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CAS No. : | 203302-97-0 | MDL No. : | MFCD00082480 |
Formula : | C9H7F3O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NFZQVADYFXRRPM-UHFFFAOYSA-N |
M.W : | 220.15 | Pubchem ID : | 2777316 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.67 |
TPSA : | 46.53 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) : | -5.72 cm/s |
Log Po/w (iLOGP) : | 1.7 |
Log Po/w (XLOGP3) : | 2.71 |
Log Po/w (WLOGP) : | 3.47 |
Log Po/w (MLOGP) : | 1.82 |
Log Po/w (SILICOS-IT) : | 2.16 |
Consensus Log Po/w : | 2.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.94 |
Solubility : | 0.25 mg/ml ; 0.00114 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.34 |
Solubility : | 0.101 mg/ml ; 0.000457 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.81 |
Solubility : | 0.341 mg/ml ; 0.00155 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.61 |
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 |
---|---|---|
Preparation 26 alpha-Bromo-<strong>[203302-97-0](3-trifluoromethoxyphenyl)acetic acid</strong> The <strong>[203302-97-0](3-trifluoromethoxyphenyl)acetic acid</strong> (9.75 g, 44.3 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 13.3 g. (100%). NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | A 12-L round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen inlet, 1-L graduated addition funnel was flushed with nitrogen, the addition funnel was capped with a rubber septum. The flask was charged with tetrahydrofuran (anhydrous, Aldrich, 2.0 L) and diisopropylamine (Aldrich, 99.5%, 229.9 g, 2.26 mol). The solution in the flask was chilled to -12 C. A solution of BuLi in hexanes (2.5 M, Aldrich, 916 mL, 2.29 mol) was added slowly to the reaction mixture over a period of 2.5 hours, maintaining the temperature in the flask below -10 C. The solution in the flask was stirred at -10 to -15 C. for 30 minutes. A solution of <strong>[203302-97-0]3-(trifluoromethoxy)phenylacetic acid</strong> (200.0 g, 0.90 mol) in 300 mL of anhydrous tetrahydrofuran was added slowly to the reaction mixture (addition time 74 min) maintaining the temperature of the reaction mixture below -10 C. The reaction mixture was stirred at -10 to --15 C. for 45 min, then chilled to -32 C. Neat cyclohexanone (Aldrich, 133.7 g, 1.36 mol) was added slowly to the reaction mixture (addition time 38 min) maintaining the temperature range below -30 C. The reaction mixture was stirred at -30 to -40 C. for 2 hours. A mixture of ice (200 g) was mixed with water (200 mL) and sat. aqueous solution of NH4Cl (400 mL), and the resulting solution was added rapidly to the contents of the flask. The bi-phasic mixture was stirred rapidly for 2 minutes, then the flask was removed from the cold bath. The layers were separated and the organic layer was evaporated in vacuum. The residue was diluted with methyl tert-butly butyl ether (1.4 L). The aqueous layer was extracted with methyl tert-butyl ether (200 mL). Combined organic solutions were washed twice with 3 M aqueous HCl (600+400 mL) and then were extracted with 0.5 M aqueous NaOH solution (2×900 mL, 1×200 mL). The aqueous extracts were combined, washed with methyl tert-butyl ether (250 mL) and acidified with concentrated aqueous HCl (90 mL). The resulting white emulsion was extracted with methyl tert-butyl ether (400 mL, 2×300 mL). Combined organic extracts were washed with a mixture of water (200 mL) and brine (30 mL), then brine alone (90 mL). The resulting solution was dried with MgSO4, suction-filtered through a paper filter and evaporated in vacuum giving a very thick yellow oil: weight 302.0 g, assayed strength 90%. Yield calculated on pure product 272 g, 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 5.153 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-2-(3-TRIFLUOROMETHOXY-PHENYL)-ACETAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and <strong>[203302-97-0]3-trifluoromethoxyphenylacetic acid</strong> (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc:CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-trifluoromethoxy-phenyl)-acetamide (0.8 g, 74%) as a white solid: mp 178-180 C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.32 min. (97%); 1H NMR (DMSO-d6) delta 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.83 (s, 2H), 4.72 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.23-8.10 (m, 7H), 8.74 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) delta 21.94, 30.90, 37.84, 48.83, 118.96, 121.43, 121.93, 127.15, 128.29, 130.07, 131.53, 133.15, 134.61, 138.80, 139.00, 148.24, 166.88, 167.41, 169.77, 169.96, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.44; H, 3.44; N, 8.46; F, 11.89. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -70 - 0℃; for 2h; | A solution of diisopropylamine (3.1 ml) in tetrahydrofuran (30 ml) was cooled to 0oC. before dropwise addition of 1.6M nBuLi in hexane (13.5 ml) and then stirred for 15 minutes and cooled to -70oC. 3-(trifluoromethoxy)-phenylacetic acid (2 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise to the reaction mixture which was then allowed to warm to 0oC., stirred for 30 minutes and then cooled back to -70oC. Methyl iodide (0.9 ml) was then added slowly and the solution stirred for further 1.5 hours at -70oC. Water was added the solution washed with diethyl ether, the aqueous phase was acidified by addition of 25% aqueous HCl and then extracted twice with diethyl ether, dried over Mg2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2; hexane/EtOAc 3:1) to afford 2-(3-trifluoromethoxy-phenyl)-propionic acid (1.5 g) as a light yellow oil. MS (ISP): 232.9 ([M-H]+)). | |
) 2-(3-Trifluoromethoxy-phenyl)-propionic acidA solution of diisopropylamine (3.1 ml) in tetrahydrofuran (30 ml) was cooled to 0 C before dropwise addition of 1.6M nBuLi in hexane (13.5 ml) and then stirred for 15 minutes and cooled to -70 C. 3-(trifluoromethoxy)-phenylacetic acid (2 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise to the reaction mixture which was then allowed to warm to 0 C, stirred for 30 minutes and then cooled back to -70 C. Methyl iodide (0.9 ml) was then added slowly and the solution stirred for further 1.5 hours at -70 C. Water was added the solution washed with diethyl ether, the acqueous phase was acidified by addition of 25% aqueous HCl and then extracted twice with diethyl ether, dried over Mg2S04, filtered and concentrated. The residue was purified by flash column chromatography (Si02; hexane/EtOAc 3: 1) to afford 2-(3- trifluoromethoxy-phenyl)-propionic acid (1.5 g) as a light yellow oil. MS (ISP): 232.9 ([M-H]+)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 1h;Inert atmosphere; | General procedure: To a stirred solution of N,O-dimethyl hydroxylamine hydrochloride (2.64 g, 27.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.49 g, 27.0 mmol) and triethylamine (3.76 mL, 27.0 mmol) in CH3CN (30 mL) was added a solution of 36 (3.82 g, 18.0 mmol) in CH3CN (20 mL) at room temperature under argon atmosphere. After being stirred for 1 h, the reaction was quenched with water. The reaction mixture was diluted with EtOAc, washed with 2 N hydrochloric acid, water, then brine, dried over MgSO4 and evaporated to give a Weinreb amide as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | A three liter reaction vessel was charged with <strong>[203302-97-0]2-(3-(trifluoromethoxy)phenyl)acetic acid</strong>(93.34 g, 0.43 mol, 1.0 equiv), 6-chloropyridazin-3-amine (55.51 g, 0.43 mol, 1.0 equiv.),ethyl acetate (1.42 L, 15 vol. versus acid), N,N-diisopropylethylamine (60.92 g, 0.47 mol, 1.1 equiv.) then fitted with a stir bar and temperature probe. The contents of the reaction vessel was placed under an atmosphere of argon(g) and stirred for 15 minutes at which time the mixture was turbid with solids on the bottom of the reaction vessel. To the stirredmixture was added propylphosphonic anhydride (T3P; 300 mL of 50% solution in ethyl acetate, 0.47 mmol, 1.1 equiv.) via a pressure equalizing addition funnel over the course of 40 minutes with a temperature increase of 20.3C to 28.1C. During the course of the addition the color of the mixture became red/orange and the turbidity cleared. The reaction was monitored by TLC (6:4 hexane / ethyl acetate) with a typical run time of 4-6 hours.When the reaction was deemed complete, water (1.5 L) was added and the mixture stirred for an additional 15 minutes. The mixture was transferred to a separatory funnel and the layers separated. The organic layer was washed with water (1.5 L) the layers separated and the organic layer washed with 10% sodium chloride solution (500 mL). The layers were separated, the organic layer transferred to a round bottom flask and the volatiles removedunder reduced pressure to give an off-white, yellow solid. To the flask was added hexanes (500 mL) and the contents stirred vigorously for 15 minutes then filtered. The solids were washed again with hexanes (500 mL) and air dried to a constant weight to afford N-(6- chloropyridazin-3 -yl)-2-(3 -(trifluoromethoxy)phenyl)acetamide (112824): yield of 121.1 g, (85%). ?H NMR (300 MHz, DMSO-d6) oe 11.63 (s, 1H), 8.38(d, J=9.4 Hz, 1H), 7.88(d,J9.4 Hz, 1H), 7.52 - 7.27(m, 4H), 3.90(s, 2H). | |
77% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 30℃; for 3h; | 3-Amino-6-chloropyridazine (55.5 g, 0.428 mol) and 3- (Trifluoromethoxy)phenylacetic acid (1.1 equiv., 0.471 mol, 104 g) were dissolved in DMF (30.0 vol., 1.66 L) in a 3000 mL three neck round-bottom flask. Addition of DIEA (1.1 equiv., 0.471 mol, 82 mL) via addition funnel was done over 5 minutes. Propylphosphonic anhydride solution (300 mL of a 50%> solution in DMF, 1.1 equiv., 0.471 mol, ) was charged into a 500 mL addition funnel and added dropwise to reaction solution (keeping reaction temperature sodium bicarbonate (80.0 vol., 4.4 L) which was chilled in an ice bath. Off-white crystalline powder was filtered through a Buchner funnel, rinsed with water (20.0 vol., 1.1 L). Dried in a 50 C vacuum to a constant weight to afford N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1117: yield of 119.6 g (77%). 1H NMR (300 MHz, DMSO-d6) delta 11.63 (s, 1H), 8.38(d, J=9.4 Hz, 1H), 7.88(d, J=9.4 Hz, 1H), 7.52 - 7.27(m, 4H), 3.90(s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ethanol; at 20℃; for 2h; | Step 1 N-(6-amino-3-(4-methoxybenzyl)-l -methyl-2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-5- yl)-2-(3-(trifluoromethoxy)phenyl)acetamide To a solution of 5,6-diamino-3-(4-methoxybenzyl)-l -methylpyrimidine-2,4(lH,3H)-dione (50 mg, 0.1 81 mmol, intermediate 59) in ethanol (3 ml) was added 2-(3- (trifiuoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDO (52 mg, 0.271 mmol) The mixture was stirred at room temperature for 2 h. The reaction was diluted with water, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered and concentrated to give N-(6-amino-3-(4-methoxybenzyl)- l -methyl-2,4- dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (70 mg, 80.1 %) as light gray solid. LCMS retention time 1.239 min; LCMS MH+ 479. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | General procedure: (4-Ethoxyphenyl)-acetic acid (74.5 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) were dissolved in DMF (2 mL) at room temperature. After stirring for 15 min phthalazin-1-ylamine (60 mg; 0.41 mmol) was added and the reaction mixture was stirred for 2 h. The solid, which precipitated during the reaction, was filtered off, washed with a small portion of DMF, acetonitrile and diethyl ether and dried at 50 C in vacuo. The filtrate was diluted with water (40 mL) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and evaporated to dryness. The residue (light yellow solid) was triturated with ethanol, filtered off, washed with ethanol and diethyl ether and dried at 50 C in vacuo. Both solids were combined; yield: 81 mg (63 %), amorphous colourless solid (purity: 100 %, Rt: 3.03 min); 1H NMR (400 MHz, DMSO-d6) delta [ppm] 10.91 (s, 1H), 9.58 (s, 1H), 8.18 (d, J = 7.9 Hz, 1 H), 8.07 - 7.84 (m, 3H), 7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 4.03 (q, J = 6.9 Hz, 2H), 3.81 (s, 2H), 1.33 (t, J = 6.9 Hz, 3H). A5" was prepared from (3-trifluoromethoxyphenyl)-acetic acid (93.8 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41 mmol), 1-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) and phthalazin- 1-ylamine (60 mg; 0.41 mmol) in DMF (2 mL) as described for example 4. After 3 h stirring at room temperature the reaction mixture was diluted with water (40 mL) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and evaporated to dryness. The residue was triturated in ethanol, filtered off, washed with diethyl ether and dried at 50 C in vacuo. From the filtrate further product was obtained by chromatography (column: 40 g RP18 silica gel; combiflash companion); yield: 58 mg (39 %), light yellow solid (purity: 98 %, Rt: 3.29 min); 1H NMR (400 MHz, DMSO-d6) delta [ppm] 11.02 (s, 1H), 9.58 (s, 1H), 8.26 - 8.15 (m, 1 H), 8.09 - 7.84 (m, 3H), 7.58 - 7.38 (m, 3H), 7.34 - 7.22 (m, 1 H), 3.98 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | Intermediate 2 (1.0 g, 3.8 mmol), 3- (Trifluoromethoxy)phenylacetic acid (1.03 g, 4.7 mmol), HATU (1.82 g, 4.7 mmol), DIPEA (1.1 ml, 8.5 mmol) were taken in DMF (6 ml). This mixture was stirred at rt under inert atmosphere for 12 h. Reaction mass was diluted with water to obtain a solid. Solid was filtered and dried to obtain the titled compound as a grey solid. JH-NMR (delta ppm, DMSO- , 400 MHz): 10.43 (s, 1H), 7.99 (d, J 2.7, 1H), 7.86 (d, J 9, 1H), 7.47-7.41 (m, 1H), 7.39-7.31 (m, 3H), 7.22 (d, J 8, 1H), 4.07 (q, J 7.1, 2H), 3.73 (s, 2H), 3.56 (d, J 12.2, 2H), 2.75 (t, J 11.4, 2H), 2.50-2.41 (m, 1H), 1.90 (d, J 11.1, 2H), 1.72-1.60 (m, 2H), 1.18 (t, J 7, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.2 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | Intermediate 7 (1.8 g, 7.2 mmol), 3- (Trifluoromethoxy)phenylacetic acid (1.9 g, 8.63 mmol), HATU (3.3 g, 8.7 mmol), DIPEA (3.8 ml, 21.6 mmol) were taken in DMF (5 ml). This mixture was stirred at rt under inert atmosphere for 12 h. Reaction mass was diluted with water and extracted with DCM. DCM layer was dried on anhydrous Na2SO/t. DCM was removed on rotavapour to obtain the titled compound (3.2 g) which was used in the next step without further purification. JH-NMR (delta ppm, DMSO-(f<, 400 MHz): 10.45 (s, 1H), 7.99 (d, J 2.6, 1H), 7.87 (d, J 9, 1H), 7.48-7.41 (m, 1H), 7.39-7.30 (m, 3H), 7.22 (d, J 8, 1H), 4.08 (q, J 7.1, 2H), 3.73 (s, 2H), 3.60-3.53 (m, 1H), 3.41-3.33 (m, 1H), 3.05- 2.96 (m, 1H), 2.86-2.78 (m, 1H), 2.70-2.50 (m, 1H), 1.95-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.63- 1.54 (m, 2H), 1.18 (t, J 7.1, 3H). MS (m/z): 452.6 [ +H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | Intermediate 15 (100 mg, 0.25 mmol), 3-(Trifluoromethoxy)phenylacetic acid (66 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), N-Ethyldiisopropyl amine (0.13 ml, 0.76 mmol) were dissolved in DMF (1.5 ml). This mixture was stirred at rt for 16 h. Reaction mass was diluted with water and extracted with DCM. Organic layer was washed with water. Organic layer was dried on anhydrous Na2SO/t. DCM was removed on rotavapour to obtain crude. Crude was purified by combi-flash using Methanol and DCM (8:92) as eluent to afford the titled compound (60 mg) as a pale-yellow solid. M.P.: 188-191C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.65 (s, 1H), 10.40 (s, 1H), 8.49 (d, J 4.8, 1H), 8.03 (d, J 2.8, 1H), 7.89 (d, J 9, 1H), 7.73 (dt, J 1.8, 7.7, 1H), 7.49-7.43 (m, 1H), 7.42-7.31 (m, 4H), 7.28-7.22 (m, 2H), 3.88 (s, 2H), 3.87 (s, 2H), 3.70 (d, J 12.6, 2H), 3.25-3.20 (m, 1H), 2.84 (t, J 11.6, 2H), 2.11 (d, J 11.5, 2H), 1.90-1.77 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | Intermediate 20 (100 mg, 0.25 mmol), 3-(Trifluoromethoxy)phenylacetic acid (66 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), N-Ethyldiisopropyl amine (0.13 ml, 0.76 mmol) were dissolved in DMF (1.5 ml). This mixture was stirred at rt for 16 h. Reaction mass was diluted with water and extracted with DCM. Organic layer was washed with water. Organic layer was dried on anhydrous Na2SO/t. DCM was removed on rotavapour to obtain crude. Crude was purified by combi-flash using Methanol and DCM (5:95) as eluent to afford the titled compound (40 mg) as a pale-yellow solid. M.P.: 151-153C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.69 (s, 1H), 10.47 (s, 1H), 8.48 (d, J 4.0, 1H), 8.04 (d, J 2.8, 1H), 7.90 (d, J 9, 1H), 7.73 (dt, J 1.7, 7.7, 1H), 7.49-7.40 (m, 2H), 7.39-7.32 (m, 3H), 7.28-7.23 (m, 2H), 3.87 (s, 4H), 3.70 (d, J 12.4, 1H), 3.49-3.39 (m, 2H), 3.14-3.06 (m, 1H), 2.99-2.90 (m, 1H), 2.10-2.04 (m, 1H), 1.80-1.65 (m, 3H). MS (m/z): 597.8 [ +H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | Intermediate 21 (1.5 g, 5.99 mmol), 3- (Trifluoromethoxy)phenylacetic acid (1.58 g, 7.17 mmol), HATU (5 g, 13.14 mmol), DIPEA (3.1 ml, 17.78 mmol) were taken in DMF (4 ml). This mixture was stirred at rt under inert atmosphere for 12 h. Reaction mass was diluted with water and extracted with DCM. DCM layer was dried on anhydrous Na2S04 and DCM removed on rotavapour to obtain crude. Crude was purified by combi-flash using MeOH and DCM (1 :99) as eluent to afford the titled compound as a brown gummy solid (1.1 g). JH-NMR (delta ppm, DMSO-<, 400 MHz): 10.93 (s, 1H), 7.98 (d, J 9.8, 1H), 7.48-7.42 (m, 1H), 7.38-7.30 (m, 3H), 7.24 (d, J 8, 1H), 4.15 (d, J 13.3, 2H), 4.06 (q, J 7.1, 2H), 3.78 (s, 2H), 2.98 (t, J 11.4, 2H), 2.63-2.55 (m, 1H), 1.89 (d, J 10.6, 2H), 1.62-1.50 (m, 2H), 1.17 (t, J 7.1, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.1 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | Intermediate 25 (2.9 g, 11.6 mmol), 3- (Trifluoromethoxy)phenylacetic acid (3.06 g, 13.9 mmol), HATU (9.7 g, 25.5 mmol), DIPEA (2 ml, 34.75 mmol) were taken in DMF (6 ml). This mixture was stirred at rt under inert atmosphere for 12 h. Reaction mass was diluted with water and extracted with DCM. DCM layer was dried on anhydrous Na2S04 and DCM removed on rotavapour to obtain crude. Crude was purified by column chromatography on 60-120 mesh silica gel using MeOH and DCM (1:99) as eluent to afford the titled compound as a brown solid (3.1 g). JH-NMR (delta ppm, DMSO-<, 400 MHz): 10.91 (s, 1H), 7.97 (d, J 9.8, 1H), 7.47-7.43 (m, 1H), 7.37-7.31 (m, 3H), 7.24 (d, J 8, 1H), 4.25 (d, J 13, 1H), 4.06 (q, J 7, 2H), 3.90 (d, J 12.9, 1H), 3.78 (s, 2H), 3.21-3.05 (m, 2H), 2.60- 2.51 (m, 1H), 2.00-1.91 (m, 1H), 1.72-1.53 (m, 2H), 1.52-1.41 (m, 1H), 1.17 (t, J 7.1, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | Intermediate 36 (150 mg, 0.38 mmol), 3-(Trifluoromethoxy)phenylacetic acid (100 mg, 0.45 mmol), HATU (316 mg, 0.37 mmol), N-Ethyldiisopropyl amine (0.2 ml, 1.134 mmol) were dissolved in DMF (1 ml). This mixture was stirred at rt for 1 h. Reaction mass was poured in to water to obtain a solid. Solid was filtered and purified the solid by column chromatography on 60-120 silica gel using MeOH and DCM (8:92) as eluent to afford the titled compound (30 mg) as a pale-brown solid. M.P.: 220-222C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.70 (s, IH), 10.92 (s, IH), 8.49 (s, IH), 8.01 (d, J 8.7, IH), 7.80-7.70 (m, IH), 7.50-7.20 (m, 7H), 4.30 (d, J 12.2, 2H), 3.92 (s, 2H), 3.87 (s, 2H), 3.50-3.40 (m, IH), 3.05 (t, J 12.2, 2H), 2.10 (d, J 11.1, 2H), 1.80-1.65 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | Intermediate 38 (75 mg, 0.19 mmol), 3-(Trifluoromethoxy)phenylacetic acid (50 mg, 0.22 mmol), HATU (158 mg, 0.42 mmol), N-Ethyldiisopropyl amine (0.1 ml, 0.5 mmol) were dissolved in DMF (1 ml). This mixture was stirred at rt for 1 h. Reaction mass was poured in to water to obtain a solid. Solid was filtered and purified by column chromatography on 60-120 mesh silica gel using MeOH and DCM (7:93) as eluent to afford the titled compound (15 mg) as a pale-brown solid. M.P.: 125-127C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.70 (s, 1H), 10.97 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.99 (d, J 9.5, 1H), 7.73 (d, J 6.9, 1H), 7.50-7.42 (m, 1H), 7.40-7.30 (m, 4H), 7.26 (d, J 7.4, 1H), 4.30 (d, J 12.2, 2H), 3.87 (s, 2H), 3.76 (s, 2H), 3.40- 3.35 (m, 1H), 3.04 (t, J 12, 2H), 2.09 (d, J 12, 2H), 1.80-1.68 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Intermediate 39 (300 mg, 1.38 mmol), 3- (Trifluoromethoxy)phenylacetic acid (360 mg, 1.63 mmol), HATU (1.2 g, 3.16 mmol), DIPEA (0.73 ml, 4.2 mmol) were taken in DMF (3 ml). This mixture was stirred at rt under inert atmosphere for 1 h. Reaction mass was diluted with water to obtain a solid. Solid was purified by column chromatography using MeOH and DCM (2:98) as eluent to afford the titled compound (50 mg) as a brown solid. JH-NMR (delta ppm, DMSO-<, 400 MHz): 10.91 (s, 1H), 7.96 (d, J 9.7, 1H), 7.48-7.42 (m, 1H), 7.38-7.30 (m, 3H), 7.23 (d, J 8.1, 1H), 4.27 (d, J 13.2, 2H), 2.86 (t, J 11.7, 2H), 2.55-2.50 (m, 2H), 1.95-1.85 (m, 1H), 1.77 (d, J 12.9, 2H), 1.73-1.58 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | 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℃; | A solution of 4-(6-amino-pyridazin-3-yloxy)-piperidine-l-carboxylic acid tert-butyl ester (86 mg, 0.29 mmol), DIEA (0.16 mL, 0.88 mmol), HATU (122 mg, 0.32 mmol) and 3- trifluoromethoxyphenylacetic acid (71 mg, 0.32 mmol) in DMF (1 mL) was stirred at room temperature overnight and then partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over Na2S04 and evaporated to a residue that was chromatographed with a silica gel column and 0- 10% MeOH in CH2C12 to afford the product, 4-{ 6-[2-(3-trifluoromethoxy- phenyl)-acetylamino]-pyridazin-3-yloxy}-piperidine-l-carboxylic acid tert-butyl ester, as an off- white/beige solid (91 mg, 63% yield). 1HNMR (600 MHz, DMSO- 6) delta 1.41 (s, 9H), 1.56- 1.61 (m, 2H), 1.96-2.02 (m, 2H) 3.16-3.24 (m,2H), 3.83 (s, 2H) 5.29-5.32 (m, IH), 7.20 (d/=9.6Hz, IH), 7.26 (d, J=7.8 Hz, IH), 7.36 (d, J= 12 Hz, 2H), 7.47 (t, J=8.4, 7.8 Hz, IH), 8.20 (d, J=9.6 Hz, IH) 11.17 (s, IH). ATR-IR (cm"1) 3131, 3064, 2981, 2933, 2861, 1697, 1677, 1610, 1588, 1520, 1433, 1401, 1367, 1346, 1301, 1257, 1240, 1212, 1153, 1130, 1102, 1025, 969, 946, 872, 848, 828, 761, 700, 634. LC-MS (ESI) m/z for C23H27F3N4O5 calculated: 496.19, observed [M+H] : 497. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;Cooling with ice; | Step 1: (S)-3-Methyl-2-[2-(3-trifluoromethoxyphenyl)acetylamino]butyric acid benzyl ester 1.50 g of (S)-2-amino-3-methylbutyric acid benzyl ester hydrochloride, 1.36 g of <strong>[203302-97-0](3-trifluoromethoxyphenyl)acetic acid</strong>, 416 mg of 1-hydroxybenzotriazole hydrate, 1.35 ml of 4-methylmorpholine and 1.18 g of N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride (DAPECI) were dissolved in about 10 ml of DMF in a flask with ice-cooling and stirred overnight. The reaction mixture was poured into saturated sodium hydrogencarbonate solution and stirred for 15 min. The suspension formed was extracted a number of times with DCM, the organic phases were combined and rinsed with dilute formic acid and water. Drying using sodium sulfate, removal of the solvent and lyophilisation of the residue gave 2.39 g of (S)-3-methyl-2-[2-(3-trifluoromethoxyphenyl)acetylamino]butyric acid benzyl ester. (Yield 92.5%, content 97.5%). MS-FAB (M+H+)=410.1 Rf (polar method): 2.69 min (MS track). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | The compound of intermediate 4 (150 mg, 594 muiotaetaomicronIota) was provided in DMF (2 mL). N,N- diisopropyiethyiamine (310 mu, 1.8 mmoi), [3-(trifiuoromethoxy)phenyi] acetic acid (170 mg, 772 muetaiotaomicronIota) and propane phosphonic acid anhydride (T3P, 450 mu, 50% in DMF, 770 muiotaetaomicronIota) were added, and the mixture was stirred at room temperature over night. Ethanol (5 mL) and water (8 mL) were added and the mixture was stirred for 15 minutes. The precipitate was collected by filtration, was washed with ethanol and dried. The remaining material was triturated with DMSO and the precipitate was removed by filtration. The filtrate was concentrated to yield 116 mg (45% of theory) of the title compound. LC-MS (method 4): R, = 1.39 min; MS (ESIpos): m/z = 419 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.915 (0.47), 1.907 (1.01), 2.322 (0.79), 2.327 (1.05), 2.332 (0.75), 2.523 (3.19), 2.540 (11.52), 2.665 (0.82), 2.669 (1.09), 2.674 (0.82), 3.765 (16.00), 7.258 (1.70), 7.261 (2.10), 7.264 (2.08), 7.279 (2.21), 7.282 (2.53), 7.285 (2.44), 7.346 (4.05), 7.355 (5.30), 7.358 (4.44), 7.374 (2.96), 7.377 (4.07), 7.381 (2.44), 7.388 (2.25), 7.392 (2.17), 7.407 (3.73), 7.410 (4.44), 7.427 (3.45), 7.430 (3.52), 7.461 (4.55), 7.480 (6.11), 7.494 (3.13), 7.497 (3.58), 7.501 (2.83), 7.514 (4.12), 7.517 (3.69), 7.532 (2.47), 7.535 (2.36), 7.891 (3.77), 7.894 (4.16), 7.912 (3.75), 7.915 (3.47), 7.961 (11.24), 8.008 (0.71), 8.065 (3.67), 8.069 (4.08), 8.085 (3.52), 8.089 (3.78), 8.653 (0.84), 8.732 (11.99), 10.695 (6.65). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), 2-(trifluoromethoxy)aniline (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), 2-(trifluoromethoxy)aniline (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 80℃; for 6h; | <strong>[203302-97-0]2-(3-(trifluoromethoxy)phenyl)acetic acid</strong> (3.5 g, 15.90 mmol) and NBS (3.11 g, 17.49 mmol) were dissolved in chloroform (100 mL) and heated at 80 C. To this was added (E)-2,2?-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.131 g, 0.79 mmol) and the reaction was stirred at 80 C. for 6 hours. The reaction was then left at ambient temperature over the weekend. Solvent was then evaporated to give crude 2-bromo-<strong>[203302-97-0]2-<strong>[203302-97-0][3-(trifluoromethoxy)phenyl]acetic acid</strong></strong> which was used without any further purification. m/z: ES+ [M+H]+ 297 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.2% | With pyridine; 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 18h; | To N, N-dimethylformamide (5 mL) was added 5,5 '- (ethane-1,2-diylbis (sulfanediyl)) bis(100 mg, 0.342 mmol), HATU (390 mg, 1.02 mmol), 2- (3- (trifluoromethoxy) phenyl) acetic acid (226 mg, 1.02 mmol) and pyridine 0.5 ml, 6.2 mmol) was added and stirred at 20 C for 18 hours. The solid was collected by filtration and washed with methanol to give the product as a white solid (148 mg, 62.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | 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 1,2-dimethoxyethane; at 20℃; for 5h; | To a mixture of 4- (6-aminopyridazin-3-ylmercapto) n-butyronitrile (195 mg, 1 mmol)To a solution of 2- (3- (trifluoromethoxy) phenyl) acetic acid (220 mg, 1 mmol) and HATU (380 mg, 1 mmol) in 10 mL of N, N- dimethylformamide was added diisopropylethylamine (258 mg, 2 mmol), stirred at room temperature for 5 hours and added with 50 mL of cold water. The resulting precipitate was collected by filtration, washed with water and the precipitate was purified by column chromatography (ethyl acetate / n-hexane = 1/4) to give the title compound (99 mg, 25%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | 3-Trifluoromethoxyphenylacetic acid (40.0 mg, 0.180 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (34.4 mg, 0.180 mmol),1-hydroxybenzotriazole (HOBT) (41.0 mg, 0.300 mmol),Dissolve in 50 ml round bottom flask using anhydrous acetonitrile.Stir at room temperature for 30 min;Add intermediate II17 (50 mg, 0.150 mmol),Triethylamine (Et3N) (62.4 mul, 0.450 mmol),Move to 85 C, stir for 12 h; TLC test,After the reaction, it was concentrated under reduced pressure.60-80 mesh silica gel sample, column chromatography separation,The eluent is dichloromethane (DCM):Methanol (MeOH) = 60:1 gave a white solid.That is, compound 33.The yield of the compound 33 was 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6 g | 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 dichloromethane; at 20℃; for 12h; | Synthesis of step 1: <strong>[187973-60-0]3-amino-6-iodopyridazine</strong> (50 g, 0.388 mol) and 3-( Trifluoromethoxy)phenylacetic acid (59.7 g, 0.271 mol) and 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) : 220 g, 0.581 mol) was placed in a 2 L single-mouth bottle, and 1500 mL of a dichloromethane solution was added thereto, and 78.5 mL of N,N-diisopropylethylamine (DIEA: 74.95 g, 0.581 mol) was added dropwise at room temperature. After stirring for 12 h, it was washed several times with a saturated sodium hydrogen carbonate solution, and then extracted twice with dichloromethane, and purified by column chromatography to yield 77.6 g of a beige solid. |
Tags: 203302-97-0 synthesis path| 203302-97-0 SDS| 203302-97-0 COA| 203302-97-0 purity| 203302-97-0 application| 203302-97-0 NMR| 203302-97-0 COA| 203302-97-0 structure
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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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