* 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.
With sodium tetrahydroborate; nickel(II) chloride hexahydrate; In methanol; at 0 - 30℃; for 6h;Inert atmosphere;
Add <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (10 g, 52.88 mmo1, compound 1) to a 250 mL three-necked flask.Nickel chloride hexahydrate (12.6g, 52.88mmoL), 150mL anhydrous methanol, replaced with nitrogen three times,The temperature of the nitrogen gas was lowered to 0 to 10 C, and sodium borohydride (6.0 g, 158.64 mmo1) was added in portions.After slowly heating up to 20 ~ 30 C, heat preservation 6h,After filtration with celite, the filtrate was concentrated to remove most methanol, and ethyl acetate (60 mL) was added.Slowly add 10% hydrochloric acid to adjust the pH = 1 to 2, and then adjust the pH of the solution to 11~12 with 15% sodium hydroxide solution, then dispense.The aqueous phase was extracted with 60 mL of ethyl acetate.After drying with anhydrous sodium sulfate, filtration, the filtrate was evaporated to give 8.8 g of pale yellow liquid compound 2 (2-fluoro-6-(trifluoromethyl)benzylamine).The yield was 86%;
With borane-THF; at 60℃;Heating / reflux;
To 2-fluoro-6- (trifluoromethyl) benzonitrile (45 g, 0.238 mmol) in 60 mL of THF was added 1 M BH3: THF slowly at 60 C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over NA2S04. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (CI) M/Z 194. 0 (MH+).
With borane-THF; at 60℃;Heating / reflux;
To 2-fluoro-6- (trifluoromethyl) benzonitrile (45 g, 0.238 mmol) in 60 mL of THF was added 1 M BH3: THF slowly at 60 C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over NA2S04. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (CI) M/Z 194. 0 (MH+).
With borane; In tetrahydrofuran; at 60℃;Heating / reflux;
To 2-fluoro-6- (trifluoromethyl) benzonitrile (45 g, 0.238 mmol) in 60 mL of THF was added 1 M BH3: THF slowly at 60 oC and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 ML) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave 4a as a yellow oil (46 g, 0. 238 mmol). MS (CI) m/z 194. 0 (MH+).
EXAMPLE 1 5-BROMO-1-(at)2-FLUORO-6-(TRIFLUOROMETHYL(at)BENZYL(at)-6-METHYLPYRIMIDINE- 2,4(IH,3H)-DIONE Step lA: Preparation of2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6- (trifluoromethyl)benzonitrile g, 0.238 mmol) in 60 mL of THF was added 1 M BH3:THF slowly at 60 C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2S04. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (CI) m/z 194.0 (MH+).
2-fluoro-3-iodo-6-trifluoromethylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.7%
Example 16: Synthesis OF 3-AMINO-7-FURAN-4-TRIFLUOROMETHYL-BENZO [B] THIOPHENE-2- carboxylic acid amide To a solution OF 2 M n-BuLi in pentane (1.62 mL, 3.24 mmol) in 8 mL of dry THF under N2 at-78 C was added 2-FLUORO-6- (TRIFLUOROMETHYL) benzonitrile (612 mg, 3.24 mmol) in 2 mL of dry THF. The mixture was stirred at-78 C for 30 min, followed by the addition of iodine (1070 mg, 4.22 mmol) in 2 mL of dry THF. The reaction mixture was warmed up and stirred for 2 h at room temperature. Water was added followed by a solution OF NA2S203. The mixture was extracted with EtOAc. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous MGSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane. The product fractions were collected and concentrated to afford 180 mg (17.7 %) of 2-fluoro-3-iodo-6-trifluoromethylbenzonitrile as a brown dark solid.
Method 16 2-Amino-6-trifluoromethylbenzenecarbonitrile 2-Fluoro-6-trifluoromethylbenzenecarbonitrile was heated at 100 C. in a saturated solution of NH3 in EtOH overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silicagel (EtOAc/Hexanes 1:5), to obtain the title compound as a white solid. GC/MS m/z 186.1 (M+), Rt 10.1 minutes.
With ammonia; In ethanol;
Method 16 2-Amino-6-trifluoromethylbenzenecarbonitrile 2-Fluoro-6-trifluoromethylbenzenecarbonitrile was heated at 100 C. in a saturated solution of NH3 in EtOH overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silicagel (EtOAc/Hexanes 1:5), to obtain the title compound as a white solid. GC/MS m/z 186.1 (M+), Rt 10.1 minutes.
With ammonia; In ethanol; at 100℃;
2-Fluoro-6-trifluoromethylbenzenecarbonitrile was heated at 100 C in a saturated solution of NH3 in EtOH overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silicagel (EtOAc/Hexanes 1: 5), to obtain the title compound as a white solid. GC/MS M/Z 186.1 (M+), Rt 10.1 minutes.
Example 13 Preparation of 2-{4-[4-(2-cyano-3-trifluoromethyl-phenyl)piperazin-1-yl]butyl}amino-4-phenylpyridine Step a: Preparation of 4-(2-cyano-3-trifluoromethylphenyl)piperazine A mixture of 3 g (15.8 mmol) of <strong>[133116-83-3]2-fluoro-6-trifluoromethylbenzonitrile</strong>, 7.5 g (87 mmol) of piperazine and 24 mL of dioxane is heated at reflux for 5 hours. The reaction medium is concentrated under a vacuum and the residue is taken up with ethyl acetate. After washing with water, the organic phase is dried over magnesium sulfate, filtered and concentrated. The product crystallises at ambient temperature. After drying under a vacuum, 3.6 g (82%) of 4-(2-cyano-3-trifluoromethylphenyl)piperazine are obtained, this being used as it is in subsequent syntheses.
In 1,4-dioxane; for 5h;Heating / reflux;
Step a: Preparation of 1-(2-cyano-3-trifluoromethylphenyl)piperazine A mixture of 3 g (15.8 mmol) of <strong>[133116-83-3]2-fluoro-6-trifluoromethylbenzonitrile</strong>, 7.5 g (87 mmol) of piperazine and 24 mL of dioxan is heated to reflux for 5 hours. The reaction medium is concentrated in a vacuum and the residue is taken up with ethyl acetate. After washing with water, the organic phase is dried on magnesium sulphate, filtered and concentrated. The product crystallises at ambient temperature. After drying in a vacuum, 3.6 g of 1-(2-cyano-3-trifluoromethylphenyl)piperazine is obtained which is used as such in the subsequent syntheses. Rf: 0.65 dichloromethane/methanol/ammonia 90/10/1
In N,N-dimethyl-formamide; at 20 - 90℃; for 4.08333h;
To a stirred solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (19.6g, 104mmol) (Aldrich) in DMF (75ml_) at room temperature under an atmosphere of argon was added piperazine (26.8g, 311 mmol, 3 equivalents). The reaction was heated to 900C for 4 hrs and 5 minutes and then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and DCM and the organic layer dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with 2%MeOH/DCM to 10%MeOH/DCM to afford the title compound (21.3g); m/z: 256 [M+H]+, retention time 1.75 mins.
2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In dimethyl sulfoxide;
Step A Synthesis of 2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene as an intermediate This compound was prepared in a manner analogous to that of Step A of Example 23, using 25.0 grams (0.132 mole) of <strong>[133116-83-3]2-fluoro-6-trifluoromethylbenzonitrile</strong>, 12.3 mL (0.135 mole) of 2-methyl-2-propen-1-ol, and 10.0 grams (0.135 mole) of powdered 85% potassium hydroxide in 250 mL of dimethyl sulfoxide. The yield of 2-methyl-3-(2-cyano-3-trifluoromethylphenoxy)-1-propene was 28.6 grams. The NMR spectrum was consistent with the proposed structure.
2-(piperidin-1-yl)-6-(trifluoromethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;
Intermediate 30: (2-(piperidin-l-yl)-6-(trifluoromethyl)phenyl)methanamine Step 1: To a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (CAS: 133116-83-3) (2 mmol) and piperidine (2.2 mmol) in 10 mL of DMF was added K2CO3 (12 mmol). The reaction was stirred at 70 C for 12 h, then cooled to RT. The reaction mixture was then extracted with water and EtOAc, washed with brine, dried over Na2S04, concentrated in vacuo, then purified by prep- TLC to provide 2-(piperidin-l-yl)-6-(trifluoromethyl)benzonitrile as a white solid.
2-(trifluoromethyl)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
To a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (1.0 g, 5.29 mmol) and K2C03 (1.46 g, 10.58 mmol) in DMF (5 mL) was added 2-(trimethylsilyl)ethanethiol (1.01 ml, 6.35 mmol). The mixture was stirred at room temperature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and evaporated to dryness in vacuo. The crude was adsorbed onto silica gel, and purified by hexane and ethyl acetate to afford the desired compound. LC/MS [M+H]+:304.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
Step A: 2-(Trifluoromethyl)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile (0711) To a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (1.0 g, 5.29 mmol) and K2CO3 (1.46 g, 10.58 mmol) in DMF (5 mL) was added 2-(trimethylsilyl)ethanethiol (1.01 ml, 6.35 mmol). The mixture was stirred at room temperature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and evaporated to dryness in vacuo. The crude was adsorbed onto silica gel, and purified by hexane and ethyl acetate to afford the desired compound. LC/MS [M+H]+:304
With trimethylaluminum; ammonium chloride; In toluene; at 20℃; for 1h;
Synthesis of compound 45.2. Compound 45.1 (2 g, 10.57 mmol, 1.00 eq), NH4C1 (0.58 g, 11.63 mmol, 1.1 eq) was dissolved in toluene (40ml). A solution of trimethylaluminium (2.0 M sol. in toluene) (5.8 ml, 11.63 mmol, 1.1 eq) was added dropwise to the above reaction mixture at room temperature. Reaction mixture was stirred for 1 hour at room temperature then refluxed overnight. After completion of reaction, toluene was evaporated and residue was diluted with 10% methanol in dichloromethane (40ml) Silica gel (2.0 g) was added to this reaction mixture and stirred for 30 minutes at ambient temperature. After 30 minutes, slurry was filtered and washed with dichloromethane & methanol filtrate was concentrated under vacuum to afford crude which was purified using trituration with 20% Ethyl acetate in hexane (50 mL). Obtained solid was filtered off and dried under vacuum to afforded compound 45.2 (2.0 g, 91 >) as a white solid, MS (ES): m/z [207] [M+H]+.
(±)-N-[7-cyano-1,1-dioxido-6-(trifluoromethyl)-2,3-dihydro-1-benzothiophen-3-yl]-N-[2-(dimethylamino)ethyl]-3-(4-fluoro-3-methylphenyl)-5-methoxyimidazo[1,2-a]pyridine-2-carboxamide[ No CAS ]
(+)-N-[7-cyano-1,1-dioxido-6-(trifluoromethyl)-2,3-dihydro-1-benzothiophen-3-yl]-N-[2-(dimethylamino)ethyl]-3-(4-fluoro-3-methylphenyl)-5-methoxyimidazo[1,2-a]pyridine-2-carboxamide[ No CAS ]
2-fluoro-3-formyl-6-(trifluoromethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 2,2,6,6-tetramethylpiperidine (4860 mg, 34.4 mmol) in tetrahydrofuran (THF) (35 mL) was slowly added a solution of n-butyllithium (n-BuLi) in hexanes (1.6 M, 19.8 mL, 31.7 mmol) at -50 C under nitrogen atmosphere. The mixture was stirred at -50 C for 30 min. To the reaction mixture was slowly added a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (12d )(5000 mg, 26.4 mmol) in THF (15 mL) at -60 C. The mixture was stirred at -50 C for 30 min under nitrogen atmosphere. To the reaction mixture was slowly added a solution of DMF (5810 mg, 79.5 mmol) in THF (5.0 mL) at -50 C under nitrogen atmosphere. The mixture was stirred at -50 C for 15 min. It was then warmed up to -10 C and stirred for 25 min. To the mixture were added acetic acid (5.0mL) and water (100 mL). The resulting mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, successively, and dried over Na2SO4. The insoluble was filtered off and the filtrate was evaporated in vacuo to give 13d (5870 mg, 27.0 mmol, quantitative yield) as brown oil. This product was subjected to the next reaction without further purification.; MS (ESI): undetected. 1H NMR (300 MHz,CDCl3) delta 7.77 (1H, d, J = 8.2 Hz), 8.25 (1H, t, J = 7.4 Hz), 10.42 (1H, s).
(2-{(S)-1-amino-3-[3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-phenyl-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)-acetic acid[ No CAS ]
3-(2-{(S)-1-amino-3-[3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-phenyl-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)-propionic acid[ No CAS ]
4-(2-{(S)-1-amino-3-[3-(2-fluoro-6-trifluoromethyl-benzyl)-5-(3-isopropyl-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)-butyric acid[ No CAS ]
5-(2-{1-amino-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-ethyl}-phenoxy)-pentanoic acid[ No CAS ]
3-(2-{(S)-1-amino-3-[3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-phenyl-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)-propionic acid sodium salt[ No CAS ]
In N,N-dimethyl acetamide; at 130℃; for 3h;Sealed tube;
In a sealed tube, a mixture of 2- fluoro-6-(trifluoromethyl)benzonitrile (4.5 g, 23.8 mmol) and guanidine carbonate (8.57 g, 47.6 mmol) in DMA (54 ml_) was stirred at 130 C for 3h. The reaction mixture was cooled to rt, diluted with EtOH and the solvent was removed under reduced pressure. The residue was mixed with cold water and the solid was isolated by filtration to give the title compound as a tan solid (5.2 g), and was used in the next step without further purification.
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