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CAS No. : | 116369-25-6 | MDL No. : | MFCD11506046 |
Formula : | C7H5BrF3NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LFTJNGSZCSGBFU-UHFFFAOYSA-N |
M.W : | 256.02 | Pubchem ID : | 14129198 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 45.23 |
TPSA : | 35.25 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) : | -5.65 cm/s |
Log Po/w (iLOGP) : | 1.94 |
Log Po/w (XLOGP3) : | 3.11 |
Log Po/w (WLOGP) : | 4.2 |
Log Po/w (MLOGP) : | 2.37 |
Log Po/w (SILICOS-IT) : | 2.38 |
Consensus Log Po/w : | 2.8 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.6 |
Solubility : | 0.0649 mg/ml ; 0.000253 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.52 |
Solubility : | 0.0775 mg/ml ; 0.000303 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.52 |
Solubility : | 0.077 mg/ml ; 0.000301 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.73 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P280-P301+P310 | UN#: | 2810 |
Hazard Statements: | H301-H317 | Packing Group: | Ⅲ |
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 |
---|---|---|
94% | With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 96h; | 59.b (b) Synthesis of tert-butyl 4-bromo-3-(trifluoromethoxy)phenylcarbamate (b) Synthesis of tert-butyl 4-bromo-3-(trifluoromethoxy)phenylcarbamate A solution of sodium hydroxide (199 mg, 4.98 mmol) in water (1.5 ml) and a solution of di-tert-butyl dicarbonate (1.09 g, 4.99 mmol) in t-butanol (1 ml) were added to a solution of 4-bromo-3-(trifluoromethoxy)aniline (510 mg, 1.99 mmol) in t-butanol (2.5 ml) at room temperature, and the resulting mixture was stirred for 4 days. After completion of the reaction, the reaction mixture obtained as a suspension was filtered by the use of a small volume of water and the filtrate was concentrated to about one-half its original volume. The resulting residue was washed with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 95/5) to obtain tert-butyl 4-bromo-3-(trifluoromethoxy)phenylcarbamate (666 mg, 94%). |
With sodium hydroxide In <i>tert</i>-butyl alcohol for 96h; | 50 Intermediate 50: 1 ,1-Dimethylethyl {4-bromo-3- [(trifluoromethyl)oxy]phenyl}carbamate; To a stirred solution of 4-bromo-3-[(trifluoromethyl)oxy]aniline (Commercially available, for example from Atomole Scientific, Wuhan, Hubei, China, 2.0 g, 7.8 mmol) in i-butanol at room temperature was added slowly 10% NaOH solution (3.10 g, 7.5 mmol), followed by di-te/t-butyl dicarbonate (1.70 g, 7.8 mmol) and the mixture was stirred for 4 days. The reaction was quenched with ice-water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous 2011/051276Na2S04 and concentrated under reduced pressure to afford the crude product. This was washed with pentane to afford the title compound (1.50 g).MS ES+ve m/z 354 (M-H).1H NMR (400 MHz, Chloroform-cf) δ ppm 1 .50 (s, 9 H), 6.58 (br s, 1 H), 7.10-7.20 (m, 1 H), 7.45-7.55 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 20℃; | 59.a Example 59; Synthesis of 4-[(1-benzylpiperidin-4-yl)amino]-2-(trifluoromethoxy)benzamide; (a) Synthesis of 4-bromo-3-(trifluoromethoxy)aniline (a) Synthesis of 4-bromo-3-(trifluoromethoxy)aniline A solution of N-bromosuccinimide (3.78 g, 21.2 mmol) in N,N-dimethylformamide (11 ml) was added dropwise to a solution of 3-trifluoromethoxyaniline (3.84 g, 21.2 mmol) in N,N-dimethylformamide (11 ml) at room temperature over a period of 40 minutes. After completion of the dropwise addition, the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (hexane/chloroform = 6/4) to obtain 4-bromo-3-(trifluoromethoxy)aniline (4.96 g, 91%). |
68% | With pyridinium hydrobromide perbromide In dichloromethane at 0℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-bromo-3-(trifluoromethoxy)phenylamine With hydrogenchloride; acetic acid; sodium nitrite In water at -15 - -5℃; for 0.75h; Stage #2: With sulfur dioxide; acetic acid; copper(l) chloride In water at 30℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In toluene; at 20℃; for 2h; | The title compound was prepared according to procedures similar to those described in Example 1 starting from 2-bromo-5-trifluoromethoxy-aniline, which was obtained as follows:A solution of 3-trifluoromethoxy-aniline (1.77 g) in toluene (20 ml) was treated with Lambda/-bromosuccinimide (1.87 g) at ambient temperature and the reaction mixture was stirred for 2 hours at ambient temperature, quenched by addition of water and the mixture extracted with ethyl acetate (3x 50 ml). The combined organic extracts were washed with aqueous sodium hydrogen carbonate (saturated), dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 95:5) to afford 4-bromo-3-trifluoromethoxy-aniline (270 mg) and 2-bromo-5- trifluoromethoxy-aniline (1.45 g), which were both characterized by mass and NMR spectra. 4-bromo-3-trifluoromethoxy-aniline: MS (ES+) 256 / 258 (MH+); IH NMR (400 MHz, CDCl3) 3.5 (brs, 2H), 6.5 (d, IH), 6.7 (s, IH), 7.3 (d, IH). 2-bromo-5-trifluoromethoxy- aniline: MS (ES+) 256 / 258 (MH+); IH NMR (400 MHz, CDCl3) 4.2 (brs, 2H), 6.5 (d, IH), 6.6 (s, IH), 7.4 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / <i>tert</i>-butyl alcohol / 96 h 2.1: N,N-dimethyl-formamide / 15 h / Reflux 2.2: 2 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water; <i>tert</i>-butyl alcohol / 96 h / 20 °C 2.1: DMF (N,N-dimethyl-formamide) / 9.5 h / 20 °C / Heating / reflux 2.2: 0.33 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydroxide / <i>tert</i>-butyl alcohol / 96 h 2.1: N,N-dimethyl-formamide / 15 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydroxide / <i>tert</i>-butyl alcohol / 96 h 2.1: N,N-dimethyl-formamide / 15 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 0 °C 4.2: 4 h / 20 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydroxide / <i>tert</i>-butyl alcohol / 96 h 2.1: N,N-dimethyl-formamide / 15 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 0 °C 4.2: 4 h / 20 °C / Reflux 5.1: water; lithium hydroxide / tetrahydrofuran; methanol / 3 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydroxide / <i>tert</i>-butyl alcohol / 96 h 2.1: N,N-dimethyl-formamide / 15 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 0 °C 4.2: 4 h / 20 °C / Reflux 5.1: water; lithium hydroxide / tetrahydrofuran; methanol / 3 h / 0 - 20 °C 6.1: thionyl chloride / toluene / 4 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 78.a (a) (a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1:4 ethanol:water (2*25 mL) to give the title intermediate as a white solid (3.87 g). HPLC method C: Retention time=21.3 min. | |
In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 23.1.a (a) (a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (300 mg, 1 mmol) dissolved in DCM (5 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM (1 mL). A white precipitate was observed. The reaction mixture was concentrated to produce the HCl salt of the title intermediate. (m/z): [M+H]+ calcd for C13H7BrF4N2O2 378.96 found 379.0. | |
3.87 g | With triethylamine In dichloromethane at 20℃; for 2h; | 1.a (a) (a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1:4 ethanol:water (2*25 mL) to give the title intermediate as a white solid (3.87 g). Analytical HPLC: Retention time=21.3 min. |
3.87 g | With triethylamine In ethanol at 20℃; for 2h; Inert atmosphere; | 78.a (a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide (a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1:4 ethanol:water (2 x 25 mL) to give the title intermediate as a white solid (3.87 g). HPLC method C: Retention time = 21.3 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-chloro-succinimide In quinoclamine; ethyl acetate | 62.a (a) (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl actetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc:hexanes) to produce the desired product as an orange-ish colored oil (1.4 g, 64% yield). |
64% | With N-chloro-succinimide In acetonitrile at 60℃; | (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl actetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc:hexanes) to produce the desired product as an orange-ish_colored oil (1.4 g, 64% yield). |
64% | With N-chloro-succinimide In acetonitrile at 60℃; Inert atmosphere; | 8.a (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc:hexanes) to produce the desired product as an orange-ish-colored oil (1.4 g, 64% yield). |
64% | With N-chloro-succinimide In acetonitrile at 60℃; Inert atmosphere; | 11 Preparation 11: 4-bromo-2-chloro-5-trifluoromethoxy-phenylamine [0278] To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mE) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mE). The reaction mixture was heated to at 60° C. overnight and extracted with ethyl acetate/watet The organic layer was dried over sodium sulfate and purified by silica gel chromatography (40 g silica, 100% hexanes to 10% EtOAc:hexanes) to produce the desired product as an orange colored oil (1.4 g, 64% yield). |
64% | With N-chloro-succinimide In acetonitrile at 60℃; Inert atmosphere; | 62.a (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine (a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60 °C overnight and extracted with ethyl actetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc: hexanes) to produce the desired product as an orange-ish_colored oil (1.4 g, 64 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide | 27 Preparation 27 Preparation 27 (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; in N,N-dimethylacetamide (3 mL) was added a solution of (2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU (401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated by rotary evaporation, extracted with ethyl acetate/sat. sodium carbonate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate:hexanes) to provide the title compound (155 mg, yield 36%). (m/z): [M+H]+ calcd for C24H28BrF3N4O4 573.12, 575.12 found 575.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane | ||
Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: dichloromethane; N,N-dimethyl acetamide / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C 7: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C | ||
Multi-step reaction with 8 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium hydrogencarbonate / water; 2-methyltetrahydrofuran / 70 °C / Inert atmosphere 8: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C | ||
Multi-step reaction with 7 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium hydrogencarbonate / water; 2-methyltetrahydrofuran / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C 5.2: 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C 5.2: 3 h / 20 °C 6.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C | ||
Multi-step reaction with 3 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 0.5 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere 5.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 50 °C 6.1: HATU / N,N-dimethyl acetamide / 0.25 h 6.2: 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 0.5 h / 50 °C 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / water; tetrahydrofuran / 4 h / 65 °C / Inert atmosphere 8: trifluoroacetic acid / dichloromethane / 5 °C 9: N-ethyl-N,N-diisopropylamine; 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) / N,N-dimethyl-formamide / 3 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C 7.1: trifluoroacetic acid / dichloromethane / 5 °C 8.1: N-ethyl-N,N-diisopropylamine; 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) / N,N-dimethyl-formamide / 0 - 20 °C 8.2: 0.75 h | ||
Multi-step reaction with 9 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6.1: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7.1: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium hydrogencarbonate / water; 2-methyltetrahydrofuran / 70 °C / Inert atmosphere 8.1: trifluoroacetic acid / dichloromethane / 5 °C 9.1: N-ethyl-N,N-diisopropylamine; 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) / N,N-dimethyl-formamide / 0 - 20 °C 9.2: 0.75 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 12 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 12 h / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 12 h / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C 5.2: 3 h / 20 °C 6.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C / Inert atmosphere 7.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; toluene / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C 7.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 8.1: HATU / N,N-dimethyl acetamide / 0.25 h / 20 °C 8.2: 20 °C | ||
Multi-step reaction with 9 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6.1: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7.1: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium hydrogencarbonate / water; 2-methyltetrahydrofuran / 70 °C / Inert atmosphere 8.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 9.1: HATU / N,N-dimethyl acetamide / 0.25 h / 20 °C 9.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C 7: trifluoroacetic acid / dichloromethane / 5 °C | ||
Multi-step reaction with 8 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium hydrogencarbonate / water; 2-methyltetrahydrofuran / 70 °C / Inert atmosphere 8: trifluoroacetic acid / dichloromethane / 5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / water; tetrahydrofuran / 4 h / 65 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: N-chloro-succinimide / acetonitrile / 60 °C 2: N,N-dimethyl acetamide / dichloromethane 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C 6: TurboGrignard / tetrahydrofuran / 2.5 h / 0 - 10 °C / Inert atmosphere 7: potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / water; tetrahydrofuran / 4 h / 65 °C / Inert atmosphere 8: trifluoroacetic acid / dichloromethane / 5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C 2.1: N,N-dimethyl acetamide / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 5.1: HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C 5.2: 3 h / 20 °C 6.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water / 95 °C / Inert atmosphere 7.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 8.1: HATU / N,N-dimethyl acetamide / 0.25 h 8.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-bromo-3-(trifluoromethoxy)phenylamine; 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Inert atmosphere; Stage #2: 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester In dichloromethane at 20℃; for 0.25h; Inert atmosphere; | 16 Preparation 16: 4-[4-(4-bromo-3-trifluoromethoxyphenylcarbamoyl)piperazin-1-yl]piperidine-1-carboxylic acid tert-butyl ester [0289] To a solution of 4-bromo-3-trifluoromethoxyphenylamine (500 mg, 2 mmol) in DCM (5 mE) was added N,N-carbonyldiimidazole (348 mg, 2.15 mmol). The reaction mixture was stirred at RT overnight and then 4-piperazin-1-yl-piperidine- 1 -carboxylic acid tert-butyl ester (579 mg, 2.15 mmol, Preparation 12) was added and the reaction mixture was stirred at RT for 15 min, and concentrated by rotary evaporation and purified by silica gel chromatography (80 g silica, 0-10% MeOH/DCM) to provide the title intermediate (776 mg, 70% yield) as a yellow powder. (m/z): [M+H] calcd for C22H30BrF3N4O4 551.14, found 551.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 6.1: HATU / N,N-dimethyl acetamide / 0.33 h / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 6.1: HATU / N,N-dimethyl acetamide / 0.33 h / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; ethyl acetate / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; ethyl acetate / 20 °C / Inert atmosphere 6: HATU / N,N-dimethyl acetamide / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2: N,N-dimethyl acetamide / dichloromethane / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / toluene; water / 90 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; ethyl acetate / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 1.05 g 2: 800 mg | Stage #1: 4-bromo-3-(trifluoromethoxy)phenylamine; [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-1H-imidazol-2-yl}pyrrolidine-1-carbonyl)propyl]carbamic acid methyl ester With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene at 100℃; Inert atmosphere; Sealed tube; Stage #2: trifluoroacetic acid With acetic acid In water; toluene Inert atmosphere; Sealed tube; Overall yield = 80 %; | 5 Preparation 5: ((S)-1-{(S)-2-[4-(4’-Amino-2’-trifluoromethoxy-biphenyl-4-yl)- 1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-2-methyl-propyl)carbamic acidmethyl ester [0265] To a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4, 5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}pyrrolidine- 1 -carbonyl)-propyl] -carbamic acid methyl ester (1.80 g, 3.63 mmol) and 4-bromo-3-trifluoromethoxy-phenylamine (1.00 g, 3.90 mmol) dissolved in toluene (5.4 mE) and water (2.7 mE) was added potassium carbonate (2.50 g, 18.1 mmol). The reaction mixture was sparged with nitrogen. Tetrakis(triphenylphosphine)-palladium(0) (0.21 g, 0.18 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. in a sealed tube overnight, diluted in ethyl acetate (100 mE) and washed with water, brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red paste (6.5 g), which was purified by silica gel chromatography (120 g silica, 0-3% MeOH/DCM) to provide the title intermediate (1.05 g) and a second fraction which was purified by reverse phase HPLC to provide the di-TFA salt of the title intermediate (800 mg). (Total yield 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 6 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 6 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; sodium hydrogencarbonate / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 2.2: 0.5 h / 20 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 50 °C / Inert atmosphere 5.2: 4 h / 50 °C / Inert atmosphere 5.3: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 6 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; sodium hydrogencarbonate / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 50 °C / Inert atmosphere 5.2: 2 h / 50 °C / Inert atmosphere 5.3: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 6 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; sodium hydrogencarbonate / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 6 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; sodium hydrogencarbonate / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 50 °C / Inert atmosphere 5.2: 2 h / 50 °C / Inert atmosphere 5.3: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 2.2: 0.5 h / 20 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 2.2: 0.5 h / 20 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 2.2: 0.5 h / 20 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 60 h / 90 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 0.5 h / 20 °C / Inert atmosphere 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 0.25 h / 50 °C / Inert atmosphere 5.2: 4 h / 50 °C / Inert atmosphere 5.3: Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / acetonitrile / 60 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 2.2: 0.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dichloromethane / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dichloromethane / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 5: acetonitrile; water; acetic acid / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / ethanol / 2 h / 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 120 °C / Inert atmosphere 2.2: 48 h / Inert atmosphere 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis(pinacol)diborane; potassium acetate / toluene / 90 °C / Inert atmosphere 3.2: 95 °C / Inert atmosphere 4.1: ethanol; acetyl chloride / ethanol / 35 - 40 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dichloromethane / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: dichloromethane / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / ethanol / 2 h / 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 120 °C / Inert atmosphere 2.2: 48 h / Inert atmosphere 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis(pinacol)diborane; potassium acetate / toluene / 90 °C / Inert atmosphere 3.2: 95 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine / ethanol / 2 h / 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 120 °C / Inert atmosphere 2.2: 48 h / Inert atmosphere 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis(pinacol)diborane; potassium acetate / toluene / 90 °C / Inert atmosphere 3.2: 95 °C / Inert atmosphere 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: dichloromethane / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 5.1: acetonitrile; water; acetic acid / 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl acetamide / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: dichloromethane / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 5.1: acetonitrile; water; acetic acid / 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; HATU / toluene; N,N-dimethyl acetamide / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: dichloromethane / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 5.1: acetonitrile; water; acetic acid / 20 °C / Inert atmosphere 6.1: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl acetamide / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: dichloromethane / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 120 °C / Inert atmosphere 3.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dichloro-ethane / 90 °C / Inert atmosphere; Sealed tube 4.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C / Inert atmosphere 5.1: acetonitrile; water; acetic acid / 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl acetamide / 20 °C / Inert atmosphere 6.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / ethanol / 2 h / 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 120 °C / Inert atmosphere 2.2: 48 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine / ethanol / 2 h / 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 120 °C / Inert atmosphere 2.2: 48 h / Inert atmosphere 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis(pinacol)diborane; potassium acetate / toluene / 90 °C / Inert atmosphere 3.2: 95 °C / Inert atmosphere 4.1: ethanol; acetyl chloride / ethanol / 35 - 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 50℃; Inert atmosphere; | 27 Preparation 27: (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester Preparation 27: (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; in N,N-dimethylacetamide (3 mL) was added a solution of (2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU (401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated by rotary evaporation, extracted with ethyl acetate/sat. sodium carbonate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate:hexanes) to provide the title compound (155 mg, yield 36 %). (m/z): [M+H]+ calcd for C24H28BrF3N4O4 573.12, 575.12 found 575.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane Inert atmosphere; | 23-1.a (a) N-(4-Bromo-3-trifluoromethoxyphenyl)-6-fluoro-nicotinamide (a) N-(4-Bromo-3-trifluoromethoxyphenyl)-6-fluoro-nicotinamide To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (300 mg, 1 mmol) dissolved in DCM (5 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM (1 mL). A white precipitate was observed. The reaction mixture was concentrated to produce the HCl salt of the title intermediate. (m/z): [M+H]+ calcd for C13H7BrF4N2O2 378.96 found 379.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; <i>tert</i>-butyl alcohol / 96 h / 20 °C 2.1: DMF (N,N-dimethyl-formamide) / 9.5 h / 20 °C / Heating / reflux 2.2: 0.33 h / 60 °C 3.1: sulfuric acid / 2.5 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water; <i>tert</i>-butyl alcohol / 96 h / 20 °C 2.1: DMF (N,N-dimethyl-formamide) / 9.5 h / 20 °C / Heating / reflux 2.2: 0.33 h / 60 °C 3.1: sulfuric acid / 2.5 h / 80 °C 4.1: sodium tris(acetoxy)borohydride; acetic acid / 1,2-dichloro-ethane / 20 °C 5.1: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water; <i>tert</i>-butyl alcohol / 96 h / 20 °C 2.1: DMF (N,N-dimethyl-formamide) / 9.5 h / 20 °C / Heating / reflux 2.2: 0.33 h / 60 °C 3.1: sulfuric acid / 2.5 h / 80 °C 4.1: sodium tris(acetoxy)borohydride; acetic acid / 1,2-dichloro-ethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water; <i>tert</i>-butyl alcohol / 96 h / 20 °C 2.1: DMF (N,N-dimethyl-formamide) / 9.5 h / 20 °C / Heating / reflux 2.2: 0.33 h / 60 °C 3.1: sulfuric acid / 2.5 h / 80 °C 4.1: sodium tris(acetoxy)borohydride; acetic acid / 1,2-dichloro-ethane / 20 °C 5.1: trifluoroacetic acid / dichloromethane / 20 °C 6.1: hydrogenchloride / diethyl ether; ethanol / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 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 4h; Inert atmosphere; |
Tags: 116369-25-6 synthesis path| 116369-25-6 SDS| 116369-25-6 COA| 116369-25-6 purity| 116369-25-6 application| 116369-25-6 NMR| 116369-25-6 COA| 116369-25-6 structure
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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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