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CAS No. : | 1737-36-6 | MDL No. : | MFCD01631468 |
Formula : | C8H4ClF3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PPHHAZOVVZBSCM-UHFFFAOYSA-N |
M.W : | 224.56 | Pubchem ID : | 2773857 |
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 : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.06 cm/s |
Log Po/w (iLOGP) : | 1.5 |
Log Po/w (XLOGP3) : | 3.68 |
Log Po/w (WLOGP) : | 4.21 |
Log Po/w (MLOGP) : | 3.24 |
Log Po/w (SILICOS-IT) : | 2.91 |
Consensus Log Po/w : | 3.11 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.74 |
Solubility : | 0.0413 mg/ml ; 0.000184 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.15 |
Solubility : | 0.0158 mg/ml ; 0.0000703 mol/l |
Class : | Moderately 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 : | 2.0 |
Synthetic accessibility : | 1.55 |
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 |
---|---|---|
62% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) In tetrahydrofuran at 70℃; for 16 h; Inert atmosphere; Sealed tube | General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 °C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | EDIC hydrochloride (0.33 mmol, 0.07 g) was added in one portion to a suspension of(4-amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine Compound Id (0.25 mmol, 0.06 g), <strong>[1737-36-6]4-chloro-3-trifluoromethyl-benzoic acid</strong> Compound 7a (0.22 mmol, 0.05 g) and HOBt (0.22mmol, 0.03 g) in DMF (5.0 mL) at 0C. The resulting suspension was warmed to r.t. and acrystal of DMAP and Et}N (0.65 mmol, 0.1 mL) were added. The mixture was stirredovernight and produced an orange-yellow suspension. The suspension was poured into waterand the aqueous layer was extracted with EtOAc (25 mL). The organic layer was washed withwater (2 X 20 mL), then a solution of 5% NaOH (10 mL) and brine. The organic layer wasseparated, dried over Na2SO<, and filtered. The solvent was removed in vacua to yield aresidue, which was purified via preparative TLC (15:1 CH2Cl2:MeOH) to provide 4-chloro-N-(4- [methyl-(tetrahydro-pyran-4-yl)~amino] -methyl} -phenyl)-3 -trifluoromethyl-benzamide'Compound 7b (0.06 g, 63%) as a pale yellow solid. MS rn/e 427 (M+H, 100%).; lodomethane (0.5 mL) was added to a solution of Compound 7b (0.07 mmol, 0.03 g) inCH2C12 (1.0 mL) at r.t. The resulting solution stood overnight, after which a pale yellowprecipitate was observed. The solvent was removed in vaciio and the yellow solid was washedwith Et2O (2 X 1 mL) to provide Compound 33 as a yellow solid (0.03 g, 96%). MS m/e 441(M+H, 100%). | |
63% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | EDIC hydrochloride (0.33 mmol, 0.07 g) was added in one portion to a suspension of (4-amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine Compound 1d (0.25 mmol, 0.06 g), <strong>[1737-36-6]4-chloro-3-trifluoromethyl-benzoic acid</strong> Compound 7a (0.22 mmol, 0.05 g) and HOBt (0.22 mmol 0.03 g) in DMF (5.0 mL) at 0 C. The resulting suspension was warmed to r.t. and a crystal of DMAP and Et3N (0.65 mmol, 0.1 mL) were added. The mixture was stirred overnight and produced an orange-yellow suspension. The suspension was poured into water and the aqueous layer was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL), then a solution of 5% NaOH (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield a residue, which was purified via preparative TLC (15:1 CH2Cl2:MeOH) to provide 4-chloro-N-(4-[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-3-trifluoromethyl-benzamide Compound 7b (0.06 g, 63%) as a pale yellow solid. MS m/e 427 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In methanol; | 21 b) Methyl 4-chloro-3-trifluoromethylbenzoate 75 g of <strong>[1737-36-6]4-chloro-3-trifluoromethylbenzoic acid</strong> were dissolved in 500 ml of MeOH, and 75 ml of SOCl2 were added dropwise. The mixture was boiled under reflux for 5 h and the volatile constituents were then removed in vacuo. The residue was taken up in 1 l of EA and this solution was washed with 500 ml of a saturated aqueous solution of Na2 CO3. The organic phase was then dried over Na2 SO4, the solvent was removed in vacuo and the product was distilled in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 12h; | A solution of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (1.02 g, 4.54 mmol), oxalyl chloride (0.59 ml, 6.81 mmol, 1.5 equiv) and catalytic DMF (50 ml) in DCM (10 ml) was stirred at 25 0C for 12 h. The solvents were removed under reduced pressure. The resulting product was utilized without further purification; m/z 244. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 12h; | A solution of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (1.02 g, 4.54 mmol), oxalyl chloride (0.59 ml, 6.81 mmol, 1.5 equiv) and catalytic DMF (50 ml) in DCM (10 ml) was stirred at 25 C for 12 hours. The solvents were removed under reduced pressure. The resulting product was utilized without further purification; m/z 244. | |
With thionyl chloride; In benzene; | (v) A mixture of <strong>[1737-36-6]4-chloro-3-trifluoromethylbenzoic acid</strong> (4.3 g), thionyl chloride (2.9 ml) and dry benzene (50 ml) was refluxed for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo 4-Chloro-3-trifluoromethylbenzoyl chloride was obtained as a waxy solid (4.5 g). |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 1h; | Step 1: Preparation of 4-chloro-N-[2-(3-methoxyphenyl)ethyl]-3-(trifluoromethyl)-benzamide To a solution of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (2.0 g, 8.9 mmol) in DCM was added oxalyl chloride (1.55 mL, 17.8 mmol) dropwise. To this solution was added a few drops of DMF. The reaction mixture was allowed to stir for 1 h and then concentrated. The residue was redissolved in DCM and to this solution were added 2-(3-methoxyphenyl)ethanamine (1.43 mL, 9.8 mmol) and TEA (2.48 mL, 17.8 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction was quenched by the addition of 1N HCl and then the solutions were separated. The organic solution was washed with brine, dried over Na2SO4, filtered, and concentrated to give 4-chloro-N-[2-(3-methoxyphenyl)ethyl]-3-(trifluoromethyl)-benzamide (3.32 g) which was used without further purification. | |
With thionyl chloride; at 50℃; | General procedure: 4.1.5.1. Method (A). The aryl carboxylic acid (0.18 mmol, 1.2 eq.) inSOCl2 (0.3 mL) was heated at 50 C until aryl carboxylic acid disappearedin TLC. After reaction was terminated, the mixture wascooled to ambient temperature and solvent was evaporated underreduced pressure. Aryl carboxylic acid chloride, a crude yellow oilwas diluted with THF and poured into N-(4-amino-2-methylphenyl)-5-methylisoxazole-4-carboxamide (4b) (34.6 mg,0.15 mmol, 1eq.) in THF (1.5 mL), was heated at 65 C until compound4b disappeared in TLC. Purification of column chromatography with MC/MeOH eluents was performed to affordcompound 6. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; | General procedure: 4-methyl-3-nitrobenzoic acid (2.7 g, 15 mM), oxalyl chloride (2.5 mL, 30 mM) and N, N-dimethylformamide (DMF, several drops) in dichloromethane (50 mL) were stirred at room temperature for 2 h. Then, the solvent and oxalyl chloride were evaporated under reduced pressure to get 4-methyl-3-nitrobenzoyl chloride. The benzoyl chloride (1 M solution in dichloromethane, 15 mL) in constant pressure funnel was added to a solution of 4-chloro-3-(trifluoromethyl) aniline (2.4 g, 12.5 mM) and triethylamine (5.2 mL, 37.5 mM) in dichloromethane (40 mL) successively, and the reaction mixture was stirred at room temperature for 5 h. Subsequently, the solvent and triethylamine were evaporated under reduced pressure to get nitroaniline. Then, reduction of the nitro group was carried out by using Fe/NH4Cl (50 mM/37.5 mM) in C2H5OH/H2O (75 mL/25 mL), heated to reflux for about 3 h. The reaction mixture was evaporated in vacuo, purified with silica gel column chromatography. Desired aniline (3 g, 72.6%) was afforded as a pale yellow solid. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; | General procedure: 4-methyl-3-nitrobenzoic acid (2.7 g, 15 mM), oxalyl chloride (2.5 mL, 30 mM) and catalytic amount of DMF (several drops) in dichloromethane (50 mL) stirred at room temperature for 2 h. Then, the solvent and oxalyl chloride were evaporated under reduced pressure to get 4-methyl-3-nitrobenzoyl chloride. The obtained benzoyl chloride was coevaparated with toluene three times to remove the oxalyl chloride. The benzoyl chloride (1 M solution in dichloromethane, 15 mL) in constant pressure funnel was added to a solution of 4-chloro-3-(trifluoromethyl) aniline (2.4 g, 12.5 mM) and triethylamine (5.2 mL, 37.5 mM) in dichloromethane (40 mL) successively. The reaction mixture stirred at room temperature for 5 h. Subsequently, the solvent and triethylamine were evaporated under reduced pressure to get substituted amide. Then, reduction of the nitro group was carried out by using Fe/NH4Cl (50 mM/37.5 mM) in C2H5OH/H2O (75 mL/25 mL), heated to reflux for about 3 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give the crude product, which purified with silica gel column chromatography. Desired aniline Aa (3 g, 72.6%) was afforded as a pale yellow solid. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane;Cooling with ice; | A mixture of 15 g (66.7 mmol) of <strong>[1737-36-6]4-chloro-3-trifluoromethyl benzoic acid</strong> (CAS 1737-36-6) in 100 ml of DCM was cooled in an ice bath before addition of 6.73 mL (80 mmol) of oxalyl chloride and a drop of DMF. The reaction was stirred overnight, warming to room temperature before concentration, and addition of CHCI3 followed by concentration (twice) to remove oxalyl chloride. The crude product was dissolved in 100 mL of CH2CI2. In a separate flask, 7.14 g of Nu,O-dimethylhydroxylamine HCI (73.3 mmol) was added to 100 mL of CH2CI2 and 37 mL of Et3N (266 mmol). After stirring 15 min the mixture was filtered and added to the acid chloride solution and the mixture was stirred 3 d. The reaction mixture was then transferred to a separatory funnel and the CH2CI2 was rinsed with water, then aqueous NaHC03 solution, before drying and concentrating to an oil. Chromatography with 0-20% EtOAc in hexane yielded 14.1 g of the title compound as an oil (79%). 1 H NMR (300 MHz, CDCI3) delta 8.08 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.1, 1.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 3.55 (s, 3H), 3.39 (s, 3H). Mass 268 (M + 1)+. | |
With thionyl chloride; In N,N-dimethyl-formamide; for 6h;Reflux; | General procedure: 2-nicotinic acid 7a (0.20 g, 1.62 mmol) was slowly added to thionyl chloride (4 mL) at 0 under stirring. Then the solution was heated to 72, and kept refluxing for about 6 h. After cooled to room temperature, the mixture was diluted with toluene (10 mL), and concentrated to near dryness in vacuo. To the obtained oily residue (8a) diluted with DCM (10 mL), compound 6 (0.47 g, 1.62 mmol) and Et3N (0.68 mL, 0.49 mmol) was added at 0 slowly. The contents were stirred for 4 h at the room temperature. After the mixture was washed with saturated brine (2 × 5 mL), the organic layer was concentrated under reduced pressure and purified by flash column chromatography (PE : EtOAc = 2: 1) to give the light yellow solid 9a (0.42g, 66%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; XPhos; In tetrahydrofuran; for 1h;Heating / reflux; | Example 1: 2-Trifluoromethoxy-4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]- benzenesulfonamide; a) 2-TrifIuoromethyl-biphenyl-4-carboxylic acid; Tu a suiuiiii of 4-criotaiupsiloniotaupsilon-3-iiotaifiuu[ur?ei?yi benzoic acid (15y, 67r?moi) in TnF (oGOr?i) is added under inert atmosphere phenylboronic acid (14.7g, 120mmol), dicyclohexylphosphino- 2,4,6-triisopropylbiphenyl (3.18g, 3.35mmol), KF (11.65g, 0.2mol) and finally Pd(OAc)2 ( 0.75 g, 6.7mmol). The reaction mixture is then stirred under reflux for 1 hour. The reaction mixture is cooled and concentrated to dryness. Purification using flash chromatography afford the title compound, m/z = 265 (M-H)" | |
palladium diacetate; XPhos; In tetrahydrofuran; for 1.5h;Heating / reflux;Product distribution / selectivity; | nrtir* Lambda P on DH-O DeltarLambda_ dicyclohexylphosphino-2,4,6-triisopropylbiphenyl is dissolved in THF and is refluxed for 90 minutes. After cooling the reaction mixture is filtered through Hyflo Super Cel and concentrated. The crude residue is purified on silica gel using diethylether/c-hexane as mobile phase. | |
With potassium fluoride;palladium diacetate; XPhos; In tetrahydrofuran; at 90℃; for 15h;Product distribution / selectivity; | To a solution of .4-chloro-3-trif.uoromethyl benzoic acid (1 eq) in THF there is added under inert atmosphere the corresponding boronic acid (1.5 eq), X-Phos (0.05 eq), KF (3 eq) and finally Pd(OAc)2 (0.05 eq), the reaction mixture is then stirred at 9O0C for 15 hours. The reaction mixture is concentrated to dryness and purified using flash chromatography to afford the title compound To a solution of <strong>[1737-36-6]4-chloro-3-trifluoromethyl benzoic acid</strong> (5g, 0.02mole) in THF (200ml) was added under inert atmosphere phenyl boronic acid (5.3g, 0.04mole), X-Phos (1g, 0.002mol), KF (4g, 0.06mole) and finally Pd(OAc)2 (240mg, 0.001), the reaction mixture is then stirred at 900C for 15 hours. The reaction mixture is concentrated to dryness and purified using flash chromatography to afford the title compound (5g,). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; | (iv) A mixture of 2-chloro-5-cyanobenzotrifluoride (0.5 g), 50% aqueous sulphuric acid (6 ml) and acetic acid (4 ml) was refluxed for 90 minutes. The mixture was poured into crushed ice and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were extracted with 5% aqueous sodium carbonate solution. The aqueous alkaline extracts were acidified with 2N hydrochloric acid solution. The aqueous acidic mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo 4-Chloro-3-trifluoromethylbenzoic acid was obtained as a colourless solid (0.5 g, mpt 159). Nuclear magnetic resonance spectrum (N.M.R.) was as follows: 1H (p.p.m. from TMS in (CD3)2SO, integral, number of peaks, J Hz): 7.50, 1H, d, 6; 8.00, 2H,m. Infrared spectrum (1R) (nujol mull): max2650 (strong and broad), 1705 (s) cmmin1. Mass spectrum: Chemical Ionisation M+1 225. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 100 - 120℃; for 0.333333 - 0.5h;Microwave irradiation;Product distribution / selectivity; | Description for D28 Ethyl 4-chloro-3-(trifluoromethyl)benzoate (D28)4-Chloro-3-(trifluoromethyl)benzoic acid (1 g, 4.45 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (0.15 ml) was added. The mixture was heated in <n="51"/>the microwave at 100 0C for 5 minutes and then 120 0C for 15 minutes. The solvent was removed in vacuo and the residue partitioned between saturated aq. sodium bicarbonate (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with further EtOAc (50 ml) and the organic phases were combined, dried with a phase separator and concentrated in vacuo to give the title compound (1.026 g) (DN108121-148A3) as a colourless oil. deltaH (methanol-d4, 400 MHz) 1.40 (3H, t), 4.41 (2H, q), 7.76 (1 H, d), 8.21 (1 H, dd), 8.33 (1 H, d). MS (ES) no mass ion observed.Description for D98 (alternative to description for D28) Ethyl 4-chloro-3-(trifluoromethyl)benzoate (D98)A solution of <strong>[1737-36-6]4-chloro-3-trifluoromethyl benzoic acid</strong> (10 g, 44.5 mmol) in ethanol (10 ml) was split equally between two microwave vials. Concentrated sulfuric acid (0.75 ml) was added to each vial (1.5 ml in total). The reactions were heated in the microwave at 120 0C for 30 minutes in total. The reaction mixtures were combined and concentrated in vacuo. The residue was partitioned between EtOAc (100 ml) and aq. sodium bicarbonate (100 ml), the organic phase was separated, washed with aq. sodium bicarbonate (100 ml) and water (2 x 100 ml) and then dried (phase separator) and the solvent removed in vacuo to give the title compound (4.126 g) as a colourless oil. deltaH (400 MHz, methanol-d4) 1.40 (3H, t), 4.41 (2H, quart), 7.76 (1 H, d), 8.22 (1 H, dd), 8.34 (1 H, d). | |
With sulfuric acid; at 100 - 120℃; for 0.333333 - 0.5h;In the microwave;Product distribution / selectivity; | 4-Chloro-3-(trifluoromethyl)benzoic acid (1 g, 4.45 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (0.15 ml) was added. The mixture was heated in the microwave at 100 0C for 5 minutes and then 120 0C for 15 minutes. The solvent <n="48"/>was removed in vacuo and the residue partitioned between saturated aq. sodium bicarbonate (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with further EtOAc (50 ml) and the organic phases were combined, dried with a phase separator and concentrated in vacuo to give the title compound (1.026 g) as a colourless oil. deltaH (methanol-d4, 400 MHz) 1.40 (3H, t), 4.41 (2H, q), 7.76 (1 H, d), 8.21 (1 H, dd), 8.33 (1 H, d).; A solution of <strong>[1737-36-6]4-chloro-3-trifluoromethyl benzoic acid</strong> (10 g, 44.5 mmol) in ethanol (10 ml) was split equally between two microwave vials. Concentrated sulfuric acid (0.75 ml) was added to each vial (1.5 ml in total). The reactions were heated in the microwave at 120 0C for 30 minutes in total. The reaction mixtures were combined and concentrated in vacuo. The residue was partitioned between EtOAc (100 ml) and aq. sodium bicarbonate (100 ml), the organic phase was separated, washed with aq. sodium bicarbonate (100 ml) and water (2 x 100 ml) and then dried (phase separator) and the solvent removed in vacuo to give the title compound (4.126 g) as a colourless oil. deltaH (400 MHz, methanol^) consistent with previous example. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; for 4h;Heating / reflux; | Process 2; <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> methyl ester; To a methanol solution (49 mL) of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> obtained in Process 1, a concentrated hydrochloric acid (11.0 mL) was added. The resultant mixture was stirred and refluxed for 4 hours. After the stirring was ended, the reaction solution was concentrated. The product was poured into a saturated sodium bicarbonate solution, and extraction was performed by using ethyl acetate. An organic layer was washed with a saturated saline solution, dried by using sodium sulfate, and further concentrated under a reduced pressure. Subsequently, chromatography (as an elution solution, 20:1 (v/v) of hexane/ethyl acetate was used) using Biotage 12s cartridge was performed, so that 983 mg of the titled compound was obtained. 1H-NMR (CDCl3): 8.36 (1H, d, J=2.0), 8.13 (1H, dd, J=2.0, J=8.4), 7.60 (1H, d, J=8.4), 3.96 (3H, s) | |
With sulfuric acid;Reflux;Product distribution / selectivity; | Step A: Preparation of Methyl 4-Chloro-3-(trifluoromethyl)benzoate. To a solution of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (10.37 g, 46.2 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.51 mL, 9.24 mmol). The mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to form a solid. The solid was filtered and washed with water. The solid was then stirred with saturated aqueous sodium bicarbonate solution to remove any residual sulfuric acid, filtered and dried under vacuum to give the title compound as a white solid (10.18 g). 1H NMR (400 MHz, CDCl3) delta ppm 3.96 (s, 3H), 7.60 (d, J = 8.34 Hz, IH), 8.14 (dd, J = 8.34, 2.02 Hz, IH), 8.37 (d, J = 2.02 Hz, IH). | |
With sulfuric acid;Reflux;Product distribution / selectivity; | Step A: Preparation of Methyl 4-Chloro-3-(trifiuoromethyl)benzoate.To a solution of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (10.37 g, 46.2 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.51 mL, 9.24 mmol). The mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to form a solid. The solid was filtered and washed with water. The solid was then stirred with saturated aqueous sodium bicarbonate solution to remove any residual sulfuric acid, filtered and dried under vacuum to give the title compound as a white solid (10.18 g). NMR (400 MHz, CDC13) delta ppm 3.96 (s, 3H), 7.60 (d, J= 8.34 Hz, 1H), 8.14 (dd, J= 8.34, 2.02 Hz, 1H), 8.37 (d, J= 2.02 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 65 Process 1 4-chloro-3-(trifluoromethyl)benzoic acid To a 2-methoxy ethanol solution (20 mL) of 2-chloro-5-cyanobenzotrifluoride (1.0 g, manufactured by Fluorochem), 2.5N sodium hydroxide aqueous solution (20 mL, manufactured by Wako Pure Chemical Industries, Ltd.) was added. The resultant mixture was stirred for 15 hours at 90 C. After the stirring was ended, 1N HCl aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, extraction was performed by using ethyl acetate, and an organic layer was dried by using sodium sulfate. Subsequently, the organic layer was concentrated under a reduced pressure, so that the titled compound was obtained. The obtained residue was directly used for the next reaction. ESI-MS: 222.9 (M-H), RTime 3.95 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (348 mumol). Triethylamine (344 mumol) was added, followed by aliquots of DMF stock solutions of HATU (320 mumol) and <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (129 mumol), and the mixture was stirred at room temperature over night. The solution was transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzamide as a solid (70%). LCMS (method B) 6.81 min; mass M+H+ 595; UV 240, 290, 340 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; HATU; In N,N-dimethyl-formamide; | In a 6 ml maximum recovery HPLC vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (347 mumol). Triethylamine (344 mumol) was added, followed by aliquots of DMF stock solutions of HATU (320 mumol) and <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (129 mumol), and the mixture was stirred at room temperature over night. The solutions were purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(3-chloro-4-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzamide as a solid (85%). LCMS (method B) 6.86 min; mass M+H+ 595; UV 235, 300, 350 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 72h;Inert atmosphere; Cooling with thawing ice; | EXAMPLE 97 4-Chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide To a mixture of <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (31 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) was added at 0 C. under an atmosphere of nitrogen a solution {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL). The solution was stirred for 3 d in a thawing ice bath. The resulting solution was diluted with dichloromethane and was washed twice with water (10 mL). The aqueous layers were extracted with dichloromethane (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO<SUB>2</SUB>, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (63 mg, 86%) as a light brown foam. MS m/e: 646.3 [M+H]<SUP>+</SUP>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20 - 80℃; | 4-(8-Nitroquinolin-4-yloxy)phenylamine (103 mL, 0.46 mmol), N-hydroxybenzotriazole (HOBt) (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarboimide (EDCl) (102 mg, 0.53 mmol) and <strong>[1737-36-6]4-chloro-3-trifluoromethylbenzoic acid</strong> (103 mg, 0.46 mmol) were dissolved in dimethylformamide (3.6 mL), and to which triethylamine was added dropwise at room temperature, which was then heated and stirred at 80 C. When the reaction was completed, the resultant was extracted with ethyl acetate and saturated sodium bicarbonate, combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=½) to obtain 125 mg of the desired compound as a brown solid (yield 71.2%).1H NMR (400 MHz, DMSO-d6): delta 6.81 (d, J=5.2 Hz, 1H), 7.39 (s, 1H), 7.41 (s, 1H), 7.82 (t, J=1.50 Hz, 1H), 7.62-7.97 (m, 3H), 8.27 (dd, J=2.03, 13.17 Hz, 1H), 8.32 (dd, J=1.21, 10.86 Hz, 1H), 8.42 (d, J=1.96 Hz, 1H), 8.61 (dd, J=1.33, 8.47 Hz, 1H), 8.82 (d, J=5.24, 1H), 10.72 (s, 1H).13C NMR (100 MHz, DMSO-d6): delta 105.61, 121.41, 121.52, 122.36, 123.78, 123.97, 125.64, 126.20, 127.04, 127.09, 131.94, 133.38, 133.96, 134.64, 136.73, 139.85, 147.98, 149.17, 153.80, 161.30, 163.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: A mixture of compound 8a, b (30 mg, 0.1 mmol), the appropriate carboxylic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in dry DMF (1.0 mL) was cooled to 0C under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added thereto at the same temperature. The mixture was then stirred at 80C for 24 h. The reaction mixture was cooled and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 24h; | (S)-1-(4-(2-(3-aminophenyl)-1H-imidazol-1-yl)pyrimidin-2-yl amino)propa n-2-ol (5 , 0.016 mmol) prepared in Example 1, <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (3.618 , 0.016 mmol), HBTU (9.1 , 0.024 mmol) and DIPEA (3.1 , 0.024 mmol) were dissolved in tetrahydrofuran solvent (0.2 ) and stirred for one day at 50 C. Upon the completion of the reaction, ethyl acetate was added to the reaction mixture, and the reaction mixture was washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfite and filtered, and the solvent was removed under reduced pressure. The residue was purified with column chromatography (silica gel, methylene chloride/methanol=10/1) for thereby preparing a target compound (5 , 62 %). [257] 1H NMR (400 MHz, DMSO-d6) delta 10.60 (1H, s), 8.37 (1H, s), 8.30 (1H, d, J = 5.24 Hz), 8.24 (1H, dd, J = 1.94 Hz, J = 1.83 Hz), 7.94 (1H, s), 7.92 (1H, s), 7.84 (1H, d, J = 8.79 Hz), 7.73 (1H, br), 7.39 (1H, t, J = 8.02 Hz), 7.30 (1H, br), 7.21 (1H, s), 7.09 (1H, d, J = 6.72 Hz), 4.50 (1H, br), 3.77 (1H, m), 3.61 (1H, m), 2.89 (2H, m), 1.26 (3H, d, J = 8.13 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | General procedure: A mixture of 4-substituted-3-nitrobenzoic acid 10a-d, 14a-g (5 mmol), EDCI (6 mmol) and HOBt in anhydrous DMF (20 mL) was stirred at room temperature for about 0.5-2 h. Then the appropriate aniline 11a-j, 7a-b (4 mmol) was added with triethylamine (5 mmol) and stirred at room temperature for 4-24 h. Then the reaction mixture was diluted to 100 mL with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated solution of NaCl, then dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel column using acetic ether and petroleum ether (1:10-1:8, v:v) as eluent to obtain compounds 12a-o, 15a-h as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 15h; | 6-(6-(3-Aminophenyl)-1H-indol-1-yl)pyrimidin-4-amine (15 mg, 0.050 mmol), <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (16.8 mg, 0.075 mmol) and HOBt (6.8 mg, 0.050 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (28.8 mg, 0.15 mmol) was added. The reaction solution was stirred at room temperature for 15 hours and the reaction mixture was added to saturated sodium bicarbonate aqueous solution. After adding water and ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx = 1:4 ? MC:MeOH = 20:1) yielded the target compound.MS m/z [M+1] 507.98; 1H NMR (400 MHz, DMSO-d 6) d 10.62 (s, 1H), 8.59 (s, 1H), 8.42 (d, 1H), 8.41 (s, 1H), 8.29 (d, 1H), 8.04 (s, 1H), 7.95 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 7.50 (t, 1H), 7.48 (d, 1H), 7.46 (d, 1H), 7.01 (s, 2H), 6.80 (d, 1H), 6.68 (s, 1H). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 15h; | Example 6 N-(3-(1-(6-aminopyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide 6-(6-(3-Aminophenyl)-1H-indol-1-yl)pyrimidin-4-amine (15 mg, 0.050 mmol), <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (16.8 mg, 0.075 mmol) and HOBt (6.8 mg, 0.050 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (28.8 mg, 0.15 mmol) was added. The reaction solution was stirred at room temperature for 15 hours and the reaction mixture was added to saturated sodium bicarbonate aqueous solution. After adding water and ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx=1:4?MC:MeOH=20:1) yielded the target compound. MS m/z [M+1] 507.98; 1H NMR (400 MHz, DMSO-d6) d 10.62 (s, 1H), 8.59 (s, 1H), 8.42 (d, 1H), 8.41 (s, 1H), 8.29 (d, 1H), 8.04 (s, 1H), 7.95 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 7.50 (t, 1H), 7.48 (d, 1H), 7.46 (d, 1H), 7.01 (s, 2H), 6.80 (d, 1H), 6.68 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; sodium hydroxide; In tetrahydrofuran; at 20℃; for 2h; | (4-(6-(3-Aminophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (30 mg, 0.068 mmol), <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (16.8 mg, 0.075 mmol) and HOBt (9.2 mg, 0.068 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (39.2 mg, 0.20 mmol) was added. After adding 1 N NaOH (1 mL) and MeOH (1 mL), the mixture solution was stirred at room temperature for 2 hours. After adding ethyl acetate and water, the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, DCM:MeOH = 20:1) yielded N-(3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide (29 mg, 0.055 mmol) as white solid.MS m/z [M+1] 532.11; 1H NMR (400 MHz, DMSO-d 6) d 8.86 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.42 (d, J = 1.64 Hz, 1H), 8.29 (dd, J = 2.04, 8.45 Hz, 1H), 8.22 (d, J = 2.00 Hz, 1H), 8.07 (d, J = 1.71 Hz, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.81 (t, J = 1.54 Hz, 1H), 7.79 (d, J = 2.18 Hz, 1H), 7.67 (d, J = 3.59 Hz, 1H), 7.54 (d, J = 1.60 Hz, 1H), 7.52 (d, J = 1.64 Hz, 1H), 7.49 (s, 1H), 6.94 (d, J = 2.48 Hz, 1H), 6.89 (d, J = 3.62 Hz, 1H). | |
With water; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; sodium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 2h; | Example 37 N-(3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide (4-(6-(3-Aminophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (30 mg, 0.068 mmol), <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (16.8 mg, 0.075 mmol) and HOBt (9.2 mg, 0.068 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (39.2 mg, 0.20 mmol) was added. After adding 1 N NaOH (1 mL) and MeOH (1 mL), the mixture solution was stirred at room temperature for 2 hours. After adding ethyl acetate and water, the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, DCM:MeOH=20:1) yielded N-(3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide (29 mg, 0.055 mmol) as white solid. MS m/z [M+1] 532.11; 1H NMR (400 MHz, DMSO-d6) d 8.86 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.42 (d, J=1.64 Hz, 1H), 8.29 (dd, J=2.04, 8.45 Hz, 1H), 8.22 (d, J=2.00 Hz, 1H), 8.07 (d, J=1.71 Hz, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.81 (t, J=1.54 Hz, 1H), 7.79 (d, J=2.18 Hz, 1H), 7.67 (d, J=3.59 Hz, 1H), 7.54 (d, J=1.60 Hz, 1H), 7.52 (d, J=1.64 Hz, 1H), 7.49 (s, 1H), 6.94 (d, J=2.48 Hz, 1H), 6.89 (d, J=3.62 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 6a (20.0 mg, 0.06 mmol), 3-trifluoromethyl-benzoic acid (23.11 mg, 0.12 mmol), HOBt (18.1 mg, 0.13 mmol), and EDCI (29.1 mg, 0.15 mmol) in dry DMF (1.0 mL) was cooled to 0 C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.002 mL, 0.015 mmol) was added at 0 C. The mixture was then stirred at 80 C for 12 h. The reaction mixture was cooled and then partitioned between water (5 mL) and ethyl acetate (5 mL) and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate (3 × 3 mL) and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 3:1 v/v then switching to hexane-ethyl acetate 1:1 v/v) to yield compound 9a (5.0 mg, 16.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 6a (20.0 mg, 0.06 mmol), 3-trifluoromethyl-benzoic acid (23.11 mg, 0.12 mmol), HOBt (18.1 mg, 0.13 mmol), and EDCI (29.1 mg, 0.15 mmol) in dry DMF (1.0 mL) was cooled to 0 C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.002 mL, 0.015 mmol) was added at 0 C. The mixture was then stirred at 80 C for 12 h. The reaction mixture was cooled and then partitioned between water (5 mL) and ethyl acetate (5 mL) and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate (3 × 3 mL) and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 3:1 v/v then switching to hexane-ethyl acetate 1:1 v/v) to yield compound 9a (5.0 mg, 16.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 6a (20.0 mg, 0.06 mmol), 3-trifluoromethyl-benzoic acid (23.11 mg, 0.12 mmol), HOBt (18.1 mg, 0.13 mmol), and EDCI (29.1 mg, 0.15 mmol) in dry DMF (1.0 mL) was cooled to 0 C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.002 mL, 0.015 mmol) was added at 0 C. The mixture was then stirred at 80 C for 12 h. The reaction mixture was cooled and then partitioned between water (5 mL) and ethyl acetate (5 mL) and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate (3 × 3 mL) and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 3:1 v/v then switching to hexane-ethyl acetate 1:1 v/v) to yield compound 9a (5.0 mg, 16.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃;Inert atmosphere; | General procedure: A mixture of compound 8 (50 mg, 0.1 mmol), 3,4-dichlorobenzoic acid (38 mg, 0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in DMF (1.0 mL) was cooled to 0 C under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added thereto at the same temperature. The mixture was then stirred at 80 C for 12 h. The reaction mixture was cooled and then partitioned between H2O and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 1:1 v/v) to yield compound 13 (26 mg, 36.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: A solution of 6 compound (10 mg, 0.028 mmol), substituted benzoic acid (0.028 mmol), HOBt (6.8 mg, 0.05 mmol), EDCI (8.05 mg, 0.04 mmol) and TEA (10 muL, 0.07 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer dried over Na2SO4. Purification of column chromatography with Hexane/ethyl acetate = 1:1 to afford compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: A solution of 6 compound (10 mg, 0.028 mmol), substituted benzoic acid (0.028 mmol), HOBt (6.8 mg, 0.05 mmol), EDCI (8.05 mg, 0.04 mmol) and TEA (10 muL, 0.07 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer dried over Na2SO4. Purification of column chromatography with Hexane/ethyl acetate = 1:1 to afford compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 24h; | General procedure: To a solution of acid (1.0 eq), HOBt (1.5 eq), EDCI (1.5 eq) and triethylamine (1.5 eq) in DMF, compound a was added and the mixture was stirred for 24h. The mixture was poured into saturated NaHCO3 solution, extracted by ethyl acetate three times and the combined organic layer was washed with water and brine, and dried over with anhydrous Na2SO4. The concentrated residue was purified by recrystallization directly from CHCl3/MeOH or purified by flash column chromatography on silica gel to give the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Example 135: Preparation of 4-chloro-N-(3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3- (trifluoromethyl)benzamide -chloro-/V-(3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide [0363] To a solution of (3-aminophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone (23mg, 0.071 mmol, 1.0 eq.), <strong>[1737-36-6]4-chloro-3-(trifluoromethyl)benzoic acid</strong> (31 mg, 0.14 mmol, 2.0 eq.) and HATU (59mg, 0.16 mmol, 2.2 eq.) in DMF (5 mL) was added DIEA (37 mg, 0.28 mmol, 4.0 eq.). The mixture was stirred at r.t. overnight, then concentrated. The resulting residue was purified via flash column chromatography (PE/EA=l/2, v/v) to afford 4-chloro-N-(3-(3-(pyridin-3-yl)quinoxaline- 6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide (25.9 mg, 68.9%). LRMS (M+H+) m/z calculated 533.1, found 533.1.1. ¾ NMR (DMSO- , 400 MHz) delta 10.78 (s, 1 H), 9.81 (s, 1 H), 9.54 (ds, 1 H), 8.71-8.79 (m, 2 H), 8.42 (dd, 2 H), 8.17-8.35 (m, 5 H), 7.93 (d, 1 H), 7.63-7.67 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 90℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 5 (0.13 mmol), the appropriate acid (0.17 mmol), HOBt (0.17 mmol), and EDCI (0.19 mmol) in dry DMF was cooled to 0 C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.16 mmol) was added at 0 C. The mixture was then stirred at 90 C for 12 h. The reaction mixture was cooled and then partitioned between water and ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography to afford the corresponding compounds 1a-l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With benzotriazol-1-ol; caesium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃; for 24h;Inert atmosphere; | General procedure: A mixture of compound 9 (34 mg, 0.1 mmol), the appropriate carboxylic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), EDCI (38 mg, 0.2 mmol), and cesium carbonate (65 mg, 0.2 mmol) in dry DMF (1.0 mL) under nitrogen atmosphere was then stirred at 80 C for 24 h. The reaction mixture was cooled and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 8 (50 mg, 0.1 mmol), the appropriate benzoic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in DMF (1.0 mL) was cooled to 0oC under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added there to at the same temperature. The mixture was then stirred at 80oC for 12 h. The reaction mixture was cooled and then partitioned between H2O and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, hexane ethyl acetate 1:1 v/v) to yield the target compounds 14-18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: A mixture of compound 9 or 10 (0.11 mmol), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.21mmol), and N,N-diisopropylethylamine (0.54 mmol) in dry DMF (1.5 mL) was stirred at 0 C for 30 min. The appropriate acid (0.16 mmol) was then added. After stirring at room temperature for 1-4 h, the reaction mixture was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1 to 1:3) to afford the corresponding compounds 11a-o and 12a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: A mixture of compound 9 or 10 (0.11 mmol), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.21mmol), and N,N-diisopropylethylamine (0.54 mmol) in dry DMF (1.5 mL) was stirred at 0 C for 30 min. The appropriate acid (0.16 mmol) was then added. After stirring at room temperature for 1-4 h, the reaction mixture was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1 to 1:3) to afford the corresponding compounds 11a-o and 12a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: A mixture of compound 8a, b (30 mg, 0.1 mmol), the appropriate carboxylic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in dry DMF (1.0 mL) was cooled to 0C under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added thereto at the same temperature. The mixture was then stirred at 80C for 24 h. The reaction mixture was cooled and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: A mixture of compound 8a, b (30 mg, 0.1 mmol), the appropriate carboxylic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in dry DMF (1.0 mL) was cooled to 0C under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added thereto at the same temperature. The mixture was then stirred at 80C for 24 h. The reaction mixture was cooled and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: A mixture of compound 8a, b (30 mg, 0.1 mmol), the appropriate carboxylic acid derivative (0.2 mmol), HOBt (36 mg, 0.3 mmol), and EDCI (38 mg, 0.2 mmol) in dry DMF (1.0 mL) was cooled to 0C under nitrogen atmosphere. Triethylamine (0.03 mL, 0.2 mmol) was added thereto at the same temperature. The mixture was then stirred at 80C for 24 h. The reaction mixture was cooled and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; Sealed tube; | General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.6% | General procedure: A mixture of 4-substituted-3-nitrobenzoic acid 10a-d, 14a-g (5 mmol), EDCI (6 mmol) and HOBt in anhydrous DMF (20 mL) was stirred at room temperature for about 0.5-2 h. Then the appropriate aniline 11a-j, 7a-b (4 mmol) was added with triethylamine (5 mmol) and stirred at room temperature for 4-24 h. Then the reaction mixture was diluted to 100 mL with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated solution of NaCl, then dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel column using acetic ether and petroleum ether (1:10-1:8, v:v) as eluent to obtain compounds 12a-o, 15a-h as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | General procedure: To a mixture of compound 7 (0.05 g, 0.17 mmol) and the appropriate aromatic carboxylic acid (0.34 mmol) in anhydrous DMF (2 mL) under argon atmosphere, N,N-diisoprpoylethylamine (DIPEA) (0.128 mL, 0.72 mmol) and HATU (0.168 g, 0.442 mmol)were added. The reaction mixture was stirred at rt for 24 h or at 80 C for 5 h (for only 8g), and then quenched with water (30 mL).The aqueous layer was extracted with ethyl acetate (3 20 mL) and the combined organic layers were washed with water and brine,dried over anhydrous Na2SO4, filtered, and the solvent wasremoved under reduced pressure. The resultant residue was purified by flash column chromatography, using the appropriate elution system to afford the target compounds 8a-g in pure form. 4.9.4 4-((2-(4-Chloro-3-(trifluoromethyl)benzamido)quinolin-5-yl)oxy)-N-methylpicolinamide (8d) Flash column chromatography was performed using (hexane:ethyl acetate, 2:1 to 1:1 v/v). White solid; yield 85%; mp 223-225 C; 1H NMR (400 MHz, CDCl3) delta 8.94 (br. s, 1H), 8.54 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 9.2 Hz, 2H), 8.13 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 2.8 Hz, 2H), 7.73-7.69 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.08 (dd, J = 5.6, 2.4 Hz, 1H), 3.04 (d, J = 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) delta 166.22, 164.35, 152.65, 150.02, 149.46, 136.86, 134.14, 133.16, 132.83, 132.17, 131.48, 130.20, 129.45, 129.13, 126.96, 126.42, 125.24, 124.36, 123.71, 115.96, 114.71, 114.31, 110.23, 26.15.; HRMS (ESI-TOF) m/z calcd for C24H16ClF3N4O3Na [M+Na]+: 523.0761, found: 523.0759. |
Tags: 1737-36-6 synthesis path| 1737-36-6 SDS| 1737-36-6 COA| 1737-36-6 purity| 1737-36-6 application| 1737-36-6 NMR| 1737-36-6 COA| 1737-36-6 structure
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