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CAS No. : | 39226-97-6 | MDL No. : | MFCD00792415 |
Formula : | C8H4ClF3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AXOAWWUSRZCGKS-UHFFFAOYSA-N |
M.W : | 224.56 | Pubchem ID : | 2736677 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 43.41 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.57 cm/s |
Log Po/w (iLOGP) : | 1.44 |
Log Po/w (XLOGP3) : | 2.96 |
Log Po/w (WLOGP) : | 4.21 |
Log Po/w (MLOGP) : | 3.24 |
Log Po/w (SILICOS-IT) : | 2.91 |
Consensus Log Po/w : | 2.95 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.28 |
Solubility : | 0.117 mg/ml ; 0.000522 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.41 |
Solubility : | 0.0882 mg/ml ; 0.000393 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.28 |
Solubility : | 0.118 mg/ml ; 0.000524 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h; | EXAMPLE 6; Preparation of N-(2-azabicyclo[2.2.2]octan-1-yl(phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide Step A. Preparation of N-((2-allyl-2-azabicyclo[2.2.2]octan-1-yl)(phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from (2-allyl-2-azabicyclo[2.2.2]octan-1-yl)(phenyl)methanamine hydrochloride; To a mixture of <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.217 g, 0.97 mmol) in dichloromethane (6.90 mL) was added oxalyl chloride (0.121 mL, 1.38 mmol) and one drop of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 30 min, whereupon it became a clear solution and was concentrated. The resulting light yellow oil was redissolved in dichloromethane (5 mL).To a mixture of (2-allyl-2-azabicyclo[2.2.2]octan-1-yl)(phenyl)methanamine hydrochloride (0.202 g, 0.69 mmol; prepared according to the procedures of Example 1, Steps A-F, substituting allyl iodide for iodomethane in step A, and forgoing basification in Step F), triethylamine (0.385 mL, 2.76 mmol), and dichloromethane (6.90 mL) was added via cannula the acid chloride prepared above. The resulting light orange mixture was stirred at room temperature for 1 h and then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (×1) and ethyl acetate (×1). The resulting organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (SiO2, 0-50% ethyl acetate in hexanes) to afford partially pure product N-((2-allyl-2-azabicyclo[2.2.2]octan-1-yl)(phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide (0.215 g, 67.3%) as a faint yellow foam solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 1.36 (d, J=5.1 Hz, 4 H), 1.46-1.61 (m, 3 H), 1.71-1.80 (m, 1 H), 1.95-2.05 (m, 1 H), 2.55 (d, J=11.1 Hz, 1 H), 2.89 (d, J=11.1 Hz, 1 H), 3.21 (dd, J=13.8, 6.9 Hz, 1 H), 3.46-3.53 (m, 1 H), 5.11 (d, 1 H), 5.20 (d, 1 H), 5.25 (dd, J=17.2, 1.4 Hz, 1 H), 5.75-5.91 (m, 1 H), 7.20-7.26 (m, 1 H), 7.28-7.35 (m, 4 H), 7.52-7.58 (m, 1 H), 7.62 (t, J=7.7 Hz, 1 H), 7.91 (dd, J=7.8, 1.3 Hz, 1 H), 8.91 (d, J=8.4 Hz, 1 H). ESI+ LCMS (M+H)+ 463.2, 465.2. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 0.5h; | Step G. Preparation of 2-chloro-N-((2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(4-(propylsulfonyl)phenyl)methyl)-3-(trifluoromethyl)benzamide from tert-butyl (2- methyl-2-azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methylcarbamate.; To a solution of <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.674 g, 3.00 mmol) in dichloromethane (6.00 ml) was added oxalyl chloride (0.525 ml, 6.00 mmol) and one drop of DMF. After 30 min, the reaction was concentrated to a yellow oil. This oil was then redissolved in dichloromethane (3 mL) to provide a 1 M solution of 2-chloro-3- (trifluoromethyl)benzoyl chloride. To a solution of tert-butyl (2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methylcarbamate (0.045 g, 0.10 mmol) was added concentrated aqueous hydrochloric acid (0.5 mL). After gas evolution ceased, the now lightly cloudy solution was concentrated to dryness. The resulting residue was redissolved in dichloromethane (1.031 ml), and triethylamine (0.115 ml, 0.82 mmol) was added followed by 1.0 M 2-chloro-3-(trifluoromethyl)benzoyl chloride in dichloromethane (0.930 ml, 0.93 mmol). This new orange solution was stirred at room temperature for 10 min and was then quenched with methanol and concentrated. This material was purified by preparative HPLC (C 18, acetonitrile in water containing 2% formic acid) to afford 2-chloro- N-((2-methyl-2-azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methyl)-3- (trifluoromethyl)benzamide (0.0301 g, 53.8%) as a white solid upon lyopholization from acetonitrile and water. IH NMR (500 MHz, DMSO-J6) delta ppm 0.93 (t, J=7.4 Hz, 3 H), 1.19 - 1.30 (m, 2 H), 1.33 - 1.45 (m, 2 H), 1.49 - 1.65 (m, 5 H), 1.80 (br. s., 1 H), 2.02 - 2.09 (m, 1 H), 2.41 (s, 3 H), 2.55 (d, J=10.8 Hz, 1 H), 3.00 - 3.05 (m, 1 H), 3.26 - 3.30 (m, 2 H), 5.16 (d, J=7.6 Hz, 1 H), 7.54 - 7.64 (m, 4 H), 7.84 (d, J=8.4 Hz, 2 H), 7.92 (t, J=4.7 Hz, 1 H), 9.06 (d, J=7.6 Hz, 1 H). m/z (ES+), (M+H)+ = 543.1695, 545.1664; MS2, HPLC tR = 1.00 min. | |
With thionyl chloride; In toluene; for 3h;Heating / reflux; | EXAMPLE 72A 2-chloro-N-[(dimethylamino)methylene]-3-(trifluoromethyl)benzamide Step A <strong>[39226-97-6]2-Chloro-3-trifluoromethylbenzoic acid</strong> (4.52 g, 20.13 mmol) and thionylchloride (10 mL, 137 mmol) were heated to reflux in toluene (40 mL) for 3 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was treated with dry toluene and concentrated under reduced pressure (3×). Step B A solution of 0.5 M ammonia in 1,4-dioxane (140 mL) at 5 C. was slowly treated with the obtained residue from step A in diethyl ether (30 mL) and then allowed to warm to room temperature overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between methylene chloride and water. The organic phase was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. Step C The crude amide from step B (20 mmol) and dimethylformamide dimethylacetal (10 mL) were combined and heated at reflux for 1.5 hours, allowed to cool to room temperature, concentrated under reduced pressure, and partitioned between water and diethyl ether. The organic phase was washed with water (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to provide the title compound. MS (DCI/NH3) m/z 279 (M+H)+; 1H NMR (CDCl3) delta 3.18 (s, 3H), 3.23 (s, 3H), 7.38 (t, 1H), 7.71 (dd, 1H), 7.88 (dd, 1H), 8.63 (s, 1H). |
With oxalyl dichloride; | Example 39:(+)-trans- 2-Chloro-3-trifluoromethyl-benzoic acid 2-(2-acetoxymethyl-1 -methyl- pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester2-Chloro-3-trifluoromethyl-benzoic acid (10.0 g, 44.5 mmol) was converted to its acid chloride using oxalyl chloride (4.6 mL, 50.7 mmol). Triethylamine (7.2 mL, 52.0 mmol) was added to a solution of compound of example 1 (13.6 g, 38.70 mmol) in dry DCM (60 mL). To this, a solution of the acid chloride dissolved in dry DCM (10.0 mL) was added drop wise and the reaction stirred at 25 C for 2 hours. The reaction mixture was poured over crushed ice, basified with saturated sodium carbonate solution (pH 10), extracted with chloroform (3 x 200 mL), and the solvent removed under reduced pressure to afford the title compound as a viscous oil.Crude yield: 25.0 g. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;Inert atmosphere; | Intermediate E: 2-Chloro-3-(trifluoromethyl)benzoyl chloride To a suspension of <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 4h; | Intermediate 12: 2-Chloro-3-(trifluoromethyl)benzoyl chloride To a suspension of <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum. | |
With thionyl chloride; for 1.5h;Heating / reflux; | Example 1. 2-Chloro-lambda/-[(1 S)-1-phenyl-2-(1-piperidinyl)ethyl]-3- (trifluoromethyl)benzamide <n="37"/>2-Chloro-3-trifluoromethyl-benzoic acid (1 12 mg, 0.5 mmol, 1 eq) was suspended in thionyl chloride (2 mL) and the mixture heated at reflux under an atmosphere of nitrogen for 1.5 h. The reaction mixture was concentrated at reduced pressure and the residue redissolved in dichloromethane (1 mL). The solution of the acyl chloride was added dropwise to a stirred solution of [(1 S)-1-phenyl-2-(1-piperidinyl)ethyl]amine (102 mg, O.deltammol, 1 eq) and triethylamine (0.10 mL, 0.75 mmol, 1.5 eq) in dichloromethane (2 mL) at 0 0C under a nitrogen atmosphere. The reaction mixture was allowed to warm to rt and was stirred for 16 h. The reaction mixture was poured into aqueous citric acid (10%; 20 mL) and the aqueous then extracted with dichloromethane (3 x 20 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate (30 mL), water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated at reduced pressure to give the crude product as an orange gum.The crude product was recrystallised from diisopropyl ether to give the title compound as an off white solid (100 mg, 49%). 1H NMR (DMSO) deltaH: 1.40-1.65 (6H, m), 2.30-2.80 (6H, m), 5.25 (1 H, m), 7.28-7.50 (4H, m), 7.70 (2H, s), 7.99 (1 H, d), 9.09 (1 H, d). Mass Spectrum (Electrospray LC/MS): Found 41 1 (MH+). C2IH2235CIF3N2O requires 410. Ret. Time 4.07 min.* |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6. Cis-threo-2-chloro-N-[(1,6-dimethyl-2-piperidyl)(phenyl)methyl]-3-(trifluoromethyl)benzamide hydrochloride 1:1 0.13 g (0.58 mmol) of <strong>[39226-97-6]2-chloro-3-trifluoromethanebenzoic acid</strong>, 0.11 g (0.59 mmol) of 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride and 0.03 g (0.24 mmol) of dimethylaminopyridine dissolved in 4 ml of dichloromethane are successively introduced into a 25 ml round-bottomed flask, 0.10 g (0.48 mmol) of cis-threo-(1,6-dimethyl-2-piperidyl)phenylmethanamine dissolved in 1 ml of dichloromethane is added and the mixture is left stirring for 5 hours. The resulting mixture is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with aqueous 1N sodium hydroxide solution, drying over magnesium sulfate, filtering evaporating off the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol. 0.18 g of oily product is obtained, which is isolated in hydrochloride form from a 0.1N solution of hydrogen chloride in 2-propanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.4. Cis-threo-2-chloro-N-[(1,4-dimethyl-2-piperidyl)(phenyl)methyl]-3-(trifluoromethyl)benzamide hydrochloride 1:1; 0.98 g (4.38 mmol) of <strong>[39226-97-6]2-chloro-3-trifluoromethanebenzoic acid</strong>, 0.85 g (4.46 mmol) of 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride and 0.22 g (1.83 mmol) of dimethylaminopyridine dissolved in 20 ml of dichloromethane are successively introduced into a 50 ml round-bottomed flask, 0.8 g (3.66 mmol) of cis-threo-(1,4-dimethyl-2-piperidyl)phenylmethanamine dissolved in 4 ml of dichloromethane is added and the mixture is stirred for 12 hours. The resulting mixture is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with aqueous 1N sodium hydroxide solution, drying over magnesium sulfate, filtering and evaporating off the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol. 0.32 g of oily product is obtained, which is isolated in hydrochloride form from a 0.1N solution of hydrogen chloride in 2-propanol. 0.28 g of hydrochloride is finally isolated in the form of a white solid. Melting point: 209-211 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; for 24h;Heating / reflux; | EXAMPLE 28A 2-[2-chloro-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazole <strong>[39226-97-6]2-Chloro-3-trifluoromethylbenzoic acid</strong> (10 g, 44.5 mmol) in sulfuric acid (1 mL) was heated at reflux in ethanol (50 mL) for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with saturated sodium bicarbonate (3×), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to provide 9.65 g of the crude ester. The obtained ester was heated with hydrazine hydrate (9.4 mL 194 mmol) in ethanol (50 mL) for 3 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide the crude acylhydrazide. The obtained acylhydrazide was combined with triethylorthoformate (20 mL 120 mmol) and para-toluenesulfonic acid monohydrate (530 mg 2.8 mmol) in toluene and heated at reflux for 2 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) m/z 249 (M+H)+; 1H NMR (CDCl3) delta 7.56 (t, 1H), 7.93 (dd, 1H), 8.15 (dd, 1H), 8.61 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1-methyl-pyrrolidin-2-one; In tetrahydrofuran; N,N-dimethyl-formamide; | Example 350 Production of 2-chloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide Using <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (88 mg, 0.39 mmol), oxalyl chloride (42 muL, 0.49 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol) and N-methylpyrrolidone (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 68%) was obtained as a white powder. 1H-NMR (DMSO-d6, 300 MHz) delta 0.75-0.86 (4H, m), 1.86-1.97 (1H, m), 6.99-7.15 (2H, m), 7.45 (1H, t, J=8.1 Hz), 7.49-7.58 (1H, m), 7.61-7.76 (2H, m), 7.88-7.95 (1H, m), 7.96-8.02 (2H, m), 8.05 (1H, d, J=9.6 Hz), 10.83 (1H, s), 11.09 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 12^{^-Chloro-S-ttrifluoromethylJphenylJcarbony^-i^-fluorophenyl)^- piperazinone (E12); A solution of <strong>[780753-89-1]1-(4-fluorophenyl)-2-piperazinone</strong> (100 mg, 0.52 mmol, prepared as described below), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), and lambda/,lambda/-dimethyl-4-pyridinamine (252 mg, 2.06 mmol) in dichloromethane (4 ml) was stirred at room temperature under argon. 2-Chloro-3- (trifluoromethyl)benzoic acid (116 mg, 0.52 mmol) was added portionwise and the <n="43"/>mixture was left overnight. Dichloromethane and aqueous 3N citric acid were then added and the mixture was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash-silica gel chromatography, eluting with 30-70percent ethyl acetate in isohexane, to give 4-[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1- (4-fluorophenyl)-2-piperazinone (101 mg) as a white solid. LC/MS [M+H]+ = 401 , retention time = 2.70 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; | Example 1^{^-Chloro-S-ttrifluoromethylJphenyllcarbony^-i^-methylphenyl)^- piperazinone (E1); A solution of 1-(2-methylphenyl)-2-piperazinone (150mg, 0.79 mmol, prepared as described below), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol), and lambda/,lambda/-dimethyl-4-pyridinamine (385 mg, 3.15 mmol) in dichloromethane (4 ml) was stirred at room temperature under argon. 2-Chloro-3- (trifluoromethyl)benzoic acid (177 mg, 0.79 mmol) was added portionwise, and the reaction mixture was left to stir at room temperature under argon overnight. Dichloromethane and aqueous 3N citric acid were added and the mixture was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash-silica gel chromatography, eluting with 30-100% ethyl acetate in isohexane, to give the product 4-[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-(2-methylphenyl)-2- piperazinone (138mg) as a white solid. LC/MS [M+H]+ = 397, retention time = 2.77 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 10 i^-Chloro^-fluorophenylJ^^^-chloro-S-ttrifluoromethylJphenylJcarbonyl}^- piperazinone (E10); <n="41"/>A solution of 1-(2-chloro-4-fluorophenyl)-2-piperazinone (75mg, 0.33 mmol, prepared as described below), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (101 mg, 0.525 mmol), and N,N-dimethyl-4-pyridinamine (160 mg, 1.31 mmol) in dichloromethane (4 ml) was stirred at room temperature under argon. 2-chloro-3- (trifluoromethyl)benzoic acid (74 mg, 0.33 mmol) was added portionwise and the reaction mixture was left to stir at room temperature under argon overnight. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash- silica gel chromatography eluting with 30-100% ethyl acetate in isohexane. The resulting product was repurified by flash-silica gel chromatography, eluting with 30- 70% ethyl acetate in isohexane, to give the product 1-(2-chloro-4-fluorophenyl)-4-[2- chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (18 mg), as a white solid. LC/MS [M+H]+ = 435, retention time = 2.84 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.87% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Example 21^{^-chloro-S-ttrifluoromethylJphenyllcarbony^-i^^-difluorophenyl)^- piperazinone (E21); To a stirred solution of 1-(2,4-difluorophenyl)-2-piperazinone (200mg, 0.943 mmol, prepared as described above for Example 19), DMAP (4-dimethylaminopyridine, 461 mg, 3.77 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (289 mg, 1.508 mmol) in dichloromethane (DCM) (3 ml) was added 2-chloro-3- (trifluoromethyl)benzoic acid (233 mg, 1.037 mmol), and the reaction was stirred at RT overnight. The reaction mixture was diluted with DCM and 3N Citric Acid (aq.), and the product was extracted into DCM (x2). The combined organic extracts were washed with water (x1 ), NaHCtheta3 (sat., aq.), brine (x1 ) and then dried (MgStheta4). The solvent was evaporated in vacuo to give a dark brown oil, 360mg, which was purified by MDAP. The relevant fractions were combined and the solvent evaporated in vacuo to give a yellow oil, which by TLC (50% EtOAc/ iso-Hexane) contained a baseline impurity. This was purified further by column chromatography on silica gel, eluting with 0-100% EtOAc / iso-Hexane. The relevant fractions were combined and the solvent evaporated in vacuo to give a pale yellow foam. LCMS and NMR shows this to contain impurities, so this was purified again by MDAP. The relevant fractions were combined and the solvent evaporated in vacuo to give a white solid, 4-[2- chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-(2,4-difluorophenyl)-2-piperazinone (95mg, 0.216 mmol, 22.87 % yield), LC/MS [M+H]+ = 419, retention time = 2.76 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.0% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 24 4-[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1 -(1 -naphthalenyl)-2- piperazinone (E24); A solution of 1-(1-naphthalenyl)-2-piperazinone (112 mg, 0.495 mmol, prepared in a manner analogous to that described in Example 22) , EDC (152 mg, 0.792 mmol) and DMAP (242 mg, 1.980 mmol) in Dichloromethane (DCM) (4 ml) was stirred at room temperature under an argon atmosphere. <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (11 1 mg, 0.495 mmol) was added portionwise and leave to stir overnight. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane (x2). The dichloromethane layer was washed with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ) then it was dried on magnesium sulfate and evaporated in vacuo. <n="54"/>Product was purified by MDAP and fractions combined and then the solvent was evaporated in vacuo to give a white solid 4-[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-(1-naphthalenyl)-2-piperazinone (75 mg, 0.173 mmol, 35.0 % yield). LC/MS [M+H]+ = 432.9, retention time = 2.97 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.98% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Example 25^{^-chloro-S-ttrifluoromethylJphenylJcarbony^-i-^^i-methylethylJphenyl]^- piperazinone (E25); A solution of 1-[2-(1-methylethyl)phenyl]-2-piperazinone (100 mg, 0.458 mmol) , EDC (141 mg, 0.733 mmol) and DMAP (224 mg, 1.832 mmol) in dichloromethane (DCM) (4 ml.) was stirred at room temperature under an argon atmosphere. 2-chloro-3- (trifluoromethyl)benzoic acid (103 mg, 0.458 mmol) was added portionwise and leave to stir overnight. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane (x2). The dichloromethane layer was washed with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ) then it was dried on magnesium sulfate and evaporated in vacuo. Product was purified by MDAP and fractions combined and then the solvent was evaporated in vacuo to give a white solid 4-[2-chloro-3-(trif luoromethyl)phenyl]carbonyl}-1 -[2-(1 -methylethyl)phenyl]-2-piperazinone (35 mg, 0.082 mmol, 17.98 % yield). LC/MS [M+H]+ = 425, retention time = 3.05 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.1. 2-Chloro-N-[phenyl(pyridin-2-yl)methyl]-3-trifluoromethylbenzamide. 1.61 g (7.16 mmol) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong>, 1.4 g (7.28 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 0.218 g (1.79 mmol) of 4-dimethylaminopyridine in solution in 60 ml of dichloromethane are placed in a 250 ml round-bottomed flask, the mixture is stirred for 15 min, 1.1 g (5.97 mmol) of phenyl(pyridin-2-yl)methanamine in solution in 60 ml of dichloromethane are added and the mixture is stirred at room temperature for 24 h. It is hydrolyzed by adding water, a 35% aqueous sodium hydroxide solution is added, the organic phase is separated, it is washed with water and then with a saturated aqueous sodium chloride solution, it is dried over magnesium sulphate, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column, eluding with a mixture of dichloromethane and methanol, and 1.34 g of product are finally isolated in the form of a yellow oil which crystallizes, and which is used as it is in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.3 g (1.37 mmol) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong>, 0.26 g (1.37 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, and 0.19 g (1.37 mmol) of 1-hydroxybenzotriazole in solution in 10 ml of dichloromethane to a 50 ml round-bottomed flask and the mixture is stirred at room temperature for 30 min. 0.3 g (1.37 mmol) of threo-(1-ethylpiperidin-2-yl)phenylmethanamine in solutin in a few ml of dichloromethane is added and the stirring is continued for 5 h. The mixture is hydrolysed with water, and it is extracted several times with dichloromethane. After washing the organic phases with water and then with a 1 N aqueous sodium hydroxide solution, drying over magnesium sulphate, filtration and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol. 0.25 g of an oily product are obtained. The product is dissolved in a few ml of propan-2-ol, 5.9 ml of a 0.1 N hydrochloric acid solution in propan-2-ol are added, and the mixture is concentrated under reduced pressure in order to reduce the volume of the solvent. After trituration, 0.15 g of hydrochloride is finally isolated in the form of a white solid. Melting point: 230-232 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 22h; | To a solution of 33 mg (0.144 mmol) <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (commercial), 75 mg (0.197 mmol) HATU and 90 ul (0.524 mmol) N-ethyldiisopropylamine in DMF (1 ml) was added a solution of 25 mg (0.131 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) in DMF (0.25 ml). The mixture was stirred at room temperature for 22 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium carbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 27 mg (52%) of the title compound as a light yellow oil. MS (m/e): MS (m/e): 397.2 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 2.1h; | Step B. Preparation of 2-chloro-N-((2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(5-methylfuran-2-yl)methyl)-3-(trifluoromethyl)benzamide from tert-butyl (2-methyl- 2-azabicyclo[2.2.2]octan-l-yl)(5-methylfuran-2-yl)methylcarbamate.; To tert-butyl (2-methyl-2-azabicyclo[2.2.2]octan- 1 -yl)(5-methylfuran-2-yl)methylcarbamate (0.061 g, 0.18 mmol) was added concentrated aqueous hydrochloric acid (1.5 mL, 2.25 mmol). After 1 min, the brown solution was concentrated to dryness to afford crude (2- methyl-2-azabicyclo [2.2.2]octan- 1 -yl)(5 -methylfuran-2-yl)methanamine dihydrochloride(0.054 g, 96%). A solution of crude (2-methyl-2-azabicyclo[2.2.2]octan-l-yl)(5-methylfuran- 2-yl)methanamine dihydrochloride (0.027 g, 0.09 mmol), <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.022 g, 0.10 mmol), and HOBt (0.020 g, 0.13 mmol) in DMF (0.586 ml) was treated with TBTU (0.040 g, 0.12 mmol) and DIPEA (0.077 ml, 0.44 mmol) sequentially. After 2.1 hr, the reaction mixture was diluted with methanol, filtered, and purified by preparative HPLC (C 18, acetonitrile in water containing ammonium carbonate, pH 10) to afford semi-pure product. This material was further purified by flash column chromatography (SiO2, 0-15% (2% ammonia in methanol) in ethyl acetate) to afford 2-chloro-N-((2-methyl-2- azabicyclo [2.2.2]octan- 1 -yl)(5 -methylfuran-2-yl)methyl)-3 -(trifluoromethyl)benzamide (0.029 g, 74.9 %) as a white foam solid. IH NMR (300 MHz, chloroform-d) delta ppm 1.41 -1.74 (m, 7 H), 1.74 - 1.88 (m, 1 H), 1.88 - 2.02 (m, 1 H), 2.27 (s, 3 H), 2.34 (s, 3 H), 2.57 (d, J=10.6 Hz, 1 H), 3.09 (d, J=10.6 Hz, 1 H), 4.96 (d, J=5.7 Hz, 1 H), 5.91 (dd, J=3.0, 0.9 Hz, 1 H), 6.12 (d, J=3.1 Hz, 1 H), 6.94 (br. s., 1 H), 7.41 (t, J=7.8 Hz, 1 H), 7.69 (d, J=7.7 Hz, 1 H),7.75 (dd, 1 H). (ES+), (M+H)+ = 441.3, 443.3; MSl, HPLC tR = 0.61 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h; | Step C. Preparation of (S*)-N-((2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l- methyl-lH-pyrazol-4-yl)phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l-methyl-lH-pyrazol-4- yl)phenyl)methyl)-2-methylpropane-2-sulfinamide.; To (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l-methyl-lH-pyrazol-4- yl)phenyl)methyl)-2-methylpropane-2-sulfinamide (0.115 g, 0.26 mmol) in methanol (2.61 ml) was added 4.0 M hydrochloric acid in dioxane (1.5 ml, 6.00 mmol). After 30 s, the clear solution was concentrated to afford crude (2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l-methyl- lH-pyrazol-4-yl)phenyl)methanamine dihydrochloride as a white solid. A solution of crude (2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l -methyl- lH-pyrazol-4-yl)phenyl)methanamine dihydrochloride (0.26 mmol), <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.064 g, 0.29 mmol), and HOBt (0.058 g, 0.38 mmol) in DMF (1.733 ml) was treated with TBTU (0.117 g, 0.36 mmol) and DIPEA (0.226 ml, 1.30 mmol) sequentially. After 16 h, the reaction mixture was diluted with methanol, filtered, and purified by preparative HPLC (C 18, acetonitrile in water containing ammonium carbonate, pH 10) to afford (S*)-N-((2-allyl-2-azabicyclo[2.2.2]octan- 1 -yl)(3 -( 1 -methyl- 1 H-pyrazol-4-yl)phenyl)methyl)-2-chloro-3 -(trifluoromethyl)benzamide (0.101 g, 71.5 %) as a light yellow foam solid. IH NMR (300 MHz, chloroform-d) delta ppm 1.32 - 1.78 (m, 8 H), 1.91 - 2.02 (m, 1 H), 2.47 - 2.70 (m, 1 H), 2.94 - 3.13 (m, 2 H), 3.48 - 3.65 (m, 1 H), 3.94 (s, 3 H), 4.93 (d, J=3.7 Hz, 1 H), 5.07 (d, J=10.4 Hz, 1 H), 5.20 (dd, J=17.1, 1.1 Hz, 1 H), 5.64 - 5.88 (m, 1 H), 7.17 (d, J=7.4 Hz, 1 H), 7.27 - 7.45 (m, 5 H), 7.58 (s, 1 H), 7.66 (dd, J=I .1, 1.3 Hz, 1 H), 7.73 (s, 0 H), 7.76 (dd, J=I.1, 1.0 Hz, 1 H). m/z (ES+), (M+H)+ 543.3, 545.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.25h; | Step B. Preparation of N-((3-bromophenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from N-((3- bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-2-methylpropane-2- sulfinamide; To N-((3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan- 1 -yl)methyl)-2-methylpropane-2- sulfmamide (0.3 g, 0.73 mmol) in methanol (3.0 ml) was added 4.0 M hydrochloric acid in dioxane (3.0 ml, 98.74 mmol). After 5 min, the orange solution was concentrated to afford crude (3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan- 1 -yl)methanamine dihydrochloride as an orange residue. To a solution of crude (3-bromophenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methanamine, dihydrochloride (0.088 g, 0.23 mmol) and DIPEA (0.201 ml, 1.15 mmol) in DMF (2.300 ml) was added HOBT (0.049 g, 0.32 mmol), 2-chloro- 3-(trifiuoromethyl)benzoic acid (0.057 g, 0.25 mmol), and TBTU (0.103 g, 0.32 mmol) sequentially. After 15 min, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by prep HPLC (C 18, acetonitrile in water containing ammonium carbonate, pH 10) to afford N-((3- bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-2-chloro-3- (trifluoromethyl)benzamide (0.048 g, 40.3 %) as a white foam solid. IH NMR (500 MHz, chloroform-d) delta ppm 1.31 - 1.52 (m, 4 H), 1.57 - 1.72 (m, 4 H), 1.92 - 2.01 (m, 1 H), 2.37 (s, 3 H), 2.48 - 2.54 (m, 1 H), 3.20 - 3.29 (m, 1 H), 4.76 (d, J=3.4 Hz, 1 H), 7.16 - 7.24 (m, 2 H), 7.26 (s, 1 H), 7.32 (br. s., 1 H), 7.39 (dt, J=7.6, 1.6 Hz, 1 H), 7.41 - 7.45 (m, 1 H), 7.67 (dd, J=I.1, 1.4 Hz, 1 H), 7.77 (dd, J=7.9, 1.4 Hz, 1 H). m/z (ES+), (M+H)+ 515.2, 517.2; MS3, HPLC tR = 2.41 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.166667h; | Step B. Preparation of 2-chloro-N-((3-(l-methyl-lH-pyrazol-4- yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-3-(trifluoromethyl)benzamide from 2-methyl-N-((3-(l-methyl-lH-pyrazol-4-yl)phenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)propane-2-sulfinamide.; To 2-methyl-N-((3-(l-methyl-lH-pyrazol-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)methyl)propane-2-sulfnamide (0.808 g, 1.95 mmol) in methanol (3.90 niL) was added 4.0 M hydrochloric acid in dioxane (3.0 mL, 12.00 mmol). After 1 min, the light yellow solution was concentrated to afford crude (3-(l-methyl-lH-pyrazol-4-yl)phenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methanamine dihydrochloride as a white/off-white solid. To a solution of crude (3-(l-methyl-lH-pyrazol-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)methanamine dihydrochloride (0.08 mmol), <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.019 g, 0.08 mmol), DIPEA (0.066 ml, 0.38 mmol), and HOBT (0.016 g, 0.11 mmol) in N,N-dimethylformamide (1.0 ml) was added TBTU (0.034 g, 0.11 mmol). After 10 min, the reaction was filtered, diluted with methanol (2.5 mL) and purified by preparative LCMS(C 18, acetonitrile in water containing ammonium carbonate, pH 10) to afford 2-chloro-N-((3- (1 -methyl- lH-pyrazol-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octan- l-yl)methyl)-3- (trifluoromethyl)benzamide (10.90 mg, 27.9 %) as an off white solid. IH NMR (300 MHz, chloroform-d) delta ppm 1.32 - 1.54 (m, 4 H), 1.54 - 1.81 (m, 4 H), 1.91 - 2.08 (m, 1 H), 2.40 (s, 3 H), 2.51 (d, J=10.9 Hz, 1 H), 3.26 (d, J=10.7 Hz, 1 H), 3.94 (s, 3 H), 4.84 (d, J=3.5 Hz, 1 H), 7.16 (d, J=7.4 Hz, 1 H), 7.27 - 7.48 (m, 5 H), 7.58 (s, 1 H), 7.68 (d, J=7.6 Hz, 1 H), 7.73 (s, 1 H), 7.76 (d, J=7.9 Hz, 1 H). m/z (ES+), (M+H)+ 517.3, 519.3; MS3, HPLC tR = 2.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of 2-chloro-N- ( (S) - ( 2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl) methyl) -3- ( trifluoromethyl)benzamide monohydrochloride (Compound 39); (1) HOBt-H2O (0.14 g) and EDC-HCl (0.17 g) were added to a DMF solution (4 ml) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong> <n="120"/>(0.18 g) and stirred at room temperature for 15 minutes. (S)- l-( (2S)-I-Allylpiperidin-2-yl) -1- (3-pgammarazin-2-gammalphenyl) methanamine (0.22 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=100:0 to 97:3) to obtain N- [ (S) - [ ( 2S) -1- allylpiperidin-2-yl] ( 3-pyrazin-2-ylphenyl) methyl] -2-chloro-3- (trifluoromethyl)benzamide (0.25 g) as a pale yellow solid.MS (ESI pos.) m/z : 515 ( [M+H]+) , (ESI neg.) m/z : 513([M-H]-) IH NMR (600 MHz, CDC13) delta ppm 1.34 - 1.87 (m, 6 H), 2.56 - 2.63 (m, 1 H), 2.87- 3.01 (m, 2 H), 3.20 - 3.27 (m, 1 H), 3.28 - 3.34 (m, 1 H), 5.02 - 5.16 (m, 3 H), 5.70 - 5.79 (m, 1 H), 7.41 - 7.45 (m, 1 H), 7.49 - 7.53 (m, 2 H), 7.70 - 7.74 (m, 1 H), 7.76 - 7.79 (m, 1 H), 7.80 - 7.86 (m, 1 H), 7.90 - 7.94 (m, 1 H), 8.05 - 8.08 (m, 1 H), 8.50 - 8.52 (m, 1 H), 8.63 - 8.66 (m, 1 H), 9.03 - 9.05 (m, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of 2-chloro-N-{ (S) - [3- ( l-methyl-lH-imidazol-5- yl)phenyl][(2S)- piperidin-2-yl]methyl} -3- ( trifluoromethyl)benzamide dihydrochloride (Compound 70); (1) HOBt-H2O (0.11 g) and EDC-HCl (0.14 g) were added to a DMF <n="122"/>solution (4 ml) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong> (0.15 g) and stirred at room temperature for 15 minutes. (S)- 1-((2S)-I-Allylpiperidin-2-yl) - 1- ( 3- ( 1-methyl- IH-imidazol-5- yl)phenyl)methanamine (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto , and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate , and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=67 : 33 to 0:100 and subsequently, silica gel, chloroform/methanol=100 : 0 to 97:3) to obtain N-{(S)- t(2S)-l-allylpiperidin-2-yl] [3- ( l-methyl-lH-imidazol-5- yl)phenyl]methyl}-2-chloro-3- (trifluoromethyl)benzamide (0.21 g) in a colorless amorphous state. MS(ESI pos.) m/z : 517([M+H]+) IH NMR (600 MHz, CDC13) delta ppm 1.30 - 1.93 (m, 6 H), 2.54 - 2.62 (m, 1 H), 2.83 - 2.91 (m, 1 H), 2.91 - 2.99 (m, 1 H), 3.18 - 3.25 (m, 1 H), 3.28 - 3.36 (m, 1 H), 3.67 (s, 3 H), 4.94 - 5.02 (m, 1 H), 5.05 - 5.15 (m, 2 H), 5.68 - 5.79 (m, 1 H), 7.10 (s, 1 H), 7.28 - 7.32 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.52 (s, 1 H), 7.67 - 7.73 (m, 1 H), 7.76 - 7.84 (m, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 3; Synthesis of 2-chloro-N- ( (S) -( (2S) -l-methylpiperidin-2-yl) (3- pyridin-3-yl <n="126"/>phenyl)methyl) -3- (trifluoromethyl)benzamide dihydrochloride (Compound 7); HOBt-H2O (87 mg) and EDC-HCl (98 mg) were added to a DMF solution (3 ml) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong> (96 mg) and stirred at room temperature for 15 minutes. (S)-I- ((2S)-I-Methylpiperidin-2-yl) -1- ( 3-pyridin-3-ylphenyl) methanamine (100 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=3:l to 1:1) to obtain 2-chloro-N- ( (S) - ( ( 2S) -1- methylpiperidin-2-yl) (3-pyridin-3-yl phenyl)methyl) -3- (trifluoromethyl)benzamide (0.14 g) in a colorless amorphous state. The obtained purified product was dissolved in ethyl acetate (4 ml) and 4 M HCl/ethyl acetate <n="127"/>solution (1 ml) was added to the mixture. The resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was solidified with a mixed solvent of chloroform (1 ml) and diisopropyl ether (3 ml). The obtained solid was collected by filtration to obtain the title compound (0.14 g) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Production Example 4 Synthesis of 3-((S)-(( 2S)-I- allylpiperidin-2-yl) ( (2-chloro-3-( trifluoromethyl)benzoyl) amino)methyl)phenyl trifluoromethanesulfonate; (1) HOBt-H2O (2.2 g) and EDC-HCl (2.5 g) were added to a DMF solution (15 ml) of <strong>[39226-97-6]2-chloro-3-trifluoromethylbenzoic acid</strong> (2.6 g) and stirred at room temperature for 30 minutes. A DMF solution (15 ml) of (S) -1- ( ( 2S) -1-allylpiperidin-2-yl) -1- (3- methoxyphenyl) <n="64"/>methanamine (3.0 g) was added thereto, and the mixture was stirred at room temperature for 3 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=50:l) to obtain N- ( (S) - ( (2S) -1- allylpiperidin-2-yl) ( 3-methoxyphenyl)methyl) -2-chloro-3- (trifluoromethyl)benzamide (3.4 g) as a colorless solid. MS (ESI pos.) m/z : 467 ( [M+H]+) , (ESI neg.) m/z : 465([M-H]-)IH NMR (200 MHz, CDC13) delta ppm 1.25 - 1.88 (m, 6 H), 2.45 - 2.64 (m, 1 H), 2.75 - 3.03 (m, 2 H), 3.10 - 3.38 (m, 2 H), 3.81 (s, 3 H), 4.88 - 4.98 (m, 1 H), 5.02 - 5.17 (m, 2 H), 5.61 - 5.83 (m, 1 H), 6.75 - 6.84 (m, 1 H), 6.90 - 7.01 (m, 2 H), 7.19 - 7.32 (m, 1 H), 7.36 - 7.48 (m, 1 H), 7.64 - 7.81 (m, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)benz-amide hydrochloride (1:1).; 2.4 g of <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (10.8 mmol), 1.45 g of hydroxybenzotriazole (10.8 mmol) and 2.1 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.8 mmol) are placed in solution in 20 ml of dichloromethane in a 250 ml round-bottomed flask and the mixture is stirred at ambient temperature for 15 minutes. 17 g (9.0 mmol) of [(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (IIc) in solution in 20 ml of dichloromethane are added and the mixture is stirred at ambient temperature overnight.The reaction medium is subsequently diluted with 10 ml of dichloromethane and then successively washed with water (5 ml), 1N sodium hydroxide solution (5 ml) and a saturated sodium chloride solution (5 ml).The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure.1.8 g of N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoro-methyl)benzamide are thus obtained. An analytical sample is obtained in the form of the hydrochloride by dissolution of the base in dichloromethane, addition of an excess of 1N hydrochloric acid in ether and then concentration under reduced pressure.1H NMR (400 MHz, d6-DMSO) delta ppm 9.09 (d, J=9 Hz, 1H), 7.94 (d×d, J=7.8 Hz and 1.8 Hz, 1H), 7.68 (m, 1H), 7.63 (m, 1H), 7.41-7.31 (m, 4H), 7.27 (m, 1H), 5.33 (d, J=8.8 Hz, 1H), 2.78 (m, 2H), 2.64 (t, J=2.9 Hz, 1H), 2.20 (m, 1H), 1.68 (m, 2H), 1.14 (m, 2H).M.p.=148-150 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; HATU; In dichloromethane; | A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (21 mg, 0.093 mmol) in DCM (8 mL) was treated with Et3N (35 muL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 32 mg (91%) of 5-[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C19H14ClF3N4O, 406.1. m/z found, 407.1 [M+H]+. 1H NMR (400 MHz, CDCl3): delta 7.84-7.75 (m, 1H), 7.62-7.43 (m, 7H), 5.11 (q, J=16.5 Hz, 1H), 4.64-4.45 (m, 1H), 4.32 (dt, J=13.2, 5.4 Hz, 0.5H), 4.05-3.95 (m, 0.5H), 3.65-3.48 (m, 1H), 3.04 (t, J=5.9 Hz, 1H), 3.01-2.76 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | To a solution of tert-butyl 2-methyl-3-(pyridin-2-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (135 mg, 0.429 mmol) in CH2Cl2 (5 mL) was added 4 M HCl in dioxane (0.43 mL, 1.72 mmol). The reaction was allowed to stir at rt for 1 h, then 1 mL MeOH was added and the reaction was stirred overnight. The reaction was concentrated to a yellow gum. It was combined with <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (155 mg, 0.690 mmol), BOP (305 mg, 0.690 mmol) and triethylamine (0.37 mL, 2.65 mmol). After stirring overnight at rt, the reaction was filtered and purified by HPLC (Agilent prep system, Waters XBridge C18 5 mum 50*100 mm column, 5-99% MeOH/20 nM NH4OH over 18 min at 80 mL/min). The desired product was isolated as a white solid (56 mg, 31%). MS (ESI) mass calcd. C20H16ClF3N4O, 420.1. m/z found, 421.1 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 8.75-8.69 (m, 1H), 7.85-7.72 (m, 2H), 7.54-7.34 (m, 3H), 7.31-7.25 (m, 1H), 5.09 (d, J=16.6 Hz, 0.5H), 4.90 (d, J=16.6 Hz, 0.5H), 4.46 (d, J=15.8 Hz, 0.5H), 4.36 (d, J=15.8 Hz, 0.5H), 4.24 (dt, J=12.8, 5.4 Hz, 0.5H), 4.10 (s, 1H), 4.04 (s, 2H), 3.92-3.87 (m, 0.5H), 3.52-3.41 (m, 1H), 2.94-2.82 (m, 1H), 2.80-2.61 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | A solution of 1-(5-fluoropyrimidin-2-yl)-4-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.30 g, 1.28 mmol), <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.34 g, 1.54 mmol), HATU (0.38 g, 1.28 mmol), and Et3N (0.18 mL, 1.28 mmol) in DMF (5 mL) was stirred for 30 min. The reaction was diluted with EtOAc (30 mL) and washed with H2O (3*20 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.51 g, 90%). 1H NMR (500 MHz, CDCl3) delta 8.80-8.43 (m, 2H), 7.82-7.44 (m, 1H), 7.27-7.15 (m, 2H), 6.66-6.60 (m, 1H), 5.95-4.92 (m, 1H), 3.77-2.54 (m, 3H), 1.74-1.53 (m, 3H). MS (ESI): mass calculated for C18H13ClF4N6O, 440.08. m/z found, 441.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | Step C. (2-Chloro-3-(trifluoromethyl)phenyl)(1-(pyridin-2-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone A solution of 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.050 g, 0.25 mmol), <strong>[39226-97-6]2-chloro-3-trifluoromethyl benzoic acid</strong> (0.056 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol, and DIPEA (0.09 mL, 0.50 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3*10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (22 mg, 22%). 1H NMR (400 MHz, CDCl3) delta 8.52 (dd, J=4.9, 1.8 Hz, 1H), 8.02 (d, J=18.1 Hz, 1H), 7.92-7.71 (m, 2H), 7.58-7.40 (m, 2H), 7.37-7.28 (m, 2H), 5.12-4.78 (m, 1H), 4.51-4.19 (m, 2H), 3.97 (ddd, J=13.4, 12.7, 9.9 Hz, 1H), 3.61-3.45 (m, 1H), 3.27-2.82 (m, 2H). MS (ESI): mass calculated for C19H14ClF3N4O, 406.1. m/z found 407.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | A mixture of Example 2F, <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (101 mg, 0.45 mmol), and N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) was stirred in a 1 : 1 solution of pyridine and N,N-dimethylformamide (5 ml) at room temperature under nitrogen for 16 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic fraction was collected and the aqueous portion was washed with additional ethyl acetate. The combined organic fractions were washed with water, brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (95:5 dichloromethane 2N ammonia in methanol) to afford the title compound. MS (ESI) m/z 543.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a stirred solution of Example 4B (3.3 g, 10.7 mmol) in a 1 :1 dimethylformamide:pyridine solution (20 mL) was added <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (2.9 g, 12.9 mmol) and N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.85 g, 15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrate. The reaction mixture was partitioned between, EtOAc (100 mL) and 1 M HC1 (200 mL). The organic layer was collected.The aqueous fraction was washed with EtOAc (100 mL). The organic fractions were combined. Purification via flash chromatography (0-100% EtOAc/hexanes) provided the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 20℃; for 2h; | To a solution of trans-tert-butyl 3-amino-4-phenylpyrrolidine-l-carboxylate (0.305 g, 1.163 mmol) and <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (0.261 g, 1.163 mmol) in dichloromethane (4.65 ml) was added triethylamine (0.486 ml, 3.49 mmol) and HATU (0.663 g, 1.744 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned with water, the organic fraction was collected, and the aqueous fraction was washed with dichloromethane. The organic fractions were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (Analogix IntelliFlash 280, SF15-12) eluting with 30% ethyl acetate / hexanes to afford the title compound. MS (ESI) m/z 469.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (1.01 g, 5.15 mmol) in DMF (17 mL) was added <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (2.31 g, 10.30 mmol), Hunig's base (3.55 mL, 20.60 mmol) and HATU (2.31 g, 10.30 mmol). The solution was allowed to stir for 30 min at rt then poured into ice water (300 mL). The resulting solid was collected by suction filtration and allowed to air dry. The solid was purified by chromatography on silica gel (0-100% ethyl acetatehexanes). The product fractions were concentrated to a white solid which was dissolved in ethanol (20 mL) and 1M NaOH (20 mL) and stirred at 80 C. for 1 h. Water (50 mL) and CH2Cl2 (50 mL) were added. The layers were separated and the water layer was extracted two times with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to an oil (1.37 g, 81%). MS (ESI) mass calcd. C14H11ClF3N3O, 329.1. m/z found, 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 7.79-7.73 (m, 1H), 7.52-7.41 (m, 2H), 7.37 (br s, 1H), 5.11 (d, J=16.6 Hz, 0.5H), 4.85 (d, J=16.6 Hz, 0.5H), 4.46 (d, J=15.9 Hz, 0.5H), 4.36 (d, J=15.9 Hz, 0.5H), 4.22-4.18 (m, 0.5H), 3.94-3.88 (m, 0.5H), 3.49-3.44 (m, 1H), 2.85-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.62-2.54 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; | Example 105 6-[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine To a solution of Intermediate 59 (200 mg, 0.74 mmol) in DCM (5 mL) was added <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (167 mg, 0.74 mmol), Triethylamine (0.62 mL, 4.48 mmol) and BOP (611.03 mg, 1.38 mmol). The solution was allowed to stir overnight. The reaction was then given an aqueous workup and extracted with DCM three times. The combined organic layers were dried over Na2SO4 and concentrated. The resulting mixture of regioisomers was purified by basic HPLC (0-99% acetonitrile) then by SFC to obtain the desired product (31 mg, 9%) MS (ESI): mass calcd. for C21H16ClF4N3O, 437.83. m/z found, 438.2 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 7.75 (d, J=7.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.45 (dd, J=14.5, 7.3 Hz, 1H), 7.35-7.27 (m, 2H), 7.22-7.13 (m, 2H), 5.01-4.95 (m, 1H), 4.45-4.38 (m, 1H), 4.27-3.84 (m, 1H), 3.78 (m, 3H), 3.50-3.37 (m, 1H), 2.74-2.66 (m, 1H), 2.62-2.43 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | A mixture of ethyl 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylate hydrochloride (0.050 g, 0.18 mmol), <strong>[39226-97-6]2-chloro-3-trifluoromethyl benzoic acid</strong> (0.045 g, 0.20 mmol), HATU (0.077 g, 0.20 mmol), and DIPEA (0.035 mL, 0.20 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3*10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH (NH3):DCM) gave the title compound (26 mg, 30%). 1H NMR (500 MHz, CDCl3) delta 8.58-8.45 (m, 1H), 8.10-7.98 (m, 1H), 7.94-7.82 (m, 1H), 7.82-7.72 (m, 1H), 7.63 (dd, J=7.6, 1.3 Hz, 1H), 7.55-7.28 (m, 3H), 6.23 (dd, J=12.3, 6.3 Hz, 1H), 5.25-5.00 (m, 1H), 4.48-4.06 (m, 2H), 4.01-3.60 (m, 3H), 3.50-2.85 (m, 3H). MS (ESI): mass calculated for C22H18ClF3N4O3, 478.1. m/z found 479.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | Example 36 (5-[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-phenyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-4-yl)methyl 2-chloro-3-(trifluoromethyl)benzoate A solution of Intermediate 233. (0.050 g, 0.22 mmol), <strong>[39226-97-6]2-chloro-3-trifluoromethyl benzoic acid</strong> (0.054 g, 0.24 mmol), HATU (0.091 g, 0.24 mmol), and DIPEA (0.04 mL, 0.24 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3*10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (30 mg, 21%). MS (ESI): mass calculated for C29H19Cl2F6N3O3, 641.07. m/z found, 642.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; HATU; In dichloromethane; at 20℃; | To a solution of 2-methyl-1-phenyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (114 mg, 0.51 mmol), 2-chloro-3-trifluoromethylcarboxylic acid (90 mg, 0.42 mmol) and HATU (319 mg, 0.84 mmol) in DCM (15 mL) was added NEt3 (0.16 mL, 1.26 mmol). The mixture was stirred at rt overnight after which time the reaction was concentrated under reduced pressure and purified by basic HPLC to provide the product as a white solid (100 mg, 55%). 1H NMR (400 MHz, DMSO-d6) delta 8.03-7.89 (m, 1H), 7.80-7.54 (m, 7H), 5.06-4.27 (m, 2H), 4.14-3.38 (m, 2H), 2.63-2.32 (m, 5H). MS (ESI): mass calculated for C21H17ClF3N3O, 419.10. m/z found, 420.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | A solution of 4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride (0.10 g, 0.44 mmol), <strong>[39226-97-6]2-chloro-3-trifluoromethyl benzoic acid</strong> (0.10 g, 0.44 mmol), HATU (0.18 g, 0.48 mmol, and DIPEA (0.19 mL, 1.1 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3*10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.06 g, 34%). 1H NMR (500 MHz, CDCl3) delta 8.02-7.94 (m, 1H), 7.80-7.58 (m, 1H), 7.51-7.39 (m, 1H), 6.60-6.50 (m, 1H), 4.42 (q, J=7.6 Hz, 1H), 2.95 (s, 4H). MS (ESI): mass calculated for C15H10ClF6N3O, 397.042. m/z found 398.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; HATU; In dichloromethane; at 20℃; | To a solution of the product of Example 49, Step A (5.5 mg, 0.028 mmol) in DCM (3 mL) was added TEA (11 muL, 0.084 mmol), <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (7 mg, 0.031 mmol) and HATU (13 mg, 0.033 mmol). The reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated and purified on 4 g SiO2 column with 0-3% NH3/MeOH CH2Cl2 to give the desired compound (9.9 mg, 87%). MS (ESI): mass calcd. for C20H13ClF3N3O, 403.1. m/z found, 404.3 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 9.06 (s, 1H), 8.09 (m 1H), 7.94-7.84 (m, 1H), 7.76-7.53 (m, 2H), 7.53-7.39 (m, 2H), 7.39-7.22 (m, 4H), 6.96-6.86 (m, 1H), 6.73 (s, 1H), 5.95 (q, J=7.0 Hz, 1H), 5.54 (s, 1H), 3.22 (q, J=7.3 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; for 3h; | Example 65 5-[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine A solution of 1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (97 mg, 0.48 mmol), 2-chloro-3-(trifluoromethyl)-benzoic acid (118 mg, 0.53 mmol) and Et3N (0.1 ml, 0.72 mmol) in DMF (2.5 ml), was treated with HATU (219 mg, 0.58 mmol) and stirred for 3 h. The reaction mixture was then concentrated and purified on silica gel with 0-4% NH3 MeOH/CH2Cl2, followed by 50-100% EA/hexanes. MS (ESI): mass calcd. for C17H12ClF3N6O, 408.1; m/z found, 409.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 8.94-8.88 (d, J=4.8 Hz, 1H), 8.88-8.82 (d, J=4.8 Hz, 1H), 7.84-7.72 (m, 1H), 7.59-7.46 (m, 2H), 7.47-7.39 (dt, J=11.5, 4.8 Hz, 1H), 5.24-5.01 (m, 1H), 4.65-4.46 (m, 1H), 4.38-4.26 (dt, J=13.4, 5.5 Hz, 0.5H), 4.13-4.00 (ddd, J=13.4, 6.9, 5.4 Hz, 0.5H), 3.68-3.50 (m, 1H), 3.50-3.43 (dt, J=6.9, 4.8 Hz, 1H), 3.43-3.16 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; | Example 99 (2-Chloro-3-(trifluoromethyl)phenyl)(3-phenyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methanone To a solution of Intermediate 58 (433 mg, 1.38 mmol) in DCM (5 mL) was added <strong>[39226-97-6]2-<strong>[39226-97-6]chloro-3-(trifluoromethyl)benzoic acid</strong></strong> (310.3 mg, 1.38 mmol), triethylamine (1.15 mL, 8.29 mmol) and BOP (611.03 mg, 1.38 mmol). The solution was allowed to stir overnight. Following dilution with water, the mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4 and conc. The resulting residue was purified by basic HPLC (0-99% acetonitrile). (356 mg, 56%). MS (ESI): mass calcd. for C20H15ClF3N3O, 405.81. m/z found, 406.2 [M+H]+. 1H NMR (CDCl3): 7.76 (ddd, J=12.1, 7.8, 1.4 Hz, 1H), 7.56-7.33 (m, 7H), 5.17-4.97 (m, 1H), 4.52-4.33 (m, 1H), 4.28 (dt, J=12.9, 5.4 Hz, 1H), 3.99 3.83 (m, 1H), 3.54-3.41 (m, 1H), 2.97 (t, J=5.8 Hz, 1H), 2.79-2.68 (m, 1H). |
Tags: 39226-97-6 synthesis path| 39226-97-6 SDS| 39226-97-6 COA| 39226-97-6 purity| 39226-97-6 application| 39226-97-6 NMR| 39226-97-6 COA| 39226-97-6 structure
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Precautionary Statements-General | |
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P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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