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CAS No. : | 208173-24-4 | MDL No. : | MFCD00061252 |
Formula : | C9H6F4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SYFHRXQPXHETEF-UHFFFAOYSA-N |
M.W : | 206.14 | Pubchem ID : | 605678 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 41.6 |
TPSA : | 17.07 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) : | -5.72 cm/s |
Log Po/w (iLOGP) : | 1.88 |
Log Po/w (XLOGP3) : | 2.59 |
Log Po/w (WLOGP) : | 4.62 |
Log Po/w (MLOGP) : | 3.23 |
Log Po/w (SILICOS-IT) : | 3.62 |
Consensus Log Po/w : | 3.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.239 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.6 |
Solubility : | 0.521 mg/ml ; 0.00253 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.9 |
Solubility : | 0.0257 mg/ml ; 0.000124 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.57 |
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 |
---|---|---|
90% | General Protocol for Synthesis of Substituted Acetophenones (Williamson Ether Synthesis) (2)To a solution of the desired alcohol (1.0 equivalent) in dry THF under nitrogen atmosphere was added KO'Bu (either 1.0 M solution in THF or solid, 1.1 equivalent). The reaction mixture was heated at 60-70 0C for 10 minutes, then substituted 4- flouroacetophenone 1 (1.0 equivalent) was added. The reaction was then stirred for 1 to 3 hours before cooling to room temperature (RT). The solvent removed in vacuo. The product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc).; General approach to synthesis of ether-phenyl-thiazolesThe synthesis of 2,5-substituted thiazoles is described in Scheme 6. Reaction of the desired alcohol para-methoxybenzyl alcohol (PMB-OH) with substituted 4- fluoroacetophenone 1 afforded the acetophenone intermediate 2. Acetophenone intermediate 2 was then converted to the corresponding bromo-acetophenone using Bu4NBr3 which, upon reaction with NaN3, provided the azido-acetophenone intermediate. Hydrogenation of the azido-acetophenone intermediate afforded amine 3, followed by coupling with orthogonally protected amino acid 4 gave amide 5. Removal of PMB group under hydrogenation gave phenol 6. Mitsunobu reaction of the phenol 6 with the desired alcohol followed by thiazole formation under Lawesson's reagent conditions afforded intermediate 7 in good yield. Removal of the protecting group from intermediate 7 afforded the final am'ino-alcohol 8. <n="114"/>Scheme 6:l-(4-(4-Methoxybenzyloxy)-3-(trifluoromethyl)phenyl)ethanone (2a)The title product was obtained according to general procedure (Scheme 1). The product was purified by silica gel column chromatography using the Combi-Flash system (HexrEtOAc) as colorless oil in 90% (4.25 g). HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 mu) is 2.02 min with gradient 50-98% acetonitrile-H2O (0.1% TFA) in 4.0 min as mobile phase. TLC (1 :3 EtOAc:Hex), R7= 0.4; 1H NMR (400 MHz, CDCl3) delta 8.20 (d, IH, J = 1.6 Hz), 8.09 (dd, IH, J= 8.8 Hz, J= 2.0 Hz)5 7.35 (d, 2H, J= 8.4 Hz)5 7.09 (d, IH5 J= 8.4 Hz)5 6.93 (d, 2H5J= 8.4 Hz), 5.21 (s, 2H), 3.82 (s5 3H), 2.58 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3 - 100% | A solution of n-octanol (13.3 g, 0.102 mol), in THF (224 mL) was treated with 1.0 M potassium t-butoxide in THF (112 mL, 1.1 equiv) at room temperature and heated to 65 0C. After 15 minutes, a solution of l-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21 g, 1.0 equiv) in THF (224 mL) was charged slowly over 30 minutes. Vigorous gas evolution was noted during the addition. The reaction was monitored by HPLC and deemed complete after 1.5 h. The reaction mixture was cooled to ambient temperature, treated with 10% aqueous citric acid (250 mL), extracted with MTBE (2 x 500 mL), dried, and concentrated to afford the product (31.99 g, 99.3%, 88.1% AUC by HPLC). This reaction was repeated with slight modification as described above (reducing the amount of THF used to dissolve the acetophenone to 3 mL/g from 10.7 mL/g with improved control of gas evolution) on a 100 g scale to give 137.1 g, >100% yield). The two lots were combined and purified by column chromatography using silica-gel (1 kg), eluted with 10% ethyl acetate: 90% heptane to afford the title product (105 g, 75% yield) as a pale yellow color oil. Impure fractions were collected and provided 22.8 g (16.3% yield) of the product. | |
60% | To a solution of the desired alcohol (1.0 equivalent) in dry THF under nitrogen atmosphere was added KO'Bu (either 1.0 M solution in THF or solid, 1.1 equivalent). The reaction mixture was heated at 60-700C for 10 minutes, then substituted 4- flouroacetophenone 1 (LO equivalent) was added. The reaction was then stirred for 1 to 3 hours before cooling to room temperature (RT). The solvent removed in vacuo. The product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc).; l-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (2)The product was purified by silica gel column chromatography using the Combi- Flash system (Hex:EtOAc) as white solid in 60% (L20 g). TLC (1:5 EtOAc:Hex), Ry= 0.4; 1H NMR (400 MHz, CDCl3) delta 8.18 (d, IH, J= 2.0 Hz), 8.10 (dd, IH, J= 8.8 Hz, J <n="74"/>= 2.3 Hz), 7.02 (d, IH, J= 8.8 Hz), 4.12 (t, 2H, J= 6.4 Hz), 2.58 (m, 3H), 1.80-1.89 (m, 2H)5 1.42-1.54 (m, 2H), 1:22*4.40 (m, 8H), 0.89 (t» 3H, J= 6.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium tert-butylate; In tetrahydrofuran; at 65℃; for 3h;Product distribution / selectivity; | l-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (Dl)1-octanol (2mL), l-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (2.62g), potassium tert-butoxide (14mL, l.OM) and tetrahydrofuran (3OmL) were heated at 650C for 3hrs to produce the title product as a brownish oil (4.0Og). The product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) as white solid in 60% (1.20 g). TLC (1:5 EtOAc:Hex), R/= 0.4; 1HNMR (400 MHz5 CDCl3) delta 8.18 (d, IH, J= 2.0 Hz)3 8.10 (dd, IH, J= 8.8 Hz, J= 2.3 Hz), 7.02 (d, IH, J= 8.8 Hz)34.12 (t, 2H, J= 6.4 Hz)3 2.58 (m, 3H), 1.80-1.89 (m, 2H), 1.42-1.54 (m, 2H), 1.22-1.40 (m, 8H)5 0.89 (t, 3H, J= 6.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In ethanol; at 20 - 60℃; for 2h; | Example A.2 4-Ethoxy-3-trifluoromethyl-acetophenone; To a stirred suspension of potassium ethanolate (2.36 g, 27 mmol) in ethanol (30 ml) was added at room temperature a solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in ethanol (10 ml). The reaction mixture was stirred at 60 C. for 2 h and evaporated. Ice/2 N HCl (50 ml) was added and the water layer was extracted with diethylether (2×100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the title compound (2.9 g, 98%) as a brown solid, which was used without further purification. MS (EI) 232.1 [M]. |
98% | In ethanol; at 20 - 60℃; for 2h; | To a stirred suspension of potassium ethanolate (2.36 g, 27 mmol) in ethanol (30 ml) was added at room temperature a solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12mmol) in ethanol (10 ml). The reaction mixture was stirred at 60C for 2 h and evaporated. Ice/2 N HCI (50 ml) was added and the water layer was extracted with diethylether (2x 100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgS04) and evaporated to give the title compound (2.9 g, 98%) as a brown solid, which was used without further purification. MS (EI) 232.1 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hydroxide; In dimethyl sulfoxide; at 20 - 40℃; for 0.5h; | Example A.3 4-(2,2,2-Trifluoro-ethoxy)-3-trifluoromethyl-acetophenone To a stirred solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in DMSO (15 ml) was added at room temperature 2,2,2-trifluoroethanol (1.7 g, 17 mmol) and potassium hydroxide (1.74 g, 27 mmol). The reaction mixture was stirred for 30 min at 40 C., ice/2N HCl (50 ml) was added and the water layer was extracted with diethylether (2*100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the title compound (3.6 g, 98%) as a brown solid, which was used without further purification. MS (EI) 286.1 [M]. |
98% | With potassium hydroxide; In dimethyl sulfoxide; at 40℃; for 0.5h; | Example A.3 4-(2,2,2-Trifluoro-ethoxy)-3-trifluoromethyl-acetophenone; To a stirred solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in DMSO (15 ml) was added at room temperature 2,2,2-trifluoroethanol (1.7 g, 17 mmol) and potassium hydroxide (1.74 g, 27 mmol). The reaction mixture was stirred for 30 min at 40 C., ice/2N HCl (50 ml) was added and the water layer was extracted with diethylether (2×100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the title compound (3.6 g, 98%) as a brown solid, which was used without further purification. MS (EI) 286.1 [M]. |
98% | With potassium hydroxide; In dimethyl sulfoxide; at 20 - 40℃; for 0.5h; | To a stirred solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in DMSO (15 ml) was added at room temperature 2,2,2-trifluoroethanol (1.7 g, 17 mmol) and potassium hydroxide (1.74 g, 27 mmol). The reaction mixture was stirred for 30 min at 40C, ice/2N HCI (50 ml) was added and the water layer was extracted with diethylether (2x 100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgS04) and evaporated to give the title compound (3.6 g, 98%) as a brown solid, which was used without further purification. MS (EI) 286.1 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium ethoxide; In ethanol; at 20 - 60℃; for 2h; | Example A.2 4-Ethoxy-3-trifluoromethyl-acetophenone To a stirred suspension of potassium ethanolate (2.36 g, 27 mmol) in ethanol (30 ml) was added at room temperature a solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in ethanol (10 ml). The reaction mixture was stirred at 60 C. for 2 h and evaporated. Ice/2 N HCl (50 ml) was added and the water layer was extracted with diethylether (2*100 ml). The combined organic layers were washed with ice-water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the title compound (2.9 g, 98%) as a brown solid, which was used without further purification. MS (EI) 232.1 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Example A.1 4-Methyl-3-trifluoromethyl-acetophenone To a stirred and cooled (0 C.) solution of potassium tert.-butanolate (1.39 g, 12 mmol) in DMSO (3 ml) was added diethyl malonate (1.9 ml, 12 mmol) and the reaction mixture was stirred for 20 min at room temperature. To the white suspension was added at room temperature 4-fluoro-3-trifluoromethyl-acetophenone (1 g, 5 mmol) and DMSO (2 ml). The reaction mixture was stirred for 6 h at 60 C. and for 16 h at room temperature. The reaction mixture was cooled (0 C.), a solution of potassium hydroxide (1.09 g, 19 mmol) in water (2 ml) was added and the mixture was stirred at 100 C. for 23 h. The mixture was poured into ice/water (40 ml) and extracted with diethyl ether (2*40 ml). The combined organic layers were washed with water (3*30 ml), brine (30 ml), dried (MgSO4) and evaporated. The crude product (0.92 g) was further purified by column chromatography on silica gel (heptane/ethyl acetate 3:1) to give the title compound (0.76 g, 77%) as a light yellow liquid. MS (EI) 202.0 [M]. | |
77% | Example A.1 4-Methyl-3-trifluoromethyl-acetophenone; To a stirred and cooled (0 C.) solution of potassium tert.-butanolate (1.39 g, 12 mmol) in DMSO (3 ml) was added diethyl malonate (1.9 ml, 12 mmol) and the reaction mixture was stirred for 20 min at room temperature. To the white suspension was added at room temperature 4-fluoro-3-trifluoromethyl-acetophenone (1 g, 5 mmol) and DMSO (2 ml). The reaction mixture was stirred for 6 h at 60 C. and for 16 h at room temperature. The reaction mixture was cooled (0 C.), a solution of potassium hydroxide (1.09 g, 19 mmol) in water (2 ml) was added and the mixture was stirred at 100 C. for 23 h. The mixture was poured into ice/water (40 ml) and extracted with diethyl ether (2×40 ml). The combined organic layers were washed with water (3×30 ml), brine (30 ml), dried (MgSO4) and evaporated. The crude product (0.92 g) was further purified by column chromatography on silica gel (heptane/ethyl acetate 3:1) to give the title compound (0.76 g, 77%) as a light yellow liquid. MS (EI) 202.0 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In hexane; N,N-dimethyl-formamide; | To a solution of 4-fluoro-3-trifluoromethyl-acetophenone (7.00 g, 34.0 mmol) in DMF (100 mL) was added 2-isopropylthiophenol (6.33 g, 37.4 mmol) followed by cesium carbonate (16.6 g, 51.0 mmol). The mixture was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate (250 mL) and water (250 mL). The organic layer was separated, washed with brine (5*250 mL), dried over MgSO4 and filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluding with 5% ethyl acetate in hexane to give a colorless oil 44 (11.5 g, 100%). 1H-NMR (CDCl3, 300 MHz) delta1.17 (d, J=6.7 Hz, 6H), 2.57 (s, 3H), 3.46 (heptete, J=6.8 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 7.24-7.29 (m, 1H), 7.45-7.50 (m, 2H), 7.53 (d, J=7.5 Hz, 1H), 7.79 (dd, J=2.0 Hz, 8.5 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H). MS (DCI) m/z 339 (M+H)+; 356 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuryl dichloride; at 50℃;Product distribution / selectivity; | Reaction 1B: 2,2-dichloro-<strong>[208173-24-4]1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone</strong>To a reaction vessel was added <strong>[208173-24-4]4-fluoro-3-(trifluoromethyl)acetophenone</strong> (2.50 g, 12.13 mmol) and sullfuryl chloride (3 mL). The reaction mixture was stirred to about 500C overnight and subsequently concentrated in vacuo to afford the alpha, alpha-dichloroacetophenone in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuryl dichloride; at 50℃; for 2h; | Preparation F:Reaction 1A: 4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amineTo a 50OmL reaction vessel was added <strong>[208173-24-4]4-fluoro-3-(trifluoromethyl)acetophenone</strong>(175mmol) and sulfuryl chloride (350mmol). The reaction mixture was stirred at 500C for about 2 hours. The reaction mixture was then concentrated to dryness. EtOH (25OmL) and thiourea (180mmol) was added to the resulting residue. The reaction mixture was then EPO <DP n="47"/>refluxed at 9O0C for about 24 hours. Subsequent concentration yielded a residue that was suspended in chloroform (50OmL) and washed twice with saturated sodium bicarbonate (25OmL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The product was triturated twice with hexanes (40OmL) and decanted to afford the desired product. MW = 262.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; | 4-Fluoro-3-(trifluoromethyl)acetophenone (2 g, 9.70 mmol) was reacted with selenium dioxide (1.6 g, 14.6 mmol) using the method described in Example 1 to give crude (4-fluoro-3-trifluoromethylphenyl)-oxoacetaldehyde as a yellow oil: m/z (ES+) 221. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.8% | In N,N-dimethyl-formamide; at 20℃;Cooling with ether-dry ice; | A mixture of 1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (1.0 g, 4.85 mmol) and sodium methoxide (288 mg, 5.33 mmol) in DMF (5 mL) was stirred for 2 h in an ice-water bath and then at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with ethyl acetate/petroleum ether = 1:40) to get 1-(4-methoxy-3-(trifluoromethyl)phenyl)ethanone (25) (950 mg) with 89.8% yield. |
In N,N-dimethyl-formamide; at 0 - 20℃; for 3.0h; | (9-1) Synthesis of 4'-methoxy-3'-trifluoromethylacetophenone (compound 9-1) To a solution of 4'-fluoro-3'-trifluoromethylacetophenone (25.0 g) in N,N-dimethylformamide (70 ml) was added sodium methoxide (7.21 g) under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling and further at room temperature for 1 hr. The reaction mixture was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (24.3 g) as a brown solid. 1H-NMR(CDCl3)delta(ppm): 2.59(3H, s), 3.99(3H, s), 7.06(1H, d, J=8.7Hz), 8.14(1H, dd, J=2.1, 8.7Hz), 8.19(1H, d, J=2.1Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 0.5h;microwave; | A solution of <strong>[208173-24-4]4-fluoro-3-(trifluoromethyl)acetophenone</strong> (500 mg, 2.43 mmol), N-(2- methoxyethyl)methylamine (649 mg, 7.28 mmol) and potassium carbonate (335 mg, 2.43 mmol) in DMSO (6 ml_) was stirred for 30 min at 150 0C in the microwave. The cooled reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. Finally 547 mg (yield: 82%) of the title compound was obtained. LC/MS (method D) (M+H)+: 276 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | 832 mul (10.5 mmol) of 2-methoxyethanol was dissolved in 15 ml absolute DMSO and to this solution NaH (504 mg (10.5 mmol)) was added. After stirring for 1 hour at RT 1.44 g (7 mmol) of 4-fluoro-3-trifluoromethyl-acetophenone was added and the mixture was stirred for an additional hour. The reaction was quenched with ice/water, extracted with DCM1 dried over sodium sulphate, filtered, evaporated under reduced pressure and purified by chromatography on silica gel. Yield: 1.13 g (62 %) LC/MS (method A) (M+1)+: 262.08 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a suspension of sodium hydride (408 mg, 10.2 mmol) in DMSO (15 ml) was added 1-boc-3-hydroxypiperidine (2.00 g, 10.2 mmol) at 00C. Stirring was continued for 30 min at 100C and 4-fluoro-3-(trifluormethyl)acetophenone (1.40 g, 6.79 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 h and then transferred into water (200 ml) at 00C. Dichloromethane (300 ml) was added. The organic phase was washed with water (200 ml) and dried over sodium sulfate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane = 1 :1 gave the desired product (1.80 g , 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Intermediate 19; 1-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine; hydrochloride; A mixture of log (49 mmol) 4-Fluoro-3-(trifluoromethyl) acetopheneone (commercially available), 27.5 g (97 mmol) titanium tetraisopropoxide and 34 mL (243 mmol) 7 N ammonia in MeOH at 0 C. was stirred over the weekend at 20 C. Subsequently, 5.5 g (146 mmol) sodium borohydride was added and the mixture allowed to come from 0 C. to room temperature over night. Water and ammonia was added and the mixture was filtered through decalit and washed with ethyl acetate. The aqueous phase was separated washed with ethyl acetate and the combined organic phases washed with NaCL sat. aq., dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography eluting with a gradient formed from DCM, methanol and ammonia. The product containing fractions were evaporated to dryness and transformed with HCl in diethyl ether to the respective hydrochloride salt. Yield: 4.4 g ( 37%). MS(m/e): 207.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform; ethyl acetate; for 6h;Reflux; | To a vigorously stirred refluxing solution of Cub (15.17 g, 67.9 mmol) in EA (40 ml), a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (7 g, 34.0 mmol) in dry chloroform (50 ml) was added one pot, then the reaction mixture was refluxed for 6h. The mixture was cooled down to RT, filtered over a pad of celite and evaporated. The residue was partitioned between EA and saturated NaHCO3 aqueous solution, then organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by FC on silica (eluting with Cy/EA from 10/0 to 8/2) to give 6.95 g of the title compound.NMR (1H, CDCI3): delta ppm 8.15 - 8.30 (m, 2 H), 7.30 - 7.39 (m, 1 H), 4.45 (s, 2 H). | |
With copper(II) iodide; In chloroform; for 6h;Reflux; | To a vigorously stirred refluxing solution of CuI2 (15.17 g, 67.9 mmol) in EA (40 ml), a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (7 g, 34.0 mmol) in dry chloroform (50 ml) was added one pot, then the reaction mixture was refluxed for 6h. The mixture was cooled down to RT, filtered over a pad of celite and evaporated. The residue was partitioned between EA and saturated NaHCO3 aqueous solution, then organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by FC on silica (eluting with Cy/EA from 10/0 to 8/2) to give 6.95 g of the title compound. <n="95"/>NMR (1H, CDCI3): delta 8.15 - 8.30 (m, 2 H), 7.30 - 7.39 (m, 1 H), 4.45 (s, 2 H). | |
3.50 g | With bromine; acetic acid; at 20℃; for 18h; | 1-[4-Fluoro-3-(trifluoromethyl)phenyl]ethanone (7.7 m[, 100 % purity, 49 mmol, GAS2081 73-24-4) was dissolved in acetic acid (70 m[), then a solution of bromine (2.5 m[,100% purity, 49 mmol) in acetic acid (5 m[) was added slowly. The mixture was stirredat RT for 18 h. The mixture was dried in vacuo to obtain 3.50 g of the title compound. |
With bromine; acetic acid; at 20℃;Inert atmosphere; | 1 -[4-Fluoro-3-(trifluoromethyl)phenyl]ethanone (380 muIota_, 100 % purity, 2.4 mmol, CAS 208173-24-4) was dissolved in acetic acid (3.7 mL) at room temperature. Bromine (120 muIota_, 100 % purity, 2.4 mmol) was added dropwise into the reaction mixture, which was stirred overnight, its colour turned from brown to orange. The mixture was concentrated under reduced pressure and used as crude material in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a stirred and cooled (0C) solution of potassium tert.-butanolate (1.39 g, 12 mmol) in DMSO (3 ml) was added diethyl malonate (1.9 ml, 12 mmol) and the reaction mixture was stirred for 20 min at room temperature. To the white suspension was added at room temperature 4-fluoro-3-trifluoromethyl-acetophenone (1 g, 5 mmol) and DMSO (2 ml). The reaction mixture was stirred for 6 h at 60C and for 16 h at room temperature. The reaction mixture was cooled (0C), a solution of potassium hydroxide (1.09 g, 19 mmol) in water (2 ml) was added and the mixture was stirred at 100C for 23 h. The mixture was poured into ice/water (40 ml) and extracted with diethyl ether (2 x 40 ml). The combined organic layers were washed with water (3 x 30 ml), brine (30 ml), dried (MgS04) and evaporated. The crude product (0.92 g) was further purified by column chromatography on silica gel (heptane/ethyl acetate 3 : 1) to give the title compound (0.76 g, 77%) as a light yellow liquid. MS (EI) 202.0 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 100℃; for 20h;sealed tube; | l-(4-Fluoro-3-(trifluoromethyl)phenyl)ethanone (510.0 mg, 2.5 mmol) and morpholine (724.2 mg, 8.31 mmol) were placed in a screw cap pressure tube. The tube was sealed and the mixture heated to 1000C for 20 hours. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 4:1 ? 3:2) to give 541.0 mg (84%) of the title substance 1H NMR (CDCl3) delta 8.23 (d, IH), 8.11 (dd, IH), 7.33 (d, IH), 3.86 (t, 4H),3.05 (t, 4H), 2.61 (s, 3H). |
84% | at 100℃; for 20h;Sealed; Pressure tube; | 1-(4-morpholino-3-(trifluoromethyl)phenyl)ethanone 1-(4-Fluoro-3-(trifluoromethyl)phenyl)ethanone (510.0 mg, 2.5 mmol) and morpholine (724.2 mg, 8.31 mmol) were placed in a screw cap pressure tube. The tube was sealed and the mixture heated to 100 C. for 20 hours. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 4:1?3:2) to give 541.0 mg (84%) of the title substance 1H NMR (CDCl3) delta 8.23 (d, 1H), 8.11 (dd, 1H), 7.33 (d, 1H), 3.86 (t, 4H), 3.05 (t, 4H), 2.61 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 -(4-Benzyloxy-3-trifluoromethyl-phenyl)-ethanone : A mixture of benzyl alcohol(10.9 ml 104.98 mmol) and KOtBu (12.96 g; 115.5 mmol) in THF (500 ml.) was heated under reflux for 10 minutes. Subsequently, 4'-fluoro-3'- (trifluoromethyl)acetophenone (21.64 g; 105 mmol) was added and the mixture heated under reflux for another 2 hours. After cooling to RT, the mixture was partitioned between EtOAc and a 5% aqueous NaHCOs solution. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O: hexanes 1 :2.5) to afford 1-(4- Benzyloxy-3-trifluoromethyl-phenyl)-ethanone (22.37 g). |
Tags: 208173-24-4 synthesis path| 208173-24-4 SDS| 208173-24-4 COA| 208173-24-4 purity| 208173-24-4 application| 208173-24-4 NMR| 208173-24-4 COA| 208173-24-4 structure
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