs, 1H), 7.65 (s, 1H), 7. 58 (t, J= 6.8 Hz, 1H), 7.42 (d, J= 7.7 Hz, 1H), 7.21 (t, J= 7. 8 Hz, 1H), 7.14-7. 06 (m, 2H), 6.99-6. 93 (m, 1H), 3.05 (bs, 1H), 2. 71 (bd, J= 11. 5 Hz, 2H), 2.19 (s, 3H), 2.03-1. 90 (m, 4H), 1.67-1. 56 (m, 2H). 3C NMR (free base, CDCI3) : 164.9, 162.2 (d, JC-F = 167.7 Hz), 137.9, 135.8, 132.0, 131.7 (d, JC-F= 8.6 HZ), 131.4, 129. 3, 128.0, 123.0, 118.6, 117.5 (D, JCF=25. 0 Hz), 114.5 (D,./C-F=21. 3 Hz), 54.9, 46.0, 43.6, 32.4. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With pyridine at 55℃; for 4h; | 160 Dissolve 6- (1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60,150 mg, 0.724 mmol) in pyridine (20 mL). Add 2-chloro-4-fluorobenzoyl chloride (208 mg, 1.08 mmol) and heat at 55 °C. After 4 hr. , cool to room temperature, concentrate and load residue onto a 5 g SCX cartridge. Wash resin with methanol, then remove product with 2 M NH3/METHANOL. Concentrate in vacuo, and silica gel chromatography eluting with 2- 10% methanol/methylene dichloride to give the free base (280 mg, 97%). Dissolve the purified oil in methanol, add NH4CI (1 eq) as a solid, and SONICATE the solution at room temperature for 15 min. Concentration in vacuo provides the title compound (280 MG, 97%). Mass spectrum (ion spray): M/Z 364.0 (M+1) ; Analysis calculated for CL8HL9N302C] 2F-0. 5 H20. Theory: C, 52.82, H, 5. 17, N, 10.27. Found: C, 52.89, H, 5.18, N, 10.37 ; MP = 135-137°C. |
Yield | Reaction Conditions | Operation in experiment |
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79% | With pyridine at 55℃; for 15h; | 167 Add 2-CHLORO-4-FLUOROBENZOYL chloride (149 mg, 0. 58 mmol) to a solution of 6-(1- CYCLOPROPYLMETHYL-PIPERIDIN-4-YLOXY)-PYRIDIN-2-YLAMINE (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and heat at 55 °C for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2CL2, wash with saturated NAHC03 solution, dry over NA2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-METHANOL in CH2CL2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1) ; H NMR (CDCI3, PPM) : 8.08 (S, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C2] H23CIFN302-HCI-0. 5H20: C, 56.13 ; H, 5.61 ; N, 9.35. Found: C, 56.12 ; H, 5.30 ; N, 9. 35. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With pyridine In dichloromethane at 0 - 20℃; for 1.5h; | 77 Add pyridine (0.66 mL, 8.21 mmol) to a solution of 4- (3-amino-phenoxy)- PIPERIDINE-1-CARBOXYLIC acid TERT-BUTYL ester (preparation 30,2. 0 g, 6.84 mmol) in dichloromethane (35 mL) at 0°C. Stir and add 2-chloro-4-fluorobenzoyl chloride dropwise (1.45 g, 7. 52 mmol). Stir at 0°C for 30 min and 1 HR. at room temperature. Dilute with dichloromethane (30 mL) and wash with sodium hydroxide (IN, 2x25 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexanes [20- 40%] to give the title compound (3.0 g, 98%). Mass spectrum (ion spray): m/z = 449.0 (M+1) ; H NMR (CDC13) : 7.87 (bs, N-H), 7.80 (dd, J = 6.1 Hz, 8.6 Hz, 1H), 7.48 (s, 1H), 7. 28-7. 24 (m, 1H), 7.21 (dd, J = 2. 5 HZ, 8. 4 Hz, 1H), 7.11 (td, J= 2. 2 HZ, 8. 4 HZ, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.73 (dd, J= 2.2 Hz, 8.4 Hz, 1H), 4.52 (septet, J = 3.6 Hz, 1H), 3.69 (ddd, J= 3.7 Hz, 7. 7 Hz, 13. 6 Hz, 2H), 3. 3-5 (DDD,-J= 3. 9 Hz, 7.7 Hz, 1-3. 6 Hz, 2H), 1.97-1. 89 (m, 2H), 1.81-1. 72 (m, 2H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With triethylamine In 1,4-dioxane for 4h; | 78 Combine 4- (3-AMINO-PHENOXY)-2-METHYL-PIPERIDINE-1-CARBOXYLIC acid test-butyl ester cis isomer 1 (preparation 35,0. 40 g, 1.31 MMOL), 1, 4-dioxane (20 mL), triethylamine (0.22 mL, 1.57 mmol) and 2-CHLORO-4-FLUORO-BENZOYL chloride (0.30 g, 1.57 mmol) with stirring. After 4 hr., partition between 4: 1 hexane : ethyl acetate (100. ML) AND 0.5M aqueous sodium hydroxide solution (100 mL). Separate the organic layer, dry over sodium sulfate, filter and concentrate to obtain of the title compound (0.60 g, 100%) : 1H NMR (CDCl3) : 7.9 (bs, 1H), 7. 8 (dd, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.2 (dd, 1H), 7. 1 (m, 1H), 7.0 (dd, 1H), 6.7 (dd, 1H), 4.7 (m, 1H), 4. 35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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With diethylaminomethyl polystyrene; In dichloromethane; at 25℃; for 3h; | 5.6.7.8-Tetrahydroimidazo[1 ,2-a]pyrazine(l17) (620 mg, 3.07 mmol) and diethylaminomethyl polystyrene (3071 mg, 9.83 mmol) were slurried in dichloromethane (DCM) (20 ml_). 2-Chloro-4-fluorobenzoyl chloride (622 mg, 3.22 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Fluorochem) was added and the slurry stirred at 25 0C for 3 h. The resin was removed by filtration, washed with dichloromethane (50 ml) and the filtrate concentrated in vacuo to afford a crude oil. The crude product was purified by flash chromatography (Isolera, 100 g, 0-100% 2M ammonia in methanokdichloromethane (1 :9)/dichloromethane) to afford product. This was further purified by flash chromatography (Isolera, 50 g, 0-100% methanokdichloromethane (1 :9)/dichloromethane), to afford product. The oil was further purified by MDAP to afford clean product as the formate salt. The solid was loaded on to an SCX cartridge (Varian, 5g) and washed with methanol. The product was eluted with 2M ammonia methanol and the filtrate concentrated to afford desired product in 330 mg as a white solid.LC/MS = 280/282 (M+H)+, retention time = 0.52 minutes (2 minute). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 4.0h; | 2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 ml_, 1.800 mmol) were dissolved at 0 0C in dichloromethane (DCM) (15 ml_). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo ) dissolved in DCM (5 ml.) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 ml.) and saturated sodium bicarbonate solution (25 ml_). The aqueous phase was extracted with dichloromethane (3 x 50 ml.) and the combined extracts were washed with water (50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanokdichloromethane (1 :9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg. LC/MS = 348/350 (M+H)+, retention time = 0.94 minutes (2 minute method) |
Yield | Reaction Conditions | Operation in experiment |
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67% | With triethylamine In dichloromethane at 20℃; | E14 E14 2-Chlow-4-fluow-N-(l-hydwxy-l,3-dihydro-benzofcJfl,2Joxaborol-6-yl)- benzamide[0464] A 250 ml round bottom flask was charged with a mixture of 6-amino- 1 - hydroxy-2,l-benzoxaborolane hydrochloride (1 g, 5.4 mmol, 1 eq), triethylamine (2.3 ml, 16.2 mmol, 3 eq) and dichloromethane (100 ml). 2-Chloro-4-fluorobenzoyl chloride (1.14 g, 5.9 mmol, 1.1 eq) was added, and the reaction mixture was allowed to stir at room temperature overnight. Aqueous hydrochloric acid (1 M, 50 ml) was added to the mixture and the suspension was vigorously mixed. The resulting white precipitate was then collected by vacuum filtration and dried under vacuum. LCMS (m/e) 306 (M+H). 1H NMR (400 MHz, DMSO-J6) δ ppm 4.96 (s, 2 H) 7.29 - 7.45 (m, 2 H) 7.59 (dd, J=9.0, 2.3 Hz, 1 H) 7.63 - 7.78 (m, 2 H) 8.15 (d, J=1.8 Hz, 1 H) 9.25 (s, 1 H) 10.53 (s, 1 H). Amount Obtained: 1.1 g, 67% yield. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In toluene; at 0 - 20℃; | To a mixture of methyl 3-(methylamino)-2-butenoate (i.e. the product of Step A) (10.25 g, 79.43 mmol) and triethylamine (13.26 mL, 9.63 g, 95.31 mmol) in toluene (125 mL) at 0 C was added dropwise 2-chloro-4-fluorobenzoyl chloride (15.25 g, 79.48 mol) in toluene (25 mL) over 30 minutes while maintaining the temperature of the reaction mixture between about 0 to 5 C. The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting dark yellow oil was triturated with hexanes and filtered to provide the title compound as a white solid (15.91 g)..H NMR (CDCI3): delta 12.60 (s, 1H), 7.20-6.90 (m, 3H), 3.30 (s, 3H), 3.11 (s, 3H), 2.35 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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58% | Stage #1: 2-chloro-4-fluorobenzoyl chloride; (S)-1-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol dihydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With ammonia In methanol; N,N-dimethyl-formamide Stage #3: tartaric acid In water; acetonitrile | 10.1 Example 10.1: (3S -l-((S -2-(2-Chloro-4-fluoro-N-methylbenzamido -3-methylbutyl -3- hydroxypyrrolidinium 2,3-dihydroxysuccinate; To a solution of (S)-l-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol dihydrochloride (0.30 g, 1.16 mmol), which is commercially available, in DMF (2 mL) was DIPEA (0.809 mL, 4.63 mmol) and 2-chloro-4-fluorobenzoyl chloride (0.223 g, 1.16 mmol) added. The resultant mixture was stirred at rt overnight. To the mixture was added NH3 in MeOH (1 mL, 2N). The reaction was concentrated under reduced pressure and the residue purified by preparative HPLC to give the neutral form of the the title compound (280 mg, 58%)). The product was dissolved in MeCN (5 mL) and a solution of DL-tartaric acid (61 mg, 0.41 mmol) in water (5 mL) was added. The resulting mixture was freeze dried in vacuo to give the title compound (280 mg, 58%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.85 - 0.93, 1.05, 1.11, 1.93, 2.25, 2.77, 3.14, 3.32 - 3.51, 4.37,4.50, 4.66, 7.12 - 7.28, 7.35. Ratio major:minor: 1 : 0.05. Total no of protons: 23(excluding the tartaric acid peak). HRMS (M+H)+: calculated 343.1588; found 343.1593. |
Yield | Reaction Conditions | Operation in experiment |
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49% | With triethylamine In tetrahydrofuran at 20℃; for 5h; | 12 N5-f4-[ (2-ch loro-4-fluorobenzoyl)ami no]phenyl}-N4-methyl- I H-imidazole-4 , 5-di- carboxamide In 720 mL THF, a mixture of 8.09 g (40.7 mmo[) N5-(4-amino-pheny[)-N4-methy[-1H- imidazo[e-4,5-dicarboxamide (Intermediate 003), 5.59 mL (40.7 mmo[) 2-ch[oro-4- f[uoro-benzoy[ ch[oride and 5.15 mL (37 mmo[) triethy[amine was stirred for 2 h atroom temperature.300 mL THF, 3.6 mL triethy[amine and 2.5 mL 2-ch[oro-4-f[uoro-benzoy[ ch[oride were added and stirring was continued to 1 .5 h.2.5 mL triethy[amine and 2.5 mL 2ch[oro-4-f[uoro-benzoy[ ch[oride were added and stirring was continued for another 1 .5 h.The suspension was concentrated and dried in vacuo. The precipitate was suspended in a mixture of 500 mL 1 N aqueous sodium hydroxide so[ution and 300 mL methano[ and stirred for 30 mm at 40 °C (water bath). The pH of the mixture was adjusted to 7 by addition of 3N aqueous hydroch[oric acid. The precipitate was fi[tered off and washed with water and dried.The crude materia[ was purified by f[ash chromatography to give a materia[ which was digested in methano[ to give 7.59 g (49% yie[d) of the tit[e compound as so[id materia[.1H-NMR (500MHz, DMSO-d6): 6 [ppm]= 2.86 (d, 3H), 7.34 (td, 1H), 7.57 (dd, 1H),7.64 - 7.74 (m, 5H), 7.91 (s, 1H), 8.81 (d, 1H), 10.49 (s, 1H), 13.40 (s, 1H), 13.66(s, 1H).LC-MS (Method 1): R = 1.00 mm; MS (ESIpos) m/z = 416 [M+H]÷. |
Yield | Reaction Conditions | Operation in experiment |
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89% | In pyridine at 20℃; for 2h; Inert atmosphere; | General Synthetic Procedure for Compound 11 General procedure: A mixture of 2'-hydroxyacetophenone (10.0 mmol) and 2-chlorobenzoyl chloride (15.0 mmol) were stirred in dry pyridine(10 mL) at room temperature for 2 h. The reaction mixture was then poured into a mixture of crushed ice (15 mL) and concentrated HCl (5 mL), extracted twice with dichloromethane, washed thrice with aqueous K2CO3, and then washed thrice with water. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give 2-acetylphenyl 2-chlorobenzoate (11-1). The remaining compounds were prepared using a similar procedure to that used for preparing 11-1. |
Yield | Reaction Conditions | Operation in experiment |
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32% | With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; | 78 2-chloro-4-fluoro-N-[(trans)-1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide A solution of 2-chloro-4-fluorobenzoyl chloride (42 μΙ, 310 μιηοΙ) in THF (1 .0 ml) was added dropwise at 0 to a mixture of 8-amino-2-(pyridin- 2-yl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , intermediate I66) (75.0 mg, 306 μιηοΙ) and triethylamine (130 μΙ, 920 μιηοΙ) in THF (1 .5 ml) and DMF (0.31 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were filtrated through a silicone filter and concentrated under reduced pressure. The crude product was recrystallized from ethanol to give the title compound 40.1 mg (32 % yield).LC-MS (Method 2): Rt= 1 .05 min; MS (ESIneg) : m/z = 400 [M-H]-1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.84), 1 .415 (1 .19), 1 .438 (2.57), 1 .446 (2.73), 1 .458 (2.96), 1 .468 (4.50), 1 .487 (3.37), 1 .498 (2.94), 1 .519 (1 .85), 1 .703 (13.80), 1 .712 (16.00), 1 .728 (10.57), 1 .734 (9.71 ), 1 .929 (4.94), 1 .939 (5.16), 1 .950 (3.06), 1 .962 (4.79), 1 .971 (4.34), 2.056 (9.48), 2.074 (13.72), 2.091 (9.97), 2.389 (0.74), 2.393 (1 .07), 2.398 (0.76), 2.584 (3.70), 2.589 (2.41 ), 2.731 (0.78), 2.735 (1 .09), 2.740 (0.76), 3.225 (0.95), 3.238 (0.99), 3.756 (0.99), 3.767 (1 .1 1 ), 3.776 (2.04), 3.786 (2.51 ), 3.795 (2.06), 3.805 (2.49), 3.815 (1 .95), 3.824 (1 .1 1 ), 3.834 (0.99), 3.994 (10.10), 4.006 (4.34), 4.012 (13.86), 4.016 (4.81 ), 4.029 (9.64), 7.193 (6.03), 7.196 (6.00), 7.205 (5.47), 7.208 (6.05), 7.21 1 (6.40), 7.214 (5.76), 7.224 (6.19), 7.226 (6.31 ), 7.318 (4.09), 7.324 (4.59), 7.339 (8.21 ), 7.346 (9.17), 7.360 (4.81 ), 7.366 (5.35), 7.526 (8.78), 7.541 (8.99), 7.547 (8.06), 7.557 (9.21 ), 7.563 (14.27), 7.580 (8.62), 7.586 (8.23), 7.859 (5.39), 7.864 (5.49), 7.877 (5.49), 7.880 (6.33), 7.882 (5.94), 7.885 (5.94), 7.898 (5.08), 7.903 (5.41 ), 8.379 (6.36), 8.381 (12.55), 8.384 (7.24), 8.400 (6.15), 8.403 (10.39), 8.405 (6.36), 8.446 (10.61 ), 8.449 (13.14), 8.451 (10.90), 8.454 (7.92), 8.459 (7.61 ), 8.461 (8.08), 8.464 (8.90), 8.466 (10.41 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In acetone at 20℃; for 2h; | 4.1.1.2 Procedure B, general procedure for amide synthesis (4a, 6a-34a) General procedure: A solution of 0.18gm (0.7mmol) of compound D dissolved in acetone was treated with 0.84mmol of the appropriate acid chloride followed by the addition of 0.12gm (1.05mmol) of TEA. The reaction mixture was left to stir at room temperature for 2h which was followed by evaporation of solvent in vacuo and the product was purified by CC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2-chloro-4-fluorobenzoyl chloride; 7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine With pyridine at 0 - 20℃; Stage #2: With ammonia In methanol at 20℃; | 1.1.5 General procedure for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidines 6-7 and [1,2,4]triazolo[1,5-a]pyridines 17-18 General procedure: The appropriate acyl chloride (2.5 equiv) was added dropwise to a solution of triazolo[1,5-a]pyrimidin-2-amine 11 or 12 or triazolo[1,5-a]pyridin-2-amine 16 (1 equiv) in pyridine at 0 C. The reaction mixture was allowed to warm up to r.t. and stirred for 1-2 h. EtOAc was added, and the organic layer was washed with HCl 1N (2 X), followed by water or brine. After solvent evaporation, the resultant residue was treated with 7 N methanolic ammonia solution and stirred at r.t. overnight to hydrolyze any potential bis-acylated product formed. The product was then purified by flash chromatography on silica gel using as eluent a gradient of EtOAC (0 - 10%) in DCM or MeOH (0 - 5%) in DCM, washed with MeOH and dried in vacuum to afford the desired compound (adapted from 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.5% | With triethylamine In tetrahydrofuran; dichloromethane at 60℃; for 24h; | 12 [Preparation Example 4: Preparation of Compound 1] General procedure: Compound [A] (1.5 g, 2.94 mmol, 1 eq) was dissolved in a mixture of 5 g of dichloromethane in 25 g of tetrahydrofuran. 4-nitrobenzoyl chloride (2.72g, 14.7mmol, 5eq) and Triethylamine (0.9g, 8.82mmol, 3eq) were added and heated at 60 ° C. After the reaction for about 24 hours, the reaction was terminated by quenching with 1M HCl solution, and filtered under reduced pressure. Purification by column chromatography (Dichloromethane: Metanol = 8: 1) afforded 1.6 g (2.0 mmol) of compound [1]. (Yield 68%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With pyridine In tetrahydrofuran at 5 - 20℃; for 2h; | 34 Example 34. 2-chloro-4-fluoro-N'-phenylbenzohydrazide (34) Following the general procedure Route C, 2-chloro-4-fluoro-N'-phenylbenzohydrazide was obtained from the coupling reaction of 2-chloro-4-fluorobenzoyl chloride (2.89 g, 15 mmol) and phenylhydrazine (1 .78 g, 16.5 mmol), in presence of pyridine (2.65 mL, 33 mmol). Phenylhydrazine is solubilized in pyridine in a 50 mL flask and cooled at 5 ° C with an ice bath. In parallel, 2-chloro-4- fluorobenzoyl chloride is dissolved in 5 mL of THF. The acyl chloride solution is then added dropwise at 5 ° C to the phenylhydrazine solution. After addition, the temperature is allowed to warm to room temperature and the medium is stirred during 2 hours. Pyridinium chloride gradually appeared in the medium. After completion of the reaction, water (30 mL) is added, pyridinium chloride dissolved and 2-chloro-4-fluoro-N'-phenylbenzohydrazide precipitated. The precipitate is filtered, washed by diethylether (3x10 mL) and dried. Compound 34 is obtained as a white solid (2.66 g, 67% yield), m.p. 159-160° C (0470) 1H NMR (400 MHz, DMSO-d6): d 10.2 (d, J = 2.8 Hz, 1 H, NH, conformer 1 ), 9.71 (s, 1 H, NH, conformer 2), 8.58 (d, 2H, CHAr, conformer 2), 8.00 (d, J = 3.2 Hz, 1 H, NH, conformer 1 ), 7.91 (s, 1 H, NH, conformer 2), 7.78 (tt, J = 7.6 Hz, J = 2,0 Hz, 1 H, CHAr, conformer 1 ), 7.62 (td, J = 8.4 Hz, J = 6.0 Hz, 1 H, CHAr, conformer 1 ), 7.58 (dd, J = 8.8 Hz, J = 2.4 Hz, 1 H, CHAr, conformer 1 ), 7.44-7.37 (m, 3H, CHAr, conformer 2), 7.34 (td, J = 8.0 Hz, J = 2.4 Hz, 1 H, CHAr, conformer 1 ), 7.15 (td, J = 8.0 Hz, J = 2.0 Hz, 2H, CHAr, conformer 1 ), 715-7.11 (m, 3H, CHAr, conformer 2), 6.84 (d, J = 8.2 Hz, 2H, CHAr, conformer 1 ), 6.81 -6.73 (m, 2H, CHAr, conformer 2), 6.73 (td, J = 8.4 Hz, J = 2.0 Hz, 1 H, CHAr, conformer 2). (0471) 13C{1H}NMR (100 MHz, DMSO-cU): 166.0 (C=0), 162.8 (d, C,v, J = 250 Hz, CF), 149.4 (C,v), 132.3 (d, Civ, J = 3 Hz), 132.3 (d, C,v, J = 1 1 Hz), 131 .8 (d, CH, J = 10 Hz), 129.2 (2CHAr), 119.1 (CH), 1 17.7 (d, CH, J = 26 Hz), 1 15.0 (d, CH, J = 21 Hz), 1 12.7 (2CHAr). (0472) IR v (cm'1): 3231 , 1651 , 1599, 1439, 1269, 1043, 929, 855, 758, 686. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.1% | With potassium carbonate In dichloromethane at 20℃; for 6h; | 4.2.2 General procedure for the synthesis of compounds 9-28 General procedure: 22-(3-amino-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 6) (1g, 2.10mmol) was dissolved in dichloromethane (20mL). Then added K2CO3 (0.58g, 4.20mmol) and benzoyl chloride derivatives (3.15mmol) to the solution and stirred for 6h at room temperature until reaction was completed. The mixture was washed with dichloromethane (30mL) and water (50mL) 3 times. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The crude production was purified by column chromatography (dichloromethane: methanol=70:1) using silica gel to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 6h; | General procedure for the synthesis of 3a-k General procedure: Compounds 3a-k were prepared according to the literature [6].2-chloro-5-nitrobenzolyl chloride (500 mg, 1.0 equiv.) was solvedin a solution of Pd(PPh3)2Cl2 (16 mg, 0.10 equiv.) and of CuI (9 mg,0.05 equiv.) in dry THF (10 mL). Then triethylamine (0.41 mL, 1.3equiv.) and alkyne (0.325 mL, 1.3 equiv.) were added via syringe.The reaction mixture was stirred for 6 h at room temperature untilthe alkyne was completely cunsumed (monitored by TLC). Solventswere evaporated, and the residue was washed with water. Theproduct was purified by chromatography on silica gel using heptaneand ethyl acetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.4% | With potassium carbonate In tetrahydrofuran for 4h; | Synthesis of compounds 5a-5f and 10a-10i. General procedure: Tothe desired intermediate 4 or 9 (1 mmol), anhydrousTHF (10 mL) and anhydrous potassium carbonate(1.5 mmol) were added. Then substituted benzoyl chloride(1 mmol) was added dropwise to the reaction mixture, andit was stirred for 4 h. Upon completion of the process, themixture was poured into 50 mL of water, the residue wasfiltered off and recrystallized from anhydrous ethanol togive the corresponding compounds 5a-5f and 10a-10ias white solids. |
Tags: 21900-54-9 synthesis path| 21900-54-9 SDS| 21900-54-9 COA| 21900-54-9 purity| 21900-54-9 application| 21900-54-9 NMR| 21900-54-9 COA| 21900-54-9 structure
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