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Structure of 42926-52-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 42926-52-3 |
Formula : | C9H9ClO2 |
M.W : | 184.62 |
SMILES Code : | O=C(Cl)C1=CC=CC=C1OCC |
MDL No. : | MFCD00016348 |
InChI Key : | MDKAAWDKKBFSTK-UHFFFAOYSA-N |
Pubchem ID : | 3016397 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H290-H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
* 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; for 0.666667h;Heating / reflux; | 2-ethoxyl benzoic acid (10.0g, 60.2mmol) was added into thionyl chloride (20ml), and the mixture was refluxed with agitation for 40 minutes, and the excess amount of thionyl chloride was evaporated under reduced pressure. The residual was dissolved into dichloromethane (150ml). Within 30 minutes and being stirred on ice bath, the afore-obtained solution of 2-ethoxyl benzoyl chloride was dropped into the compound (1a) (7.0g, 56.8mmol) dissolved in tetrahydrofuran (80ml) and triethylamine (8.5ml, 61.0mmol). After completion, the mixture was stirred for 1 hour at 0C . After being washed with water and filtrated with diatomaceous earth, the reaction solution was mixed with 20g of silica gel and evaporated to dryness. The resulting residual was eluted with dichloromethane by using silica gel(80g) column to obtain 7.5g of solid product (3a) with the yield of 48%. Furthermore, the sample for analysis was prepared by column chromatography (developing agent: dichloromethane: n-hexane=1:2) and recrystallization (dichloromethane: n-hexane=1:5). mp 183~184C (sublimation 162C); IR (cm-1) : 3326, 3309, 2981, 2938, 2915, 2854, 2208, 1647, 1593, 1471, 1309, 1302, 1232, 1039, 923, 727, 655, 648; 1H NMR (CDCl3) : delta 1.70 (t, J=7.0Hz, 3H), 2.15 (s, 3H), 4.32 (q, J=7.0Hz, 2H), 6.24 (s, 1H), 7.04 (d, 1H), 7.10 (m, 1H), 7.51 (dd, 1H), 8.20 (dd, J=7.9 and 1.8Hz, 1H), 10.69 (brs, 1H), 10.80 (s, 1H); 13CNMR (CDCl3) : delta (CH3) 10.6, 15.0; (CH2) 65.7; (CH) 110.3, 112.3, 121.4 132.1, 134.2; (C) 78.7, 115.6, 119.2, 119.4, 136.7, 157.0, 163.2; MS (ES+) : m/z 287 (M+NH4) . Elemental analysis (C15H15N3O2) : C 66.90%; H 5.61%; N 15.60%; 0 11.88%. The compound (3b) was prepared from compound (1b) according to the above-mentioned method with the yield of 41%. mp 58~61C; IR (cm-1) : 3596, 3336, 2969, 2937, 2877, 2216, 1676, 1658, 1603, 1571, 1537, 1475, 1431, 1292, 1232, 1122, 1037, 927, 789, 752, 577; 1H NMR (CDCl3): delta 0.88 (t, J=7.4Hz, 3H), 1.58 (t, J=7.0Hz, 3H), 1.75(m, 2H), 2.16 (s, 3H), 3.73 (t, J=7.4Hz, 2H),4.30 (q, J=7.0Hz, 2H), 6.36 (s, 1H), 7.04 (d, 1H), 7.11 (m, 1H), 7.48 (dd, 1H), 8.23 (dd, J=7.9 and 1.8Hz, 1H), 9.62 (brs, 1H) ; 13C NMR (CDCl3) : delta (CH3) 11.1, 14.8; (CH2) 23.6, 48.3, 65.2; (CH) 112.5, 117.0, 121.3, 132.5, 134.1; (C) 89.2, 115.6, 119.8, 120.5, 131.2, 157.1, 165.0; MS (ES+): m/z 329 (M+NH4). | |
With thionyl chloride;N,N-dimethyl-formamide; In hexane; for 1h;Heating / reflux; | To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h; | Example 9A 2-ethoxy-N-(4-trifluoromethyl-thiazol-2-yl)-benzamide A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0 C. was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h; | A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0 0C was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride | |
With 1-methyl-pyrrolidin-2-one; thionyl chloride; In ethyl acetate; for 1h;Reflux; | Compound (16a) (10.0 g, 29.9 mmol) was added to AcOEt (100 ml), and then triethylamine (15.1 ml, 3.6 eq. ) was added thereto, followed by stirring at room temperature for one hour. The solution was cooled to about 0C. Separately, N- methylpyrrolidone (200 mu) and AcOEt (50 ml) were added to 2- ethoxybenzoic acid (5.95 g, 1.2 eq.), and then thionyl chloride (2.83 ml, 1.3 eq. ) was added thereto, followed by heating at reflux for one hour to prepare a solution of 2-ethoxybenzoyl chloride. The solution of 2-ethoxybenzoyl chloride was added at 0C to the Compound (16a) -containing solution, which had been obtained as above, followed by striing at the same temperature for 30 minutes. After the completion of the reaction, water (50 ml) and concentrated hydrochloric acid (5 ml) were added thereto, and extraction and liquid separation was performed. Subsequently, the organic layer was washed with water (50 ml) and a 25% NaOH aqueous solution (5 ml), and concentrated to dryness to obtain an oily product. EtOH (50 ml) and water (20 ml) were added to the oily product, followed by dissolution, and a seed crystal was added thereto, followed by cooling and aging. The precipitated crystals were then collected by filtration, and dried at 45C to give Compound (1a) (9.70 g) . Compound (1a): 1H NMR (CDCl3, 400 MHz) delta 1.40 (d, J = 6.0 Hz, 6H) , 1.49 (t, J = 6.9 Hz, 3H), 4.19 (q, J = 6.9 Hz, 2H) , 4.63 (d, J = 5.5 Hz, 2H) 4.69 (sept, J = 6.0 Hz, 1H) , 6.63 (t, J = 75 Hz, 1H) , 6.95 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H) , 7.23 (d, J = 8.2 Hz 1H) , 7.43 (td, J = 8.0, 1.4 Hz, 1H),7.59 (dd, J = 8.2, 1.8 Hz, 1H) 7.67 (d, J = 1.8 Hz, 1H) , 7.67 (s, 1H) , 8.24 (dd, J = 7.8, 1.8 Hz, 1H), 8.56 (br-s, 1H). | |
With thionyl chloride; N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: Benzo[d][1,3]dioxole-5-carboxylic acid (8.00 g, 48.1 mmol), SOCl2 (10.4 mL, 144 mmol) and DMF (0.15 mL, 2 mmol) were mixed together in a flask protected with CaCl2 trap and stirred magnetically at r.t. After 24 h, the homogeneous mixture was diluted with toluene (100 mL) and concentrated on a rotary evaporator at 40 C; the residue was diluted with CHCl3 (20 mL) at -10 C and added dropwise to stirred aqueous ammonia (25%, 30 mL) at -10 C. The layers were separated, the aqueous layer was extracted with CHCl3 (2 × 25 mL) and the combined organic extracts were concentrated on a rotary evaporator at 20-80 C. The residue was used without further purification. | |
With thionyl chloride; In dichloromethane; at 100℃; for 0.5h;Cooling with ice; | 1) Preparation of 2-ethoxybenzoyl chloride: lm0l 2-ethoxybenzoic acid was dissolved in methylene chloride to give 2-ethoxybenzoyl chloride at a concentration of lOOOmI / L , Ice bath conditions slowly dropping l.lmol thionyl chloride, drop after completion, 100 C refluxing reaction for 30 minutes, vacuum distillation to remove dichloromethane, 2-ethoxy benzoyl chloride, without further purification , Direct follow-up reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Example 150 [0543] ethyl methyl 2-aminobenzoate (1.29 mL, 9.92 mmol) in dichloromethane (25.0 mL) and triethylamine (4.15 mL, 29.8 mmol) was treated at 0 C. with <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (1.83 g, 9.92 mmol). The reaction mixture was stirred at 0 C. for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 2.70 g (91%) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t2 (Method 2)=3.908 min; m/z (M+H)+ 300.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In ethyl acetate; at 0 - 25℃; for 2h;Product distribution / selectivity; | Preparation Ia: l-methyl-3-n-propyl-4- (2-ethoxybenzamido) -pyrazole-5-carbox- amide (V)In a 250 mL three-neck bottle, (XI) (21.8 g, 0.10 mol) was dissolved in ethylacetate (200 mL) and triethylamine (32 ml, 0.23 mol) to prepare a solution in an ice bath. 2- ethoxybenzoyl chloride (17.0 mL, 0.11 mmol) was added to the solution below 5 0C, and the mixture was stirred at room temperature for 2 hours. Water (170 mL) and petroleum ether (100 mL) were added to stop the reaction, and the mixture was stirred for another 0.5 h. The solid was filtrated and poured into water (170 mL) and stirred for 0.5 h, filtrated and dried (70 0C, 12 h) to afford compound (V) as a white solid (32.0 g, yield 95 %) . m.p. 153 - 154 0C. The product was re- crystallized from ethyl acetate/petroleum ether. 1H NMR (CDCI3, 300 MHz) delta: 0.93 (3H, t) , 1.54 (3H, t) , 1.65 (2H, m) , 2.54 (2H, t), 4.06 (3H, s), 4.31 (2H, q) , 5.62 (IH, br s) , 7.05 (IH, d) , 7.13 (IH, t), 7.54 (IH, t) , 7.91 (IH, br s) , 8.27 (IH, dd) , 9.47 (IH, s) . |
87% | With triethylamine; In dichloromethane; at 0 - 25℃; for 2h;Product distribution / selectivity; | Preparation 1 : l-methyl-3-n-propyl-4- (2-ethoxybenzamido) -pyrazole-5-carbox- amide (V)In a 250 mL three-neck bottle, (XI) (20 g, 0.11 mol) was dissolved in dichloromethane (100 mL) and triethylamine (22.2 g, 0.22 mol) to prepare a solution in an ice bath. 2- ethoxybenzoyl chloride was added to the solution below 5 0C, and the mixture was stirred at room temperature for 2 hours. Water (40 mL) was added to stop the reaction, and the layers were separated. The organic phase was washed with brine (30 mL) and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, followed by concentration. The resulting residue was purified by re- crystallizing from ethyl acetate/petroleum ether to obtain (V) (31.5 g, yield 87 %) as a white solid, m.p. 153 - 154 0C. 1H NMR (CDCl3, 300 MHz) delta: 0.93 (3H, t), 1.54 (3H, t), 1.65 (2H, m) , 2.54 (2H, t) , 4.06 (3H, s) , 4.31 (2H, q) , 5.62 (IH, br s) , <n="19"/>7 . 05 ( IH, d) , 7 . 13 ( IH, t ) , 7 . 54 ( IH , t ) , 7 . 91 ( IH , br s ) , 8 . 27 ( IH , dd) , 9 . 47 ( IH, s ) . |
87% | With triethylamine; In dichloromethane; at 25℃;Cooling with ice; | To a 250 mL three-neck flask, were added the compound of formula (XI) (20 g, 0.11 mol), dichloromethane (100 mL) and triethylamine (22.2 g, 0.22 mol) to prepare a solution in an ice bath below 5 C., followed by the slow addition of <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong>. After the mixture was stirred at room temperature for 2 hours, water (40 mL) was added to quench the reaction, and the layers were separated. The organic phase was washed with brine (30 mL) and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, followed by concentration. The resulting residue was purified by re-crystallising with ethyl acetate/petroleum ether to obtain the compound of formula (V) (31.5 g, yield 87%) as a white solid. m.p. 153154 C.; 1H NMR (CDCl3, 300 MHz) delta: 0.93 (3H, t), 1.54 (3H, t), 1.65 (2H, m), 2.54 (2H, t), 4.06 (3H, s), 4.31 (2H, q), 5.62 (1H, br s), 7.05 (1H, d), 7.13 (1H, t), 7.54 (1H, t), 7.91 (1H, br s), 8.27 (1H, dd), 9.47 (1H, s). |
80% | With dmap; triethylamine; In dichloromethane; at 50℃; for 0.166667h;Microwave irradiation; | 1-methyl-3-propyl-4 - (2-ethoxy methyl amido) pyrazole-5-carboxamide preparation: heating the prepared 7.5mmol2-ethoxy formyl chloride dissolved in 15 mu L methylene chloride (that is, the concentration of 500mol/L), adding 2.25mmol4-dimethyl aminopyridine, 19mmol triethylamine, stirring slowly dripping 19mmol4-amino-1-methyl-3-n-propyl -1H-pyrazole-5-carboxamide, microwave heating 50 C reaction 10 minutes, after the reaction of methylene chloride is removed by reduced pressure distillation, a small amount of ethanol re-crystallization, drying after filtration, a kind of white obtained 1-methyl-3-propyl-4 - (2-ethoxy methyl amido) pyrazole-5-carboxamide, the yield is 80%; |
With triethylamine; In dichloromethane; at 20℃; for 1h; | 50 g of the compound II was added to the reaction flask, 400 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature, and 2 equivalents of the acid-binding agent triethylamine was added thereto, and the compound I was added thereto, and the mixture was stirred at room temperature for 1 hour, and the dichloromethane was distilled off under reduced pressure, and 250 ml of ethanol was added thereto. 3 equivalents of sodium hydroxide, the temperature was raised to reflux reaction for 3 hours, the reaction was cooled to room temperature, about half of the solvent was distilled off under reduced pressure, 400 ml of purified water was added, and hydrochloric acid was added to adjust pH = 8-9, stirring was continued for 1 hour, suction filtration and drying were obtained. Product 80g, yield 93.3%, HPLC purity 99.72% |